IMMUNOLOGY

USMLE STEP 1
by
Dr. Heba jihad
Dr. Heba Tutoring Immunology

THE IMMUNE SYSTEM

✴ The immune system is designed to recognize and respond to non-self antigen in a
coordinated manner. Additionally, it recognizes and eliminates cells that are
diseased, damaged, distressed, or dying.

✴ The immune system is divided into 2 complementary arms: the innate (or native or
natural) immune system and the adaptive (or acquired or specific) immune systems.

✴ Innate immunity provides the body's early line of defense against microbial
invaders.

✴ Once the barriers of the innate immune response have been breached, the adaptive
immune response is activated in an antigen-specific fashion to provide for the
elimination of antigen and lasting protection from future challenge.

Comparison of Innate and Adaptive Immunity:

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The features of adaptive immunity are designed to give the individual the best
possible defense against disease:

★ Specificity is required, along with immunologic memory, to protect against

persistent or recurrent challenge.
★ Diversity is required to protect against the maximum number of poten- tial
pathogens.
★ Specialization of effector function is necessary so that the most effective defense
can be mounted against diverse challenges.
★ The ability to distinguish between self (host cells) and non-self (pathogens) is vital
in inhibiting an autoimmune response.
★ Self-limitation allows the system to return to a basal resting state after a challenge
to conserve energy and resources and to avoid uncontrolled cell proliferation
resulting in leukemia or lymphoma.

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The innate and adaptive arms of the immune response do not operate independently
of one another:

1. Phagocytic cells process and display antigen to facilitate stimulation of specific

T lymphocytes.

2. Macrophages secrete immunoregulatory molecules (cytokines), which help

trigger the initiation of specific immune responses.

3. T. lymphocytes produce cytokines, which enhance the microbicidal activities of

phagocytes.

4. Antibodies produced by plasma cells bind to pathogens and activate the

complement system to result in the destruction of the invaders.

5. Antibodies produced by B lymphocytes bind to pathogens and assist with

phagocytosis (opsonization).

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Ontogeny of Immune Cells

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✴ Hematopoiesis involves the production, development, differentiation, and mat-

uration of the blood cells (erythrocytes, megakaryocytes and leukocytes) from
multipotent stem cells. The site of hematopoiesis changes during development.

✴ During embryogenesis and early fetal development, the yolk sac is the site of
hematopoiesis. Once organogenesis begins, hematopoiesis shifts to the liver and
spleen, and finally, to the bone marrow where it will remain throughout adulthood.

✴ These multipotent stem cells found in the bone marrow have the ability to undergo
asymmetric division. One of the 2 daughter cells will serve to renew the population
of stem cells (self-renewal), while the other can give rise to either a common
lymphoid progenitor cell or a common myeloid progenitor cell (potency).

✴ The multipotent stem cells will differentiate into the various lymphoid and myeloid
cells in response to various cytokines and growth factors.
1. The common lymphoid progenitor cell gives rise to B lymphocytes, T
lymphocytes and natural killer (NK) cells.

2. The common myeloid progenitor cell gives rise to erythrocytes,

megakaryocytes/thrombocytes, mast cells, eosinophils, basophils, neutrophils,
monocytes/macrophages and dendritic cells.

Myeloid cells
1. Monocytes:
Location: Bloodstream.
Identification: Kidney bean shaped nucleus, CD14 positive.
Function: Phagocytic, differentiate into tissue macrophages.

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2.Macrophages:
Location: Tissues.
Identification: Ruffled membrane, cytoplasm with vacuoles and vesicles,
CD14 positive.
Function: Phagocytosis, secretion of cytokines.

3. Dendritic cells:
Location: Epithelia, tissues.
Identification: Long cytoplasmic arms.
Function: Antigen capture, transport, and presentation.

4.Neutrophils:
Location: Bloodstream.
Identification: Multilobed nucleus (3-5 lobes); small pink granules.
Function: Phagocytosis and activation of bactericidal mechanisms.

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5. Eosinophils:
Location: Bloodstream.
Identification: Bilobed nucleus, large pink granules.

Function:
Defense against parasitic infections:

✴ When a parasite enters the bloodstream, it is bound by free IgE.

✴ The resultant antigen-antibody complex then binds an IgE Fc receptor located on

the eosinophil cell surface.

✴ Upon binding, the eosinophil releases major basic protein and other enzymes from
its granules, substances that damage and destroy antibody-bound parasites.

✴ This mechanism is an example of antibody-dependent cellular cytotoxicity (ADCC),

a method of killing that depends on the ability of the immune cell to recognize
specific antibody bound to cell and trigger the death of that cell without the use of
complement.

✴ Macrophages and NK cells also rely on ADCC.

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Regulation of type I hypersensitivity reactions

Eosinophilic granules contain histaminase, an enzyme that degrades histamine,
which helps to reduce the severity of atopic symptoms.

6. Basophils:
Location: Bloodstream.
Identification: Bilobed nucleus, large blue granules.
Function: Nonphagocytic, release pharmacologically active substances
(histamine) during allergic responses.

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7. Mast cells:
Location: tissues, mucosa, and epithelia.
Identification: Small nucleus, cytoplasm packed with large blue granules.
Function: Release of granules containing histamine during allergic responses.

Lymphoid cells
1. Lymphocytes:
Location: Bloodstream, lymph nodes, spleen.
Identification: Large, dark nucleus, small rim of cytoplasm.
• B cells: CD19, 20, 21.
• T cells: CD3.
• TH cells: CD4.
• CTLs: CD8.
Function:
1. B cells produce antibody.
2. T helper cells regulate immune responses.
3. Cytotoxic T cells (CTLs) kill altered or infected cells.

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2. Natural killer (NK) lymphocytes:

Location: Bloodstream.
Identification: Lymphocytes with large cytoplasmic granules CD16 CD56
positive.
Function: Kill tumor/virus cell targets or antibody-coated target cells (ADCC).

✴ Natural killer cells are derived from lymphoid stem cells and comprise
approximately 10% of all circulating lymphocytes.

✴ Do not express CD4, CD8 or CD3 molecules on their surface. They do express either
CD16 or CD 56.

✴ Do not require the thymus for maturation and are present in athymic patients.

✴ Have no antigen-specific activities, do not require exposure to antigen for

activation, and do not possess antigen memory ability.

✴ NK cells recognize and kill cells with decreased or absent MHC class I antigen cell
surface expression, such as virus infected cells and tumor cells.

✴ They are large cells with cytoplasmic granules containing perforins, which produce
holes in target cell membranes, and granzymes, chemicals that induce target cell
apoptosis.

✴ The target cell subsequently undergoes apoptosis.

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3. Plasma cells:
Location: Lymph nodes, spleen, mucosal associated lymphoid tissues, and
bone marrow.
Identification: Small dark nucleus, intensely staining Golgi apparatus.
Function: End cell of B-cell differentiation, produce antibody.

✦ Myeloid cells are in the innate branch.

✦ Lymphoid cells (except NK cells) are in the adaptive branch.
✦ B lymphocytes, so called because they complete their development in the bone
marrow, and T lymphocytes, so called because they pass from their origin in the
bone marrow into the thymus, where they complete their development.

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The antigen recognition molecules of lymphocytes

• Each of the cells of the lymphoid lineage is clinically identified by the characteristic
surface moleculesthat they possess.
• The B lymphocyte, in its mature ready-to-respond form (the naive B lymphocyte),
wears molecules oftwo types of antibody or immunoglobulin called IM and gD
embedded in its membrane
• The naive T cell wears a single type a of genetically related molecule, called the T-
cell receptor (TCR), on its surface.

• The naive B-cell antigen receptors are IgM and IgD.

• The T-cell antigen receptor is made of αlpha and Beta chains.

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B lymphocytes antigen receptors

✴ The antigen receptor of the B lymphocyte, or membrane-bound immunoglobulin, is
a four-chain glycoprotein molecule.

✴ This immunoglobulin has two identical halves, each composed of a long, or heavy
chain, and a shorter, light chain.

✴ The two halves are held together by disulfide bonds into a shape resembling a "Y"
and some flexibility of movement is permitted between the halves by disulfide
bonds forming a hinge region.

✴ On the N -terminal end of the molecule where the heavy and light chains lie side by
side, a "pocket" is formed whose three-dimensional shape will accommodate the
noncovalent binding of one, or a very small number, of related antigens.

✴ The unique three-dimensional shape of this pocket is called the idiotype.

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• Membrane-bound lg has two heavy and two light chains.

• A "hinge" region joins the heavy chains.
• The idiotype of the molecule resides in the N-terminal pocket of heavy and light
chains.
• The isotype of the molecule is determined by domain toward the C-terminus.

T lymphocytes antigen receptors

✴ The antigen receptor of the T lymphocyte is composed of two glycoprotein chains
that are similar in length and are thus designated a and ß chains.

✴ On the N-terminal end of the molecule, a groove is formed between the two chains,
whose three- dimensional shape will accommodate the binding of a small antigenic
peptide presented on the surface of an antigen-presenting cell (macrophage,
dendritic cell, or B lymphocyte).

✴ This groove forms the idiotype of the TCR.

✴ Notice that there is no hinge region present in this molecule, and thus its
conformation is quite rigid.

✴ The membrane receptors of B lymphocytes are designed to bind unprocessed

antigens of almost any chemical composition, whereas the TCR is designed to bind
only cell-bound peptides.

✴ Also, although the B-cell receptor is ultimately modified to circulate freely in the
plasma as secreted antibody, the TCR is never released from its membrane-bound
location.

✴ In association with these unique antigen-recognition molecules on the surface of B

and T cells, accessory molecules are found whose function is in signal transduction.

✴ Thus, when a lymphocyte binds to an antigen complementary to its idiotype, a

cascade of messages transferred through its signal transduction complex will
culminate in intracytoplasmic phosphorylation events, which will activate the cell.

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✴ In the B cell, this signal transduction complex is composed of two single-chain

immunoglobulin relatives known as lg-a and Ig-ß and two other molecules
designated CD (cluster of differentiation) 19 and 21.

✴ In the T cell, the signal transduction complex is a multichain structure called CD3.

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The generation of receptor diversity

• Because the body requires the ability to respond specifically to all of the millions of
potentially harmful agents it may encounter in a lifetime, a mechanism must exist to
generate the millions of idiotypes of antigen receptors necessary to meet this
challenge.

• If each of these idiotypes were encoded separately in the germline DNA of

lymphoid cells, it would require more DNA than is present in the entire cell.

• The generation of this necessary diversity is accomplished by a complex and

unique set of rearrangements of DNA segments that takes place during the
maturation of lymphoid cells.

• In the first place, it was discovered that individuals inherit a large number of
different segments of DNA, which may be recombined and alternatively spliced to
create unique amino acid sequences in the N -terminal ends (variable domains) of
the chains that compose their antigen recognition sites.

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• For example, to produce the heavy chain variable domain of their antigen receptor,
B-lymphocyte progenitors select randomly and in the absence of stimulating
antigen to recombine three gene segments designated variable (V), diversity (D),
and joining (J) out of hundreds of germline-encoded possibilities to produce
unique sequences of amino acids in the variable domains (VDJ recombination).

• An analogous random selection is made during the formation of the ß chain of the
TCR.

• Next, the B-lymphocyte progenitor performs random rearrangements of two types

of gene segments (V and J) to encode the variable domain amino acids of the light
chain.
• An analogous random selection is made during the formation of the a chain of the
TCR.

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• While heavy chain gene segments are undergoing recombination, the enzyme
terminal deoxyribonucleotidyl transferase (Tdt) randomly inserts bases (without a
template on the complementary strand) at the junctions of V, D, and J segments (N-
nucleotide addition).

• When the light chains are rearranged later, Tdt is not active, but it is active during
the rearrangement of all gene segments in the formation of the TCR.

• This generate more diversity than the random combination of V, D, and J segments
alone.

• Needless to say, many of these gene segment rearrangements result in the

production of truncated or nonfunctional proteins.

• When this occurs, the cell has a second chance to produce a functional strand by
rearranging the gene segments of the homologous chromosome.

• If it fails to make a functional protein from rearrangement of segments on either

chromosome, the cell is induced to undergo apoptosis or programmed cell death.

• In this way, the cell has two chances to a produce a functional heavy (or B) chain. A
similar process occurs with the light or a chain. Once a functional product has been
achieved by one of these rearrangements, the cell shuts off the rearrangement and
expression of the other allele on the homologous chromosome (a process known as
allelic exclusion).

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• This process ensures that B and T lymphocytes synthesize only one specific antigen-
receptor per cell.

• Because any heavy (a or B) chain can associate with any randomly generated light
(or a) chain, one can multiply the number of different possible heavy chains by the
number of different possible light chains to yield the total number of possible
idiotypes that can be formed. This generates yet another level of diversity.

✦ In Severe combined immunodeficiency (SCID), there is an autosomal recessive

nonsense mutation in rag 1 or rag2 genes (which encodes for recombinase enzyme
needed for gene rearrangement) →Total lack of B and T cells → Total defects in
humoral and cell mediated immunity.

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The Selection of Lymphocytes

Selection of B lymphocytes
• As lymphoid progenitors develop in the bone marrow, we have seen that they make
random rearrangements of their germline DNA to produce the unique idiotypes of
antigen-recognition molecules that they will use throughout their lives.

Primary lymphoid organs are sites of lymphoid-cell development (lymphopoiesis):

Bone marrow (B lymphocytes), Thymus (T lymphocytes)

Secondary lymphoid organs are sites of antigen exposure:

Spleen, Lymph nodes, Mucosal- associated lymphoid tissues.

✦ B lymphocytes complete their development in the Bone marrow.

✦ Because these gene segment rearrangements occur randomly and in the absence
of stimulation with foreign antigen, it stands to reason that many of the idiotypes of
receptors produced could have a binding attraction or affinity for normal body
constituents. These cells, if allowed to develop further, could develop into self-
reactive.

✦ Lymphocytes that could cause harm to the host. Therefore, one of the key roles of
the bone marrow stroma and interdigitating cells is to remove such potentially
harmful products.

✦ Cells whose idiotype has too great affinity for normal cellular molecules are either
deleted in the bone marrow (clonal deletion) or inactivated in the periphery (clonal
anergy).

✦ In such a way, only those cells that are selectively unresponsive (tolerant) to self-
antigens are allowed to leave the bone marrow.

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Selection of T lymphocytes
✦ Immature lymphocytes destined to the T-cell lineage leave the bone marrow and
proceed to the thymus, the second primary lymphoid organ dedicated to the
maturation of T cells.

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✦ The thymus is a bilobed structure located above the heart that consists of an outer
cortex packed with immature T cells and an inner medulla into which cells pass as
they mature.

✦ As the developing thymocytes begin to express their TCRs, they are subjected to a
rigorous two-step selection process.

✦ Because the TCR is designed to bind antigenic peptides presented on the surface of
antigen-presenting cells (APCs) in the body, a selection process is necessary to
remove those cells that would bind to normal self-antigens and cause
autoimmunity, as well as those that have no attraction whatsoever for the surfaces
of APCs.

✦ This is accomplished by exposure of developing thymocytes to high levels of a

unique group of membrane-bound molecules known as major histocompatibility
complex (MHC) antigens.

✦ The MHC is a collection of highly polymorphic genes on the short arm of

chromosome 6 in the human.

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There are two classes of cell-bound MHC gene products (classes I and I):

MHC Class I molecules:

• Expressed on all nucleated cells in the body.
• They are expressed in codominant fashion, meaning that each cell expresses two A,
two B, and two C products (one from each parent).
• The molecules (A, B, and C) consist of an (a) heavy chain with three extracellular
domains and an intracytoplasmic carboxy-terminus.
• A second light chain, ß2-microglobulin.
• A groove between the first two extracellular domains of the (a) chain is designed to
accommodate small peptides to be presented to the TCR.

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MHC Class II molecule:

• Expressed (also codominantly) on the antigen-presenting cells of the body
(macrophages, B lymphocytes, dendritic cells, and Langerhans cells).

• The molecules are two chain structures of similar length, called a and ß, and each
possesses two extracellular domains and one intracytoplasmic domain.

• A groove that will accommodate peptides to be presented to the TCR is formed at

the N-terminal end of both chains.

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Within the thymus, each of these MHC products, loaded with normal self-peptides, is
presented to the developing thymocytes:
1. Those that have TCRs capable of binding with low affinity will receive a positive
selection signal to divide and establish clones that will eventually mature in the
medulla.

2. Those that fail to recognize self-MHC at all will not be encouraged to mature
(failure of positive selection).

3. Those that bind too strongly to self MHC molecules will be induced to undergo
apoptosis (negative selection) because these cells would have the potential to
cause autoimmune disease.

• Although immature thymocytes express two accessory molecules on their surfaces

designed to stabilize. the interaction between MHC and TCR called CD4 and CD8,
as the affinity of the TCR for class I or class MHC is 'evaluated;' the cells are directed
to express only CD8 if their TCR binds class I molecules and only CD4 if their TCR
binds class Il molecules.

• This selection process is an extraordinarily rigorous one. A total of 95 to 99% of all

T-cell precursors entering the thymus are destined to die there.

• Only those with TCRs appropriate to protect the host from foreign invaders will be
permitted to leave to the periphery: CD4+ cells that recognize class II MHC are
destined to become "helper" T cells (TH), and CD8+ cells that recognize class I
MHC are destined to become cytotoxic T cells (CTLs).

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• Immature T-lymphocytes express both the CD4 and CD8 cell surface antigens in
addition to a completeTCR or a pro-TCR.
• These lymphocytes exist in the thymic cortex where they undergo positive
selection and in the thymic medulla where they undergo negative selection.
• Cells with "good" receptors receive positive selection.
• Cells with "useless" receptors receive no positive selection.
• Cells with "bad" receptors receive negative selection.
• CD4+ cells that recognize class I| MHC = TH cells.
• CD8+ cells that recognize class I MHC = CTLs.
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Lymphocyte Recirculation and Homing

• Lymphocytes of the B- and T-cell lineages that have completed their selection in the
bone marrow and thymus respectively are now mature, naive lymphocytes ready to
begin their role in the surveillance of the body against invaders.

• These mature, naive lymphocytes will begin the process of recirculation through the
body, which is essential for ensuring that the limited number of cells with receptors
for specific antigen is enabled to search for that antigen throughout the body.

• Naive cells preferentially recirculate through the peripheral (secondary) lymphoid

organs, the lymph nodes, spleen, and mucosal-associated lymphoid tissue (MALT)
to maximize the chances of encounter with foreign antigen and thereby initiate
specific immune responses.

Lymph nodes
• Lymph nodes are the small nodular aggregates of secondary lymphoid tissue found
along the lymphatic channels of the body and are designed to initiate immune
responses to tissue-borne antigens.

• Functions are nonspecific filtration by macrophages, storage of B and T cells, and

immune response activation.

• Each lymph node is surrounded by a fibrous capsule that is punctured by afferent

lymphatics, which bring lymph into the subcapsular sinus.

• The fluid percolates through an outer cortex area that contains aggregates of cells
called follicles.

• The lymph then passes into the inner medulla and the medullary sinus before
leaving the node through the hilum in an efferent lymphatic vessel.

• Ultimately, lymph from throughout the body is collected into the thoracic duct,
which empties into the vena cava and returns it to the blood.

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• Follicle:
- In outer cortex.
- Site of B-cell localization and proliferation.
- 1° follicles are dense and dormant.
- 2° follicles have pale central germinal centers and are active.

• Paracortex:
- Houses T cells.
- Region of cortex between follicles and medulla.
- Not well developed in patients with DiGeorge syndrome.
- Paracortex enlarges in an extreme cellular immune response (EBV and other viral
infections → paracortical hyperplasia → lymphadenopathy).

• Medulla:
- Consists of medullary cords (closely packed lymphocytes and plasma cells) and
medullary sinuses.
- Medullary sinuses communicate with efferent lymphatics and contain reticular cells
and macrophages.

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Spleen
• The spleen is the secondary lymphoid organ designed to initiate immune responses
to blood-borne antigens.
• A single splenic artery enters the capsule at the hilum and branches into arterioles,
which become surrounded by lymphocytes, the periarteriolar lymphoid sheaths
(PALS).
• This constitutes the white pulp.
• T cells are found in the periarteriolar lymphatic sheath (PALS) within the white pulp.
• B cells are found in follicles within the white pulp.
• The marginal zone, in between the red pulp and white pulp, contains APCs and
specialized B cells, and B is where APCs capture blood-borne antigens for
recognition by lymphocytes.
• Macrophages found nearby in spleen remove encapsulated bacteria.
• The arterioles ultimately end in vascular sinusoids, which make up the red pulp.
• From here, venules collect blood into the splenic vein, which empties into the portal
circulation.

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The First Response to Antigen

• An immunogen is a substance that can stimulate the immune system to produce an
immune response. The terms immunogen and antigens are used interchangeably.

For a molecule to be an immunogen, it needs to fit three basic criteria:

1. It must be recognized as foreign.
2. It must have a certain degree of chemical complexity.
3. t must have a large a molecular weight.

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B lymphocytes are capable of recognizing molecules of almost any chemical

composition.
T lymphocytes recognize peptides only when presented to them in the groove of an
MHC molecule on the surface of an antigen-presenting cell.

Antigenic determinants or epitopes

• The immune system does not recognize the antigen molecule as a whole but reacts
to structurally limited parts of the molecule called epitopes.

• They are very small, composed of just four to five amino acids or monosaccharide
residues.

• They determine the specificity of the antigen.

• The same antigen may possess different epitopes.

• Antigens that share one or more similar epitopes are known as cross-reactive
(heterophile antigens).

• Heterophile antigens are a group of similar antigens found in unrelated animals.

• Heterophile antibodies produced against heterophile antigens of one species will

cross react with others.

Hapten
• This is a low molecular weight substance which is incapable of inducing immune
response alone but when coupled with a carrier molecule (protein) it can act as an
antigen.

• Examples of haptens are drugs (penicillin).

• Drug allergies to penicillin and other agents such as streptomycin, aspirin, sulfa
drugs, succinyl choline, and some opiates can be induced by small doses of the
drug and are not consequences of the pharmacologic or physiologic effects of the
drugs.

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• Most drugs are low molecular weight compounds that are not capable of inducing
immune responses by themselves they act as haptens.

• Inside the body, however, these agents can become conjugated to body proteins
(the carrier), and the hapten-carrier conjugate serves as the immunogen for the
ensuing allergic response.

• Typically, an allergic response occurs 7 to 14 days following exposure, and the first
symptoms may be mild. Subsequent drug exposures can result in severe and life-
threatening anaphylaxis.

Acute inflammatory response

• Antigens are normally introduced into the body across the mucosa or the epithelia.

• The acute inflammatory response is often the first response to this invasion and
represents a response of the innate immune system to block the challenge.

• The first step in the acute inflammatory response is activation of the vascular
endothelium in the breached epithelial barrier.

• Cytokines and other inflammatory mediators released in the area as a result of

tissue damage induce expression of selectin-type adhesion molecules on the
endothelial cells.

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• Neutrophils are usually the first cell to bind to the inflamed endothelium and
extravasate into the tissues, peaking within 6 hours.

• Monocytes, macrophages, and even eosinophils may arrive 5 to 6 hours later in

response to neutrophil-released mediators.
Steps in Extravasation
The extravasation of phagocytes into the area requires four sequential, overlapping
steps:
Step 1: Rolling
✴ Phagocytes attach loosely to the endothelium by low-affinity, selectin-carbohydrate
interactions.
✴ E-selectin molecules on the endothelium bind to mucin-like adhesion molecules on
the phagocyte membrane and bind the cell briefly, but the force of blood flow into
the area causes the cell to detach and reattach repeatedly, rolling along the
endothelial surface until stronger binding forces can be elicited.

Step 2: Activation by chemoattractants

✴ Chemokines released in the area during inflammation, such as interleukin 8 (IL-8),
complement split product C5a, and N-formyl peptides produced by bacteria bind
to receptors on the phagocyte surface and trigger a G-protein-mediated activating
signal.
✴ This signal induces a conformational change in integrin molecules in the phagocyte
membrane that increases their affinity for immunoglobulin-superfamily adhesion
molecules on the endothelium.

Step 3: Arrest and adhesion

✴ Interaction between integrins and Ig-superfamily cellular adhesion molecules (lg
CAMs) mediates the tight binding of the phagocyte to the endothelial cell.
✴ These integrin-Ig-CAM interactions also mediate the tight binding of phagocytes
and their movement through the extracellular matrix.

Step 4: Transendothelial migration

✴ The phagocyte extends pseudopodia through the vessel wall and extravasates into
the tissues.

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Clinical Correlate
• Leukocyte adhesion deficiency is a rare autosomal recessive disease in which
there is an absence of CD18, which is the common B2 chain of a number of integrin
molecules. A key element in the migration of leukocytes is integrin-mediated cell
adhesion, and these patients suffer from an inability of their leukocytes to undergo
adhesion-dependent migration into sites of inflammation.
• The first indication of this defect is often omphalitis, a swelling and reddening
around the stalk of the umbilical cord.
• These patients susceptible to suffer recurrent, chronic bacterial infections.
• These patients frequently have abnormally high numbers of granulocytes in their
circulation, but migration into sites of infection is not possible, so abscess and pus
formation do not occur.
• Bacterial infections in these patients can be treated with antibiotics, but they recur.

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Neutrophils release chemoattractive factors that call in other phagocytes:

Phagocytosis
✴ Once chemotaxis of phagocytic cells into the area of antigen entry is accomplished,
these cells ingest and digest particulate debris, such as microorganisms, host
cellular debris, and activated clotting factors.

✴ This process, called phagocytosis, involves:

1. Extension of pseudopodia to engulf attached material.
2. Fusion of the pseudopodia to trap the material in a phagosome.
3. Fusion of the phagosome with a lysosome a to create a phagolysosome.
4. Digestion.
5. Exocytosis of digested contents.

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Opsonization
• Both macrophages and neutrophils have membrane receptors for certain types of
antibody (IgG) and certain complement components (C3b).

• If an antigen is coated with either of these materials, adherence and phagocytosis is

enhanced.

• Thus, antibody and complement are called opsonins, and the means by which they
enhance phagocytosis is called opsonization.

• Protein A of Staphylococcus aureus impedes opsonization by binding to the Fc

component of gG.

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Intracellular Killing
• During phagocytosis, a metabolic process known as the respiratory burst activates a
membrane-bound oxidase that generates oxygen metabolites, which are toxic to
ingested microorganisms.

• Two oxygen-dependent mechanisms of intracellular digestion are activated as a

result of this process:
1. NADPH oxidase reduces oxygen to superoxide anion, which generates hydroxyl
radical and hydrogen peroxide, which are microbicidal.

2. Myeloperoxidase in the lysosomes acts on hydrogen peroxide and chloride ions to

produce hypochlorite (the active ingredient in household bleach), which is
microbicidal.

In addition, the lysosomal contents of phagocytes contain oxygen independent

degradative materials:
• Lysozyme: digests bacterial cell walls by cleaving peptidoglycan.
• Defensins: circular peptides that form channels in bacterial cell membranes.
• Lactoferrin: chelates iron.
• Hydrolytic enzyme.

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Clinical Correlate
1. Chronic granulomatous disease (CGD) is an inherited deficiency in the
production of neutrophils NADPH oxidase.
✦ This defect eliminates the phagocyte's ability to produce many critical oxygen-
dependent intracellular metabolites (02 -, OH, and H202).
✦ The two other intracellular killing mechanisms remain intact (myeloperoxidase +
H202 > HOCI and lysosomal contents).
✦ If the patient is infected with a catalase-negative organism, the H202 waste product
produced by the bacterium can be used as a substrate for myeloperoxidase, and
the bacterium is killed.
✦ If, however, the person is infected with a catalase-positive organism
(Staphylococcus aureus, Pseudomonas cepacia, Serratia marcescens, Nocardia
species, Aspergillus species) the myeloperoxidase system lacks its substrate
(because these organisms destroy H202), and the patient is left with the oxygen-
independent lysosomal mechanisms that prove inadequate to control rampant
infections.
✦ Thus, CGD patients suffer from chronic, recurrent infections with catalase-positive
organisms.

• Failures of phagocytic cells to generate oxygen radicals are easily detected by the
nitroblue tetrazolium.

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• The nitroblue tetrazolium test is carried

out by adding nitroblue tetrazolium to a
sample of patient neutrophils:

• Properly functioning neutrophils are able

to produce reactive oxygen species such
as superoxide, and these chemicals are
able to reduce nitroblue tetrazolium,
leading to formation of a dark blue
pigment within the cells.

• Cells from patients with CGD are unable

to reduce nitroblue tetrazolium because they cannot produce reactive oxygen
species due to a genetic defect resulting in NADPH oxidase deficiency.

2. Pus consists of a thin, protein-rich fluid,

known as liquor puris, and dead leukocytes,
primarily neutrophils.
• During infection, macrophages and
surrounding endothelial cells release
cytokines such as interleukin-8 (IL-8) that
trigger neutrophils to enter the site of
infection via chemotaxis.
• IL-8 also induces phagocytosis in
neutrophils once they have arrived.
• Interleukin-8 is a chemokine produced by
macrophages that induces chemotaxis
and phagocytosis in neutrophils.
• Other significant chemotactic agents
include n-formylated peptides,
leukotriene B4, and complement
component C5a.

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The Processing and Presentation of Antigen

MHC class I
✴ MHC molecules are designed to bind small peptides and present them to T cells.

✴ The class I molecule is synthesized in the endoplasmic reticulum of the cell and
proteins are loaded there by an endogenous pathway.

✴ Proteins synthesized in the cell cytosol are routinely degraded in proteasomes, and
the peptides from these proteins are transported through a peptide transporter,
known as the TAP complex, into the endoplasmic reticulum, where they have the
opportunity to bind to freshly synthesized MHC class I proteins.

✴ These are then transported to the cell membrane where they may be presented to
CD8+ T lymphocytes.

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MHC class II
✴ Class Il MHC peptides are displayed only by antigen presenting cells.

✴ MHC Class I| is used to present antigens that antigen presenting cells (dendritic
cells, macrophages and B-lymphocytes) have encountered in the body and have
taken up by phagocytosis or endocytosis.

✴ Material in the environment such as bacterial organisms or freely circulating

antigenic material is taken up by antigen presenting cells and degraded by
acidification after phagosome-lysosome fusion.

✴ MHC Class Il molecules are synthesized in the rough endoplasmic reticulum and
routed to the endosomes by the Golgi apparatus.

✴ Each MHC class II molecule Il has a peptide fragment called an invariant chain
bound to its antigen binding site.

✴ Fusion of the vesicles containing MHC Class Il with the acidified phagolysosomes
containing foreign antigen leads to degradation of the invariant chain and loading
of antigen onto the MHC Class |I molecule.

✴ The MHC Class I molecule-protein antigen complexes are then displayed on the
surface of antigen presenting cells where they are available to bind the T-cell
receptors (TCR) on T-lymphocytes and initiate a T-cell response to the antigen they
display.

✴ Without lysosomal acidification, antigen processing in association with MHC class I|

antigens would not occur, and MHC Class II would be unable to bind antigen and,
therefore, unable to bind the TCR.

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Note:
• Langerhans cells are dendritic cells found in the skin that act as professional antigen
presenting cells.
• Langerhans cells are the form of dendritic cell most commonly found in the skin and
mucous membranes.
• These cells are derived from the myeloid cell line and they possess characteristic
racquet-shaped intracytoplasmic granules known as Birbeck granules.

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• Because of the extreme polymorphism of the HLA system in humans, when tissues
are transplanted between nonidentical individuals, cells of the transplant are often
targeted by CTLs as abnormal.

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Activation of T Lymphocyte
✦ The binding of the TCR of the mature, naive T cell to the MHC peptide complex of
the APC provides the first signal to the T cell to begin its activation. This provides
the antigenic specificity of the response. The interaction is stabilized by the
coreceptors CD4 and CD8 which bind to MHC class Il and MHC class I molecules,
respectively.
✦ The costimulatory molecules B7 (CD80/86) on APCs bind to CD28 on the mature,
naïve T cells, providing the second signal necessary for successful activation.
✦ Under normal conditions, B7 is expressed at low levels on APCs. In the presence of
infection or inflammation, the expression will increase, enhancing activation of the
mature, naïve T cells. Later in the immune response, B7 will preferentially bind to
CTLA-4 or PD-1, effectively turning off the T-cell response.
✦ Intimately associated with the T cell receptor is the CD3 signal transduction
complex. Interaction of cell adhesion molecules on the surface of the APCs and T
cells allows for the formation of the immune synapse.
✦ The proliferation of naive T cells in response to antigen recognition is mediated
principally by an autocrine growth pathway, in which the responding T cell secretes
its own growth-promoting cytokines and also expresses receptor molecules for
these factors.
✦ IL-2 is the most important growth factor forT cells and stimulates the proliferation of
clones of T cells specific to that antigen.

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Note:
1. Several surface molecules are involved in the activation of mature, naive T
lymphocytes:
A. First (primary) signal: recognition of the MHC-peptide complex by the T cell
receptor and coreceptors (CD4 and CD8).
B. Second (costimulatory) signal: recognition of B7 by CD28.

2. Superantigens are viral or bacterial proteins that cross-link the variable domain of
a T-cell receptor to an a chain of a class Il MHC molecule.
• This cross-linkage provides an activating signal that induces T-cell activation and
proliferation, in the absence of antigen-specific recognition of peptides in the MHC
class II groove. Il
• Because superantigens bind outside of the antigen-binding cleft, they activate any
clones of T cells expressing a particular variable B sequence and thus cause
polyclonal activation of T cells, resulting in the overproduction of IFN-y.
• This, in turn, activates macrophages, resulting in overexpression of proinflammatory
cytokines (IL-1, IL- 6 and TNF-a).
• Excess amounts of these cytokines induce systemic toxicity.
• Molecules produced during infectious processes and known to act as superantigens
include staphylococcal enterotoxins, toxic-shock syndrome toxin-1 (TSST-1), and
streptococcal pyrogenic exotoxins.

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Development of the Th1, Th2, and Th17

• The activated CD4+ (helper) T lymphocytes, which have thus been generated in the
lymph nodes and spleen following antigen administration, are now ready to serve
as the orchestrators of virtually all the possible effector mechanisms that will arise
to destroy the antigenic invaders.

• The effector mechanisms that are controlled totally or at least in part by Th cells
include antibody synthesis, macrophage activation, cytotoxic T-cell killing, and NK
cell killing.

• There are 3 major classes of helper T (Th) cell that arise from the same precursor,
the naive Th lymphocyte (or Tho cell):
1. Th1.
2. Th2.
3. Th17.

• The pattern of differentiation is determined by the antigen or type of pathogen

causing the infection and the cytokines produced in response to the antigen.

A. Differentiation of a Th0 cell into a ThI cell:

Differentiation of a Th0 cell into a Th1 cell is stimulated by intracellular pathogens
(viruses and intracellular bacteria). These pathogens induce a strong innate immune
response with the resultant production of IL-12 by macrophages and IFN- by NK cells.

In turn, Th1 cells secrete high levels of the inflammatory cytokine IFN-y which does
the following:
• Amplifies the Th1 response
• Inhibits the Th2 response.
• Activates macrophages.

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B. Differentiation of a Th0 cell into a Th2 cell:

• Differentiation of a ThO cell into a Th2 cell seems to be encouraged in response to
large extracellular parasites such as helminths or allergens.

• Due to the inability to phagocytose these pathogens, there is not significant

macrophage or NK-cell stimulation.

• In this way, naive ThO cells seem to produce IL-4 constitutively, and in the absence
of IL-12 stimulation, these cells will upregulate their production of IL-4 to encourage
differentiation into Th2 cells.

• Several cytokines are produced by Th2 cells, including IL-4, IL-5, IL-10, and IL-13.

• These cytokines not only determine the stimulatory pathways that the cells will
employ, but they also expand and develop the cells of the respective subset.

• For example, IFN-y produced by Th1 cells promotes further Th1 development and
inhibits the proliferation of Th2 cells.

• IL-4 and IL-10 produced by Th2 cells promote Th2 differentiation and inhibit the
activation of THI cells.

• Thus, each subset amplifies itself and cross regulates the other set so that immune
responses become increasingly polarized over time, reaching extremes in cases
where antigen exposure becomes chronic.

C. Differentiation of a Th0 cell into a Th17 cell:

• Differentiation of a Th0 cell into a Th17 cell occurs in the presence of
extracellular bacterial and fungal infections.

• Local cells react to the infection by secreting IL-1, IL-6, and TGF-ß,
inducing the development of Th17 cells.

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• The activated Th17 cells will in turn secrete the cytokines IL-17, IL 21
and IL-22:
1. IL-17 induces local cells to increase chemokine production recruiting neutrophils.
2. IL-22 stabilizes interactions between cells in the endothelium decreasing
permeability.
3. IL-17 and IL-22 induce secretion of anti-microbials by the endothelium.

D. Another population of T cells that arises from the Th0 is the T

regulatory cell (T Reg cell):
• Help maintain specific immune tolerance by suppressing CD4 and CD8 T-cell
effector functions. Have been shown to be critical for the prevention of
autoimmunity.

• Identified by expression of CD3, CD4, CD25, and FOXP3.

• Activated regulatory T cells (Tregs) produce anti-inflammatory cytokines (IL-10, TGF-

ß).

IPEX (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked)

syndrome:
✦ X linked recessive disorder (male child).
✦ Genetic deficiency of FOXP3→ autoimmunity.
✦ Characterized by enteropathy, endocrinopathy, nail dystrophy, dermatitis, and/or
other autoimmune dermatologic conditions.
✦ Associated with diabetes in male infants.

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Development of Cytotoxic T Lymphocytes

✦ Like CD4+ T cells, CD8+ T cells require both a primary and a costimulatory signal to
become activated.
✦ The main difference between them is that CD8+* cells recognize their specific
antigen presented by MHC class molecules and rely upon the cytokines produced
by T helper cells to proliferate and ultimately differentiate into cytotoxic T
lymphocytes (CTLs).

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Activation of B lymphocytes
• As mature naive B lymphocytes leave the bone marrow following successful
rearrangement of their membrane immunoglobulin receptor genes, they recirculate
throughout the body, attracted to follicular areas of the lymph nodes and spleen.

• If antigen entering these secondary lymphoid organs binds to and cross-links the
idiotypes of the immunoglobulin, this provides the first signal for the activation of
the B lymphocyte.

• The antigens that B lymphocytes encounter are divided into 2 categories: thymus-
independent (TI) antigens and thymus-dependent (TD) antigens.

A. Thymus Dependent-Antigen Activated B Lymphocytes:

• Most antigens introduced in the body fall into the category of thymus-
dependent (TD) antigens.

• Response to such molecules requires the direct contact of B cells with

helper T cells and are influenced by cytokines secreted by these cells.

• After the cross-linking of receptors on the B-cell surface with antigen,

the material is endocytosed and processed via the exogenous pathway
to generate an MHC class II-peptide complex, which is then inserted
into the membrane of the professional APCs.

• Simultaneously, expression of B7 is upregulated on the B lymphocytes,

making the cells effective presenters of antigen to CD4+ T cells in the
area. Once a CD4+ T cell recognizes its specific peptide displayed on
MHC class II molecules, the 2 cells form a conjugate. The CD4+ T cell is
activated and differentiates into a helper T cell.

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• Expression of CD40L on the surface of the helper T cell is upregulated and interacts
with CD40 on the B cell to provide the second signal for B-cell activation.

• The B cells respond by proliferating and differentiating into plasma cells and
memory B cells.

B. Thymus Independent-Antigen Activated B Lymphocytes:

• Certain mature, naive B lymphocytes are capable of being activated by
macromolecules such as lipids, polysaccharides, and lipopolysaccharides without
having to interact with helper T cells. These antigens are called thymus-
independent (TI) antigens, and they directly stimulate B cells to proliferate and
differentiate into plasma cells.

• The response to thymus-independent antigens is generally weaker than the

response to other classes of antigens, resulting in the secretion of IgM antibodies
only (no class switching) and the absence of immunologic memory.

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Isotype switching
• As the B lymphocyte receives cytokine signals from the activated Th2 cells in the
secondary lymphoid organs, it is induced to undergo isotype switching, changing
the heavy-chain constant domains to classes of antibodies with new and different
effector functions.

• It does this by rearranging the DNA encoding the constant region of the heavy
chain by activating switch regions that cause the intervening DNA to be looped out,
excised, and degraded.

• The idiotype is then joined to a new constant region domain coding, and an
antibody molecule with identical antigenic specificity but a new effector function is
produced.

• This isotype switch is one-way: Because the excised DNA is degraded, a cell that
has begun to produce an isotype downstream from IgM coding can never produce
lgM again.

• This is why IgM is the principal immunoglobulin of the primary immune response
when antigen is first encountered, and it is replaced in later responses by
antibodies of different isotypes.

• Isotype switching (from IgM to other types of immunoglobulins) occurs in the

germinal centers late in the primary response.

• Isotype switching first requires interaction of the CD40 receptor on activated B-cells
with the CD40 ligand expressed by activated T-cells.

• Afterward, isotype switching can occur through genetic rearrangement of the heavy
chain constant regions.

• This process is modulated by T-cell cytokines such as IL-2, IL-4, IL-5, IL-6, and IFN-y.

• Th2 helper cells release IL-13 which, together with IL-4, preferentially promotes B-
cell IgE production.

• Th2 cells also secrete II-5, which activates eosinophils and promotes IgA synthesis.

• One hypothesis for the pathogenesis of asthma is an excess of Th2 cell activity
relative to Th 1 cell activity, causing excessive IgE production, an abnormal
propensity to Type I hypersensitivity reactions, and an associated chronic
eosinophilic bronchitis.

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X-Linked Hyper-JgM Syndrome:

✦ Hyper-IgM syndrome results from an inability of B-lymphocytes to undergo isotype
switching from IgM to other immunoglobulin isotypes such as gD, IgG, IgE and IgA
due to genetic deficiencies in the CD-40 T-lymphocyte ligand that is essential in
inducing B-cells to switch classes.

✦ Therefore, Th cells from these patients will fail to express functional CD40L on their
membrane and will thereby fail to give the costimulatory signal necessary for the B-
cell response to T-dependent antigens, so only IgM antibodies are produced.

✦ The B-cell response to T-independent antigens is unaffected.

✦ The disease results in elevated or normal levels of IgM and a failure to synthesize all
other isotypes of immunoglobulin heavy chain constant regions.

✦ Clinical effects of this illness include recurrent sinus and airway infections (deficient
lgA).

✦ Treatment is with intravenous gamma globulin.

Somatic hypermutation
• During the activation of B lymphocytes by Th2 cells, intense proliferation of the B
cells results in the formation of germinal centers in the follicles of the lymph nodes
and spleen.

• During the intense proliferative response of the B cell, random mutations in the
coding of the variable domain region may occur. This is called somatic
hypermutation.

• Clones of cells with higher receptor affinity will begin to predominate in the
germinal center. This clonal selection results in the predominance of clones capable
of producing antibodies with increasing affinity for the antigen, a process known as
affinity maturation.

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Humoral immunity
• The biologic function of segments of the antibody molecule was first elucidated by
digestion of these molecules with proteolytic enzymes.

• If an antibody molecule is digested with papain, cleavage occurs above the

disulfide bonds that hold the heavy chains together. This generates three separate
fragments, two of which are called Fab (fragment antigen binding), and one is
called Fe (fragment crystallizable).

• Cleavage of the antibody molecule with pepsin generates one large fragment
called F(ab')2 and a digested Fc fragment. The bridging of antigens by antibody
molecules is required for agglutination of particulate antigens or the precipitation
of soluble antigens.

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The primary humoral response

✦ The first isotype of immunoglobulin that can be produced by a B cell with or
without T-cell help is IgM.

✦ This is because coding for the constant domains of the heavy chain of IgM (u
chains) are the first sequences downstream from the coding for the idiotype of the
molecule.

✦ The IgM molecule on the surface of the B cell is a monomer, but the secreted form
of this molecule is a pentamer, held together in an extremely compact form by a J
chain synthesized J by the cell.

• The design of the IM pentamer maximizes the effector functions critical to the body
early during antigenic challenge.

• Because of its multimeric structure (5 of the Y-shaped monomers joined into one
unit), plasma IgM has five times the capacity for binding antigenic epitopes as any
monomeric immunoglobulin unit.

• The valence of the molecule is therefore 10. In other words, 10 identical epitopes
can be simultaneously bound, as compared with 2 for the monomeric structure.

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• This makes IgM the most effective immunoglobulin isotype at "sponging" the free
antigen out of the tissues and proves critical, as the humoral response evolves, in
trapping antigen so that it can be presented to the lymphocytes that will ultimately
refine the choice of effector mechanism.

• The multimeric structure of IgM also makes it the most effective antibody at
activating complement, a set of serum proteases important in mediating
inflammation and antigen removal.

• Serum IgM is incapable of binding to cellular Fc receptors and thus cannot act as an
opsonin or a mediator of antibody-dependent cell mediated cytotoxicity (ADCC).

• Although the binding strength (affinity) of the idiotype for the epitope may not be
strong early in the immune response, the IgM molecule possesses the highest
avidity (number of combining sites available to bind epitopes) of any
immunoglobulin molecule produced in the body.

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Antibodies of secondary immune responses

1.IgG:
✦ The predominant isotype of immunoglobulin that begins to be produced after IgM
during the primary immune response is IgG.

✦ IgG is a monomeric molecule.

✦ IgG activates complement, acts as an opsonin, and mediates ADCC. It is also

actively transported across the placenta by receptor-mediated transport and thus
plays a crucial role in protection of the fetus during gestation.

✦ Macrophages, neutrophils and B-lymphocytes express cell surface proteins known

as Fc receptors (FcR) that bind specifically to the Fc portion of gG molecules. This
binding is essential for the process of opsonization.

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2. Ig A:
✦ Two forms: It is present in serum as a monomer, while its secretory form is a dimer.

✦ Secretory IgA generally exists as a dimer and serves as a major protective defense
of the mucosal surfaces of the body.

✦ Its sole function appears to be the inhibition of binding of toxins or adhesive

microbial components to the mucosa of the digestive, respiratory, and urogenital
systems.

✦ It does not activate complement or act as an opsonin.

✦ It is particularly important as a component of the colostrum, or the first breast milk

fed to an infant after birth, where it functions to provide the infant with passive
mucosal immunity.

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✦ Secretory IgA (that which is released across the mucosa of the respiratory, digestive,
and urogenital tracts) differs from serum IgA in an important fashion.

✦ As the IgA dimer is produced by plasma cells and B lymphocytes, it becomes bound
to poly-lg receptors on the basolateral side of the epithelia, is endocytosed, and is
released into the lumen bound to a secretory piece that is the residue of the
receptor.

✦ The secretory component thus serves an important function in transepithelial

transport, and once in the lumen of the tract, has a function in protecting the
molecule from proteolytic cleavage.

Note:
1. IgA protease is an enzyme produced by Neisseria gonorrhoeae and Neisseria
meningitidis.
- Both of these organisms gain access to the human bloodstream by penetrating
mucosal surfaces, N. Gonorrhoeae in the genital region and N. meningitidis in the
nasopharynx.
- Secretory lgA exists on mucosal surfaces and in secretions and acts to bind and
inhibit the action of pili and fimbriae as well as other cell surface antigens that
normally mediate mucosal adherence and penetration.
- A protease cleaves secretory IgA at its hinge region rendering it ineffective.

2. Selective IgA deficiency is the most commonly occurring primary

immunodeficiency. It is thought to occur due to failure of B-cells to switch from IgM to
lgA production.
- Most commonly these patients are asymptomatic, but classically this
immunodeficiency predisposes to recurrent sinopulmonary and GI tract infections
due to the absence of secretory IgA.
- Recurrent otitis media, sinusitis, bronchitis or pneumonias are caused by
encapsulated bacteria, such as H. influenzae or S. pneumoniae.
- Gastrointestinal infections manifest as recurrent acute or chronic diarrhea due to
viral, bacterial, and G. lamblia infections.

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- Patients with selective IgA deficiency often form IgG antibodies directed against
lgA (anti-IgA antibodies). When transfused with blood or blood products containing
small amounts of IA these patients may develop potentially fatal anaphylactic
reactions.
- Gamma-globulin preparations should not be used for treatment of these patients as
it may increase the synthesis of anti-lgA antibodies because the patient's body
recognizes it foreign.

3. Ig E:
• IgE binds allergenic antigen at its Fab sites and binds Fc receptors on mast cells and
basophils.

• Once multiple IgE molecules bind antigen and the Fc receptor on the mast cell or
basophil and subsequently cross-link with each other, these cells will degranulate
thereby releasing multiple vasoactive substances allergen mediating immediate
(type I) hypersensitivity.

• It does not activate complement or act as an opsonin.

Immunodeficiencies Involving B Lymphocytes:

• Patients with B-cell deficiencies usually present with recurrent pyogenic infections
with extracellular pathogens.
• The absence of immunoglobulins for opsonization and complement activation is a
major problem.
• The T-cell immune system is intact, and T-cell activities against intracellular
pathogens, delayed type hypersensitivity, and tumor rejection are normal.
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Complement
• The complement system is a set of interacting proteins released into the blood after
production in the liver.

• System of hepatically synthesized plasma proteins that play a role in innate

immunity and inflammation. Membrane attack complex (MAC) defends against
gram - bacteria.

• Activation:
1. Classic pathway: IgG or IM mediated. GM makes classic cars.

2. Alternative pathway: microbe surface molecules.

3. Lectin pathway: mannose or other sugars on microbe surface.

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Function:
Mediate inflammation, enhance phagocytosis by opsonization, and cause lysis of

particles by membrane pore formation.

• C3b: opsonization.

• C3a, C4a, C5a: anaphylaxis.

• C5a: neutrophil chemotaxis.

• C5b-9: cytolysis by MAC.

• Opsonins: C3b and gG are the two 1° opsonins in bacterial defense; enhance

phagocytosis.

• C3b also helps clear immune complexes.

Opsonin (Greek) = to prepare for eating.

Note:

Even though gram-positive bacteria may be resistant to the membrane attack

complex of complement, the early components of the cascade mediate localized

inflammation and opsonize the bacteria.

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Inhibitors:
Decay-accelerating factor (DAF, aka CD55) and C1 esterase inhibitor help prevent

complement activation on self-cells.

Complement disorders:
1.Complement protein deficiencies:
A. Early complement deficiencies (C1-C4): Increases risk of severe, recurrent
pyogenic sinus and respiratory tract infections; susceptibility to type Ill
hypersensitivity reactions (due to C3 deficiency).

B. Terminal complement deficiencies (C5-C9): Terminal complement deficiency

increases susceptibility to recurrent Neisseria bacteremia.

2.Complement regulatory protein deficiencies:

A. C1 esterase inhibitor deficiency:
• Causes hereditary angioedema due to unregulated activation of kallikrein > T
bradykinin. Characterized by V C4 levels.

• ACE inhibitors are contraindicated (also 1 bradykinin).

• Symptoms include facial swelling (without urticaria), life-threatening laryngeal

edema, and gastrointestinal manifestations (nausea/vomiting, colicky pain,
diarrhea).

• Management of acute attacks involves supportive care and the administration of C1

INH concentrate or a kallikrein inhibitor.

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B. DAF (GPI-anchored enzyme) deficiency: Causes complement-mediated lysis of

RBCs and paroxysmal nocturnal hemoglobinuria.

Note
• Both IgG antibodies and IgM antibodies are capable of, and essential for, triggering
the classical complement pathway after binding a C1 molecule.
• The classical pathway would not be able to proceed in the absence of either IgM or
IgG.
• C1 is the complement component that when activated is able to release the
catalytic factors responsible for the next steps in the classical complement pathway.
• In order to be activated, C1 must bind the Fc portions of two different antibodies at
specific C1 binding sites.
• Because IgM circulates in pentameric form (five IgM molecules joined together at
their Fc regions by a J chain peptide), it is much more effective in initiating the
complement cascade than gG which circulates monomeric form (a single circulating
immunoglobulin).
• The complement binding site on both IgG and IgM is located in the FC portion
closer to the hinge region.

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The Generation of Cell-Mediated E"ector Mechanisms

• The cell-mediated arm of the immune response (CMI) is designed to identify and
eradicate antigenic stimuli that arise from inside the cells of the body.
• This occurs when cells of the host become infected with intracellular pathogens,
such as viruses, some parasites and bacteria, or when malignant transformation
causes cells to express aberrant surface molecules.
• In such cases, Th1 cells primed in the lymph nodes and spleen serve to provide the
cytokine stimuli to activate the three potential effector cells to destroy the infected
or altered cells: macrophages, cytotoxic CD8+ T lymphocytes (CTLs), and NK cells.

Activation of macrophages
✦ One example of a cell-mediated effector mechanism that is enhanced by the action
of Th1 cells is macrophage killing.
✦ This is a critical protective mechanism in the defense against organisms invading
macrophages and attempting to live there (mycobacteria, Leishmania) or in the case
where phagocytosed microbes have protective mechanisms that make them
resistant to intracellular digestion (Listeria).
✦ In CMI against phagocytosed microbes, the specificity of the response arises from T
cells, but the actual effector function is mediated by the phagocytes.
✦ This provides an important link between the adaptive and innate immune
responses, and in essence, converts phagocytes into agents of the adaptive immune
response. The most important cytokine elaborated by Th1 cells and CD8+ T
lymphocytes to enhance the microbicidal capabilities of phagocytes is IFN-y.

✦ Note:
1. Within the lymph nodes and lung, mature T helper cells produce interferon- (IFN-
y).
• This interferon is a key mediator in the maturation of macrophages, thereby
enabling them to contain an infection with Mycobacterium tuberculosis.
• IFN- y is responsible for the formation of the phagolysosome (which contains harsh
bactericidal acids) in infected macrophages.
• It also stimulates the release of inducible nitric oxide synthase (¡NOS), an enzyme
that initiates a series of reactions that ultimately produce reactive nitrogen
intermediates and free radicals. These products are capable of destroying various
components of the mycobacterial cell.

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• The role of IFN- y is important in other regards as well, since it is responsible for
both granuloma formation and caseous necrosis.
• The activated macrophages (which were initially stimulated by IFN- y) produce TNF,
which recruits monocytes to the area.
• These monocytes differentiate into epithelioid histiocytes and cluster in a circular
fashion around the M. tuberculosis organisms.
• This immune reaction causes "walling off' of the tuberculous foci with the creation
of caseating granulomas, which consist of epithelioid cells, Langhans
multinucleated giant cells, fibroblasts and collagen.
• For most individuals, the formation of this caseating granuloma (arrow in below
image) successfully limits the bacteria from spreading and effectively controls the
infection.
• Without the T helper cell and its associated IFN- y, the host would be unable to
mount an effective response and the tuberculous infection would progress
unchecked.

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2.Host defense against mycobacterial infections depends on the interactions

between macrophages and T cells.
• Interferon gamma (IFN-gamma), a Th1 cytokine, is a key factor in the elimination of
these infections.
• Specifically, macrophages infected with mycobacteria produce interleukin 12,
which in turn stimulates T cells and natural killer cells to produce IFN-gamma.
• IFN-gamma then binds to its receptor, leading to receptor dimerization and
activation of Janus kinases 1 and 2.
• This results in nuclear signaling via STAT1 and transcription of IFN-gamma-
regulated genes, which promote mycobacterial killing by phagocytes.
• Autosomal recessive deficiencies of the IFN-gamma receptor (or other elements of
this pathway) result in disseminated mycobacterial disease in infancy or early
childhood.
• Once identified, these patients require lifelong treatment with continuous
antimycobacterial antibiotics.

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3. IL-12 stimulates the differentiation of "naive" T-helper cells into the Th1
subpopulation.
• Without Th1 cells, the synthesis of IFN-y required for activation of macrophages
does not occur.
• Activated macrophages are necessary for delayed hypersensitivity reactions and
cytotoxicity against intracellular organisms, such as mycobacteria.
• Patients with IL-12 receptor deficiency suffer from severe mycobacterial infections
due to the inability to mount a strong cell mediated granulomatous immune
response. They are treated with IFN-y.

4. The findings of hilar adenopathy, pulmonary infiltrates, and non-caseating lung

granulomas in an African American female point to a diagnosis of sarcoidosis.
• Sarcoidosis is thought to result from a dysregulated cell-mediated immune
response to an unidentified antigen that results in the formation of granulomas.
• Granuloma formation is a manifestation of cell-mediated immunity driven by
products of Th 1 type T CD4+ helper T cells, particularly IL-2 and interferon-y (IFN-
y), which stimulate Th1 type cell proliferation and macrophage activation,
respectively.
• Immunologic abnormalities in sarcoidosis include intraalveolar and interstitial
accumulation of CD4+ T cells, resulting in high CD4:CD8 T-cell ratios in
bronchoalveolar lavage (BAL) fluid.

5.In silicosis, there may be disruption of macrophage phagolysosomes by internalized

silica particles.
• Macrophage killing of intracellular mycobacteria may be impaired as a result,
causing increased susceptibility of patients with silicosis to pulmonary tuberculosis.

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Activation of cytotoxic T lymphocytes

• The CTL recognizes the cell it will ultimately kill by interaction between its TCR and
MHC class I antigens on the surface of the target cell.

• CTs are capable of differentiation and cloning by themselves in the presence of the
appropriate peptide/class I MHC antigen stimulus but are much more effective in so
doing if they are assisted by signals from Th1 cells.

• The Th1 cell secretes IL-2 which acts on CD8+ cells to enhance their differentiation
and cloning.

• Interferons produced in the area will increase the expression of MHC molecules to
make targets more susceptible to killing.

The death of the target may be mediated in distinct fashions:

A. First, perforin present in the CTL granules creates pores in the membrane of the
target cell through which granzymes (serine proteases) enter the target, inducing
the activation of caspases, which activate the "death domain”.

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B. Furthermore, activated CTLs express a membrane protein called Fas ligand (FasL),
which may bind to its complementary structure on the target, Fas. When this
occurs, caspases are induced and death results.

Note:
• Infectious mononucleosis (IM) is a disease characterized by sore throat, malaise,
lymphadenopathy ,myalgias, splenomegaly, and fever.
• The causative agent in IM is the Epstein-Barr virus.
• After infecting the pharyngeal mucosa and tonsillar crypts, the virus gains access to
the bloodstream where it preferentially infects B-lymphocytes by binding to the
CD21 cell surface receptor.
• These reactive (atypical) CD8+ T-lymphocytes may be seen on peripheral blood
smear in IM.
• They classically appear as cells much larger than quiescent lymphocytes with
abundant cytoplasm, an eccentrically placed nucleus, and a cell membrane that
appears to conform to the borders of neighboring cells.
• Atypical lymphocytes observed in the peripheral blood smears of patients with
infectious mononucleosis represent activated CD8+ cytotoxic T-lymphocytes.

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Activation of natural killer cells

• Another cell-mediated effector mechanism enhanced by the action of Th1 cells is
NK cell killing.

• NK cells are the only lymphocyte members of the innate branch of the immune
response.

• They exhibit the capacity to kill cells infected with some viruses and tumor cells, and
they kill via the same mechanisms of inducing apoptosis observed with CTLs
(granzymes, perforin).

• NK activity is increased in the presence of interferons (IFNs stimulated during viral

infections) and IL-12 (produced by phagocytic cells during the induction of Th1
responses).

• NK cells employ two categories of receptors (One delivers an activation signal, and
one delivers an inhibitory signal):

A. The activation signals seem to be received from binding of lectins possibly

conserved among many groups of common pathogens.

B. The inhibitory molecules on the NK cell seem to bind MHC class I antigens. Thus, a
cell with normal MHC class I antigens will be protected from killing. In the absence
of the MHC class I inhibitory signal, the NK cell will kill the target cell.

C. MHC class I antigen expression may be downregulated during virus infections, and
these antigens may be lost among tumor cells, which are genetically unstable and
may delete portions of their genome.

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Antibody-dependent cell-mediated cytotoxicity

• A final mechanism of cell-mediated cytotoxicity that bridges humoral and cell-
mediated effector systems in the body is antibody-dependent cell-mediated
cytotoxicity (ADCC).

• A number of cells with cytotoxic potential (NK cells, macrophages, neutrophils, and
eosinophils) have membrane receptors for the Fc region of IgG.

• When IgG is specifically bound to a target cell, the cytotoxic cells can bind to the
free Fc "tail" and subsequently cause lysis of the target cell.
• Although these effectors are not specific for antigen, the specificity of the idiotype
of the antibody directs their cytotoxicity.

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Interferons
Examples: IFN-a, IFN-ß, IFN-Y

Mechanism of action:
• A part of innate host defense, interferons interfere with both RNA and DNA viruses.

• Cells infected with a virus synthesize these glycoproteins, which act on local cells,
priming them for viral defense by downregulating protein synthesis to resist
potential viral replication and by upregulating MHC I expression to facilitate
recognition of infected cells and enhance the activity of T cytotoxic and T natural
killer cells. Also play a major role in activating antitumor immunity.

Clinical use:
✦ IFN-a: chronic hepatitis B and C, Kaposi sarcoma, hairy cell leukemia, condyloma
acuminatum, renal cell carcinoma, malignant melanoma.

✦ IFN-B: multiple sclerosis

✦ IFN-v: chronic granulomatous disease.

Adverse effects: Flu-like symptoms, depression, neutropenia, myopathy, interferon-

induced autoimmunity.

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Cytokines
• Cytokines are peptide or glycoprotein mediators that are produced by cells of the
immune system and have an effect on the behavior and properties of many cells.

Many different and overlapping names have been given to the various cytokines:
• Cytokines produced by lymphocytes are often called lymphokines.
• Many cytokines are given the name interleukin (IL), followed by a number.
• Chemokines are cytokines that are involved in the migration and activation of cells,
especially phagocytic cells.
• Interferons are cytokines of inducing body cells to resist viral replication, but they
have other important functions, as well.

Important cytokines:
Secreted By macrophages:
IL-1:
• Also called osteoclast-activating factor.
• Causes fever, acute inflammation.
• Activates endothelium to express adhesion molecules.
• Induces chemokine secretion to recruit WBCs.

IL-6: Causes fever and stimulates production of acute phase proteins.

IL-8: Major chemotactic factor for neutrophils.

IL-12:
• Induces differentiation of T cells into Th1 cells.
• Activates NK cells.

TNF-a:
• Mediates septic shock.
• Activates endothelium.
• Causes WBC recruitment, vascular leak.
• Causes cachexia in malignancy.
• Maintains granulomas in TB.

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Secreted By All T cells:

IL-2: Stimulates growth of helper, cytotoxic, and regulatory T cells, and NK cells.

IL-3:
• Supports growth and differentiation of bone marrow stem cells.
• Functions like GM-CSF.

From Th1 cells:

Interferon-y:
• Secreted by Th1 and NK cells in response to IL-12 from macrophages.
• Stimulates macrophages to kill phagocytosed pathogens.
• Increases MHC expression and antigen presentation by all cells.

From Th2 cells:

IL-4:
• Induces differentiation into Th2 cells.
• Promotes growth of B cells.
• Enhances class switching to IgE and IgG.

IL-5:
• Promotes differentiation of B cells.
• Enhances class switching to IgA.
• Stimulates growth and differentiation of eosinophils.

IL-10:
• Modulates inflammatory response.
• Decreases expression of MHC class II and Th1 cytokines.
• Inhibits activated macrophages and dendritic cells.
• Also secreted by regulatory T cells.

Note:
1. TGF-ß and IL-10 both attenuate the immune response.
Of the cytokines released in the setting of tissue injury, TGF-B and IL-10 are thought
to down-regulate local cytokine production and inflammatory reactions contributing
to the systemic acute phase
response.

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2. Acute-phase reactants are Factors whose serum concentrations change significantly

in response to inflammation; produced by the liver in both acute and chronic
inflammatory states.
• Notably induced by IL-6.

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Vaccination and Immunotherapy

• Immunity to infectious organisms can be achieved by active or passive
immunization.

• The goal of passive immunization is transient protection or alleviation of an existing

condition, whereas the goal of active immunization is the elicitation of protective
immunity and immunologic memory.

• Active and passive immunization can be achieved by both natural and artificial
means.

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Vaccination Induces an active artificial immune response (humoral and/or cellular) to

specific pathogens.

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Thymus-independent antigens:
• Antigens lacking a peptide component (lipopolysaccharides from gram-negative
bacteria); cannot be presented by MHC to T cells.

• Streptococcus pneumonia, Neisseria meningitidis, and Haemophifus influenzae are

encapsulated bacteria whose polysaccharide capsule components can be
covalently bound to protein carriers and used as vaccine antigens.

• The protein carriers convert the polysaccharides from T-cell independent to T-cell
dependent antigens.

• Approved carrier proteins include mutant nontoxic diphtheria toxin, Neisseria

meningitidis outer membrane protein complex, and tetanus toxoid.

• The Haemophilus influenzae type b (Hib) vaccine contains bacterial capsular

polysaccharide conjugated with diphtheria toxoid.

Thymus-dependent antigens:
• Antigens containing a protein component (diphtheria vaccine).

• Class switching and immunologic memory occur as a result of direct contact of B

cells with Th cells (CD40-CD40L interaction).

Note
1.One general principle of vaccination dictates that local secretory antibody synthesis
is best promoted when specific mucosal surfaces are directly stimulated by antigen.
• When both live and killed vaccines are applied to a mucosal surface, the live
attenuated viral vaccines appear more effective of the two in generating prolonged
mucosal lA secretion.
• The live vaccines are thought to colonize the natural site of viral entry, producing a
greater and more prolonged immune response there.
• When a live attenuated vaccine (the Sabin oral polio vaccine) is applied to mucosal
surfaces, it appears to promote more prolonged synthesis and secretion of local
mucosal IgA than does a killed vaccine (the Salk inactivated polio vaccine).
• This increase in mucosal lA offers immune protection at the normal site of viral
entry.

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2. The influenza vaccine is thought to prevent serious cases of the flu by increasing
the host circulating antibodies against the hemagglutinin (HA) of the selected viral
strains.
Upon subsequent exposure to live influenza virus, these antibodies interfere with the
binding of the HA to the sialic acid - containing oligosaccharides of host cell plasma
membrane glycoprotein receptors.
The live virus is prevented from entering cells via receptor-mediated endocytosis.

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Diseases Caused by Immune Responses: Hypersensitivity and

Autoimmunity
• Hypersensitivity diseases are conditions in which tissue damage is caused by
immune responses.
• They may result from uncontrolled or excessive responses against foreign antigens
or from a failure of self-tolerance, in which case they are called autoimmune
diseases.
• Hypersensitivity diseases are classified on the basis of the effector mechanism
responsible for tissue injury.

Four types (ABCD): Anaphylactic and Atopic (type I), AntiBody-mediated (type II),
Immune Complex (type III), Delayed (cell-mediated, type IV).

Types I, II, and Ill are all antibody mediated.

Type I (immediate) hypersensitivity

• This is the only type of hypersensitivity mediated by IgE antibodies.

• The effector cells of the immediate hypersensitivity reaction are mast cells,
basophils, and eosinophils.

• First contact with antigen is asymptomatic. Upon initial exposure (first contact) to
allergen, a patient who will eventually develop an allergic or anaphylactic response
will undergo antibody class switching to lgE in B lymphocytes specific for these
allergens.

• IgE produced by B-lymphocytes and plasma cells binds to IgE Fc receptors on

basophils in the blood and mast cells in the tissues.

• Re-exposure (second time contact) to these allergens will result in cross-linking of

IgE molecules on the surface of basophils and mast cells with resultant
degranulation and release of histamine, proteases, heparin, leukotrienes and
prostaglandins.

• Cross-linking of two lgE molecules on the surface of the cell by one molecule of
allergen is required to cause degranulation.

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• Two phases:
1. Immediate (minutes): antigen crosslinks preformed IgE on presensitized mast cells
→ immediate degranulation → release of histamine (a vasoactive amine) and
tryptase (a marker of mast cell activation).
2. Late (hours): chemokines (attract inflammatory cells like eosinophils) and other
mediators (leukotrienes) from mast cells inflammation and tissue damage.

✦ This degranulation can cause a response as mild as an urticaria wheal, or as severe

as anaphylaxis.

✦ The agents released by mast cells and basophils can cause systemic vasodilatation,
increases in vascular permeability, and bronchoconstriction leading to the
hemodynamic and respiratory instability characteristic of anaphylactic shock, and
without prompt treatment with epinephrine this condition will lead to death.

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• Examples of type I hypersensitivity disorders:

1. Allergic and atopic disorders (allergic rhinitis, hay fever, eczema, hives, asthma).
2. Anaphylaxis (bee sting, some food/drug allergies).

✦ NOTE:
• The high-affinity lgE receptor is found on mast cells and basophils and a plays a
primary role in mediating the allergic response.
• The receptor normally binds the Fc portion of circulating lgE, coating the cell with
various antigen-specific IgE molecules.
• When a multivalent antigen comes in contact with the cell, multiple IgE antibodies
become cross- linked, resulting in aggregation of the high-affinity IgE receptors o n
the mast cell surface.
• This clumping of receptors leads to the activation of non-receptor tyrosine kinases,
triggering an intracellular cascade that ultimately results in mast cell and basophil
degranulation.

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Type II hypersensitivity
Antibodies bind to cell-surface antigens → cellular destruction, inflammation, and
cellular dysfunction.

✦ Cellular destruction (cytotoxic):

‣ Cell is opsonized (coated) by antibodies, leading to either:
1. Phagocytosis and/or activation of complement system.
2. NK cell killing (antibody-dependent cellular cytotoxicity).

✦ Examples:
1. Autoimmune-hemolytic anemia.
2. Immune thrombocytopenia.
3. Transfusion reactions.
4. Hemolytic disease of the newborn.

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✦ Inflammation:
Binding of antibodies to cell surfaces → activation of complement system and Fc
receptor-mediated inflammation.

✦ Examples:
1. Goodpasture syndrome.
2. Rheumatic fever.
3. Hyperacute transplant rejection.

✦ Cellular dysfunction (non-cytotoxic):

Antibodies bind to cell surface receptors → abnormal blockade or activation of
downstream process.

✦ Examples:
1. Myasthenia gravis.
2. Graves disease.
3. Pemphigus vulgaris.

Hemolytic disease of the newborn (erythroblastosis fetalis):

• An important example of type II hypersensitivity is HDNB, also known as
erythroblastosis fetalis.

• The Rh (D) antigen is a blood group antigen present on the erythrocytes of Rh-
positive individuals.

• About 85% of people are Rh+.

• If a pregnant woman is Rh- and the father is Rh+, there is a chance that the fetus will
also be Rh+.

• This situation will pose no problem in the first pregnancy, as the mother's immune
system will not usually encounter fetal blood cell antigens until placental separation
at the time of birth.

• At that time, however, Rh+ fetal red blood cells will enter the maternal circulation
and stimulate a T- dependent immune response, eventually resulting in the
generation of memory B cells capable of producing IgG antibody against RhD.

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• In a subsequent pregnancy with another Rh+ fetus, this maternal IgG can be
transported across the placenta, react with fetal Rh+ red cells, and activate
complement, producing hemolytic disease.

• Hemolytic disease of the newborn can be prevented by treating the Rh- mother
with RhoGAM™, a preparation of human anti-RhD IgG antibody, at 28 weeks of
gestation and again within 72 hours after birth.

• RhoGAM binds fetal erythrocyte surface Rh antigens within the maternal circulation,
preventing their interaction with the maternal immune system and thus preventing
sensitization.

• Fetal erythrocytes coated by this antibody are then sequestered and eliminated by
the mother's spleen.

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• The clinical picture in the affected infant includes severe anemia,

hepatosplenomegaly, jaundice (possibly leading to kernicterus) and possible fetal
demise.

1.With maternal blood types A and B, erythroblastosis fetalis and hemolytic disease of
the newborn do not occur, as the naturally occurring antibodies (anti-A and B) are of
the IgM type and cannot cross the placenta.

• In contrast, in type O mothers, the antibodies are predominantly gG and can cross
the placenta to cause fetal hemolysis.

• The association of a type A or B fetus with a type O mother occurs in approximately

15% of pregnancies; however, HDN occurs in only 3% of these pregnancies.

• Unlike Rh disease, ABO disease can occur with the first pregnancy because anti-A
and anti-B antibodies are formed early in life from exposure to A- or B-like antigens
present in foods, bacteria, and viruses.

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2.The acute hemolytic transfusion reaction is an example of an antibody-mediated

(Type lI) hypersensitivity reaction.

‣ Resuscitation following motor vehicle accidents often includes blood transfusion in

serious cases.
‣ Acute hemolytic reactions occur within minutes of starting a blood transfusion and
are due to ABO incompatibility between the donor and recipient.
‣ Anti-ABO antibodies in the recipient bind the corresponding antigens on transfused
donor erythrocytes.
‣ These antigen-antibody complexes activate complement, resulting in the
production of the C3a and C5a complement components (anaphylatoxins) as well
as the membrane attack complex (C5 through C9).
‣ Anaphylatoxins cause vasodilatation and symptoms of shock, while the membrane
attack complex leads to red blood cell lysis.
‣ Acute transfusion reactions can be fatal.
‣ The symptoms include chills and shortness of breath. Patients may also experience
fever, hypotension, disseminated intravascular coagulation (DIC), renal failure and
hemoglobinuria (dark urine).
‣ Treatment includes immediate cessation of the transfusion and supportive
measures.

3. Goodpasture syndrome involves autoantibodies against basement membrane

collagen of glomerular and alveolar epithelia (Type II hypersensitivity).
‣ These antibodies cause inflammatory destruction of the basement membrane in
lung alveoli and in renal glomeruli.

4.Myasthenia gravis (MG) results from an autoimmune type lI, antibody mediated,
hypersensitivity reaction against skeletal myocyte surface acetylcholine receptors.

‣ Extraocular muscle weakness is a common presenting symptom of myasthenia

gravis, an autoimmune disease caused by autoantibodies against the acetylcholine
receptors on the postsynaptic membrane of the neuromuscular junction.
‣ Normally, acetylcholine binding causes opening of these ligand-gated sodium
channels, and the subsequent influx of sodium ions generates an excitatory
postsynaptic potential (EPSP).

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‣ In order to produce a self-propagating muscle action potential, there must be a

sufficient number of activated acetylcholine receptors.

Type III (immune complexes) Hypersensitivity

• Immune complex: antigen-antibody (mostly |gG) complexes activate complement,
which attracts neutrophils; neutrophils release lysosomal enzymes.

• Can be associated with vasculitis and systemic manifestations.

• Examples:
1. SLE.
2. Polyarteritis nodosa.
3. Poststreptococcal glomerulonephritis.
4. Serum sickness.
5. Arthus reaction.

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• Serum sickness:
The prototypic immune complex disease. Antibodies to foreign proteins (serum
antitoxin) are produced and 1-2 weeks later, antibody-antigen complexes form and
deposit in tissues → complement activation → inflammation and tissue damage.

• Serum sickness-like reactions are associated with some drugs (monoclonal

antibodies) and infections (hepatitis B).

• Sulfonamides are included among the list of drugs which can provoke this
condition.

• This often results in hypocomplementemia, including a decreased serum C3 level.

• Associated findings include fever, urticaria, arthralgias, glomerulonephritis,

lymphadenopathy, and a low serum C3 level 5-10 days after intravascular exposure
to antigen.

• Arthus reaction:
‣ A local subacute antibody mediated hypersensitivity reaction.

‣ Intradermal injection of antigen into a presensitized (has circulating IgG) individual

leads to immune complex formation in the skin.

‣ Characterized by edema, necrosis, and activation of complement.

NOTE:
• Post-streptococcal glomerulonephritis is mediated by a type Ill (immune complex)
hypersensitivity D reaction.
• During infection, antibodies form against antigens expressed by nephritogenic
strains of group A B- hemolytic streptococci (Streptococcus pyogenes).
• These anti-streptococcal antibodies combine with streptococcal antigens to form
immune complexes that are deposited along the glomerular basement membrane
(type Ill hypersensitivity.

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• These deposits can then be visualized as electron-dense subepithelial "humps" on

electron microscopy and as granular depositions within the mesangium and
glomerular capillary walls on IgG and C3 immunofluorescence.
• Patients with post-streptococcal glomerulonephritis present with edema, hematuria,
and an antecedent history of streptococcal infection (impetigo, cellulitis,
pharyngitis).

Type IV (T-cell mediated) Hypersensitivity

• Two mechanisms, each involving T cells (no antibody involved):
1. Inflammatory reaction: effector CD4 T cells recognize antigen and release
inflammation-inducing cytokines (interferon-y).
2. Direct cell cytotoxicity: CD8+ cytotoxic T cells kill targeted cells.

• Response does not involve antibodies (vs types 1, 11, and Ill).

• These reactions are referred to as "delayed" responses because, unlike reactions

mediated by antibody that occur minutes after antigen exposure (ABO blood group
incompatibility, hyperacute rejection, erythroblastosis fetalis), delayed reactions
occur one to two days following antigen exposure (this is why you need to wait 48
to 72 hours for your annual PPD test to be read!).

✦ Examples:
1. Contact dermatitis (poison ivy, nickel allergy).
2. Graft-versus-host disease.

✦ Tests:
1. PPD for TB infection.
2. Patch test for contact dermatitis.
3. Candida skin test for T cell immune function.

4T's: T cells, Transplant rejections, TB skin tests, Touching (contact dermatitis).

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NOTE:
Contact dermatitis Vs. Atopic dermatitis
1. Atopic dermatitis (Eczema):
Often associated with atopic diseases (asthma, allergic rhinitis).
It's a type I hypersensitivity reaction.

2. Contact dermatitis:
Often associated with poison ivy and nickel allergy.
It's a type IV hypersensitivity reaction.

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Immunodeficiency Diseases
If individuals experience defects in the functioning of any of the components of the
immune system, clinical manifestations are common.

B-cell disorders
A. X-linked (Bruton) agammaglobulinemia:
Defect:
‣ It is a B-cell immunodeficiency disorder in which the Bruton tyrosine
kinase (BTK) gene codes for a defective version of this critical signal
transduction molecule.
‣ Normal Bruton tyrosine kinase function is necessary for the proper
maturation of B-cells.
‣ Defect in BTK, a tyrosine kinase gene → no B-cell maturation.
‣ X-linked recessive (Increased in Boys).

Presentation:
‣ This is an X-linked condition that results in a deficiency of all forms of
antibody and low B cell counts B due to a defect in B lymphocyte
maturation.
‣ T cell numbers and function are intact.
‣ Recurrent bacterial and enteroviral infections after 6 months (V
maternal IgG).
‣ They are deficient in all types of immunoglobulins, including IgA
(which predisposes to recurrent lower respiratory tract infections and
Giardia lamblia infection).

Findings:
‣ Absent B cells in peripheral blood, V g of all classes.
‣ Germinal centers contained within lymphoid follicles are B where B
lymphocytes normally go to proliferate and undergo somatic
hypermutation after exposure to antigen. Without B cells, there would
be no lymphoid follicles or germinal centers in the lymph nodes.
‣ Live vaccines contraindicated.

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B.Selective IA deficiency:
Defect:
‣ Selective gA deficiency is the most commonly occurring primary immunodeficiency.
‣ It is thought to occur due to failure of B-cells to switch from IgM to IgA production.

Presentation:
‣ Most commonly these patients are asymptomatic, but classically this
immunodeficiency predisposes to recurrent sinopulmonary and Gl tract infections
due to the absence of secretory lgA.
‣ Recurrent otitis media, sinusitis, bronchitis or pneumonias are caused by
encapsulated bacteria, such as H. influenzae or S. pneumoniae.
‣ Gastrointestinal infections manifest as recurrent acute or chronic diarrhea due to
viral, bacterial, and G. lamblia infections.
‣ Increase Atopy and Autoimmune diseases.

When transfused with blood or blood products containing small amounts of gA these
patients may develop potentially fatal anaphylactic reactions. Gamma-globulin
preparations should not be used for treatment of these patients as it may increase the
synthesis of anti-lgA antibodies because the patient’s body recognizes it as a foreign.

Findings: Decrease IgA with normal IgG, IgM levels.

C.Common variable immunodeficiency:

Defect: Defect in B-cell differentiation. Many causes.

Presentation: Onset in late teens. Can be acquired in 20s-30s; increase risk of

autoimmune disease, bronchiectasis, lymphoma, sinopulmonary infections.

Findings: ↓ plasma cells, ↓ immunoglobulins.

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D. Transient hypogammaglobulinemia of infancy:

Defect: Delayed onset of normal IgG synthesis.

Presentation: Detected in 5th to 6th month of life, resolves by 16-30 months; 1

susceptibility to pyogenic bacteria.

Findings: ↓ IgG in early life of infancy.

T-cell disorders
A. Thymic aplasia (DiGeorge syndrome):
Defect: 22q11 microdeletion; maldevelopment of the third and fourth pharyngeal
pouch derivatives → absent thymus and parathyroid gland.

Presentation:
‣ The immunodeficiency results from aplasia of the thymus leading to an extreme
deficiency in the number of mature T-lymphocytes.

‣ T-lymphocytes are synthesized in the bone marrow, but they require processing in
the thymus in order to mature and be effective in the body.

‣ T-cell immunodeficiencies such as DiGeorge syndrome predispose patients to

recurrent infections by viral, fungal, protozoan and intracellular bacterial
pathogens.

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Other classic clinical associations with DiGeorge syndrome are:

1. Tetany resulting from hypocalcemia due to parathyroid gland aplasia.
2. Aortic arch abnormalities (teratology of fallot, truncus arteriosus).
3. Distorted facies due to aberrant formation of the mandible and palate (frequently
with a cleft palate), and low-set ears.

Findings:
↓ T cells, PTH, V Ca.

• Absent thymic shadow on CXR.

• The paracortex is the region of the lymph node populated primarily by T

lymphocytes. In DiGeorge syndrome, this region is poorly developed due to a
deficiency of mature T lymphocytes.

CATCH-22: Cardiac defects [tetralogy of Fallot, truncus arteriosus]), Abnormal facies,

Thymic hypoplasia → T-cell deficiency (recurrent viral/fungal infections), Cleft palate,
Hypocalcemia 2° to parathyroid aplasia→ tetany.

B. IL-12 receptor deficiency:

Defect: ↓ Th1 response. Autosomal recessive.

Presentation: Disseminated mycobacterial and fungal infections; may present after

administration of BCG vaccine (live attenuated vaccine).

Findings: ↓ IFN-y.

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C.Autosomal dominant hyper-IgE syndrome (Job syndrome):

Defect:
1. Th1 cells cannot make IFN-y.
2. Deficiency of Th17 cells due to STAT3 mutation impaired recruitment of
neutrophils to sites of infection.

Presentation:
Learn the ABCDEF's to get a Job: Cold (noninflamed) staphylococcal Abscesses,
retained Baby teeth, Coarse facies, Dermatologic problems (eczema), ↑ IgE, bone
Fractures from minor trauma.

↑ IgE is due to ↓ IFN-Y → no inhibition of Th2 differentiation→ ↑ IL4 - ↑ IgE.

Findings: ↑ IgE, eosinophils.

D. Chronic mucocutaneous candidiasis:

Defect:
‣ T-cell dysfunction.
‣ Heterogeneous group of immune system defects → impaired cell-mediated
immunity against Candida sp. Classic form caused by defects in AIRE.

Presentation: Noninvasive Candida albicans infections of skin and mucous

membranes.

Findings:
‣ Absent in vitro T-cell proliferation in response to Candida antigens.
‣ Absent cutaneous reaction to Candida antigens.

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Note:
1.Candida albicans is a component of the normal human skin and mucous membrane
flora.
• Candida does not cause disseminated infections in healthy people, but can induce a
number of serious diseases when the immune system is weakened.
• Candida is, therefore, an opportunistic pathogen.
• Host immune defense against Candida is provided by T-lymphocytes and
neutrophils.
• These two components of the antifungal defense have distinct functions:

A. T-lymphocytes (in particular Th cells):

• They are important for the prevention of superficial Candida infection.
• Individuals with deficient T-cell function are susceptible to localized Candida
infections such as oral thrush, cutaneous candidiasis, and Candida vulvovaginitis.
• The role of T-lymphocytes in host defense from Candida can be seen in HIV-positive
patients.
• These individuals have frequent superficial Candida infections, but rarely suffer
from disseminated candidiasis.

B. Neutrophils:
• They prevent the hematogenous spread of Candida.
• Disseminated candidiasis is more likely to occur in neutropenic patients and those
with inherited impairments of phagocytosis.
• If HIV-positive patients also have neutropenia, they are at risk for both localized and
disseminated candidiasis.
• Examples of disseminated disease caused by Candida species include right-sided
endocarditis, liver and kidney abscesses, and candidemia.
• For this reason, localized candidiasis is common in HIV-positive patients, while
neutropenic individuals are more likely to have systemic disease.

• The candida skin test gauges the delayed-type (type IV) hypersensitivity reaction.
• Failure to generate a response to this test is referred to as anergy.
• The active cells in the cell-mediated response are macrophages, CD4 and CD8 T-
lymphocytes and NK cells.

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E.MHC | Class Deficiency:

Defect:
‣ A recessively inherited deficiency in the production of MHC class I molecules has
been described in rare individuals.
✴ Some of these cases result from the failure of TAP molecules to transport MHC I
molecules to the surface of the cell, and others are due to the production of
aberrant or nonfunctional MHC I molecules themselves.
✴ Other causes may be a genetic mutation of B2 macroglobulin which is important for
the proper folding of MHC class I.

Presentation:
‣ These patients, as anticipated, suffer from profound deficiencies of
CD8T cells, although numbers of CD4 T cells are normal.

‣ This is because MHC class expression in the thymus is essential to the

development of committed CD8 cells.

‣ Patients are susceptible to multiple, recurrent viral infections, but

interestingly, not all viral infections appear to be involved.

‣ It may be that they are able to compensate in the case of some specific
viral infections, by using NK cells to control those infections, whereas
other viruses require killing by CD8+ cells alone.

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B- and T-cell disorders

A. Severe combined immunodeficiency (SCID):
Defect:
✦ Several types including defective IL-2R gamma chain (most common, X-linked).
✦ Gamma chain is a protein that is shared by the receptors for many interleukins,
these interleukins and their receptors are involved in the development and
differentiation of T and B cells.
✦ Adenosine deaminase deficiency is the second most cause of SCID.
✦ Adenosine deaminase is present in all cells of the human body, and it functions to
deaminate adenosine to inosine as an initial step in the elimination of excess
adenosine from the cell.
✦ Adenosine accumulation is toxic to lymphocytes and leads to widespread death of
both and B lymphocytes with resultant combined cellular and humoral
immunodeficiency.
✦ Because both humoral and cell-mediated immunity are deficient in these patients,
they are vulnerableto increased infections by bacteria, viruses and fungi.

Presentation:
Patients with SCID present with recurrent infections caused by bacteria, viruses, fungi,
and opportunistic pathogens as well as failure to thrive, thrush and chronic diarrhea
within the first year of life.

Findings:
• ↓ T-cell receptor excision circles (TRECs).

• Absence of thymic shadow (CXR), germinal centers (lymph node biopsy), and T cells
(flow cytometry).

Treatment:
1. Bone marrow transplant (no concern for rejection).

2. Retroviral gene therapy for this illness is promising. Retroviral vectors are used to
"infect" patient hematopoietic stem cells with the genetic code for adenosine
deaminase thereby resulting in production of this enzyme by all daughter cells of
that stem cell.

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B. _Ataxia-telangiectasia:
Defect:
✦ It is an autosomal recessive condition that occurs due to mutation of ATM gene.
ATM (Ataxia Telangiectasia Mutated) gene is responsible for DNA break repair.
✦ Defects in ATM → gene failure to repair DNA double strand breaks → cell cycle
arrest.
✦ DNA in patients with ataxia-telangiectasia is hypersensitive to X-ray radiation that
causes multiple chromosomal breaks.

Presentation:
✦ Cerebellar ataxia, telangiectasias (abnormal dilatations of capillary vessels), and
increased risk of sinopulmonary infections (due to IgA deficiency) constitute a
characteristic triad of ataxia telangiectasia.
✦ Cerebellar atrophy leads to the ataxia that occurs in the first years of life.
✦ Oculocutaneous telangiectasia is another manifestation but is usually delayed.
✦ The risk of cancer in these patients is increased significantly because of inefficient
DNA repair (↑ risk of lymphoma and leukemia).

✦ Findings: ↓ IgA, IgG, and lgE. Lymphopenia, cerebellar atrophy.

C. Hyper-IgM syndrome:
Defect:
✦ Genetic deficiency in the CD-40 T-lymphocyte ligand that is essential in inducing B-
cells to switch classes.
✦ Therefore, Th cells from these patients will fail to express functional CD40L on their
membrane and will thereby fail to give the costimulatory signal necessary for the B-
cell response to T-dependent antigens, so only IgM antibodies are produced.
✦ The B- cell response to T-independent antigens is unaffected.

Presentation: Severe pyogenic infections early in life; opportunistic infection with

Pneumocystis, Cryptosporidium, CMV.

Findings:
Normal or ↑ IgM. ↓ IgG, lgA, IgE. These patients fail to make germinal centers during
a humoral immune response.

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D. Wiskott-Aldrich syndrome:
Defect:
✦ Mutation in WAS gene (X-linked recessive); leukocytes and platelets unable to
reorganize actin cytoskeleton → defective antigen presentation.
✦ It results from a mutation on the X-chromosome and, therefore, is only present in
males as an x-linked disorder.

Presentation:
• The Wiskott-Aldrich syndrome consists of the triad of eczema, thrombocytopenia,
and recurrent infections due to combined B-lymphocyte and T-lymphocyte
deficiency.
WATER: Wiskott-Aldrich - Thrombocytopenia, Eczema, Recurrent (pyogenic)
infections.
• Infections worsen as the patient ages and become most apparent initially after
transplacental maternal IgG and maternal mucosal gA derived from the colostrum
are degraded at approximately 6 months of age.

Treatment is with an HLA-matched bone marrow transplantation.

Findings: ↓ to normal IgG, IgM. ↑ IgE, IgA. Fewer and smaller platelets.

E. Bare Lymphocyte Syndrome/MHC class I| deficiency:

Defect:
Results from defects in the transcription factors required to coordinate their
expression on the cell surface.

Presentation:
✦ Because MHC class I antigens are expressed normally, they do have CD8 cells,
although their function is diminished by the absence of Th1 cell cytokines.

✦ Immune problems tend to appear early in infancy and present as a mild form of
severe combined immunodeficiency (SCID) with increased susceptibility to
pyogenic and opportunistic infections.

✦ However, these defects can be distinguished from true SCID in that these patients
will have T cells that can respond to nonspecific T-cell mitogens, such as
phytohemagglutinin.

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✦ They do not develop graft versus-host disease when given HLA-mismatched bone
marrow transplants because they do not express the MHC class II molecules against
which such grafted cells can react.

Phagocyte dysfunction
A.Leukocyte adhesion deficiency (type 1):
Defect:
• LAD results from the absence of CD 18. Autosomal recessive.
• This leads to the inability to synthesize the beta-2 integrins LFA 1, affecting tight
adhesion and transmigration of inflammatory cells to the site of inflammation.
• Integrins are essential for the migration of leukocytes from the vascular space to the
tissues where they exert their effect.

Presentation:
• Recurrent bacterial skin and mucosal infections, absent pus formation, impaired
wound healing, delayed separation of umbilical cord (> 30 days).
• The first indication of this defect is often omphalitis, a swelling and reddening
around the stalk of the umbilical cord.

Findings:
• ↑ Neutrophils. Absence of neutrophils at infection sites.
• These patients frequently have abnormally high numbers of granulocytes in their
circulation, but migration into sites of infection is not possible, so abscess and pus
formation do not occur.

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B.(Chédiak-Higashi syndrome:
Defect:
• Defect in lysosomal trafficking regulator gene (LYST).
• Microtubule dysfunction in phagosome-lysosome fusion; autosomal recessive.
• This causes abnormal giant lysosomal inclusions that are visible on light microscopy
of a peripheral blood smear.

Presentation:
• Recurrent pyogenic infections by staphylococci and streptococci, partial albinism,
peripheral neuropathy, progressive neurodegeneration, infiltrative
lymphohistiocytosis.
PLAIN: Progressive neurodegeneration, Lymphohistiocytosis, Albinism (partial),
recurrent pyogenic Infections, peripheral Neuropathy.

Findings:
• Giant granules in granulocytes and platelets.
• Pancytopenia. Mild coagulation defects.

C.Chronic granulomatous disease:

Defect:
• Chronic granulomatous disease (CGD) is most frequently an X-linked disorder
resulting from a deficiency of NADPH oxidase.

• Deficiency of this enzyme leads to an inability of neutrophils to form the oxidative

burst to kill organisms in their phagolysosomes.

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• Organisms that produce catalase are ineffectively killed by these defective

neutrophils while organisms that do not produce catalase can still be killed due to
accumulation of bacterial hydrogen peroxide within the phagosome.

Presentation:
↑ susceptibility to catalase + organisms (Need PLACESS): Nocardia, Pseudomonas,
Listeria, Aspergillus, Candida, Burkholderia Cepacia, E. coli, S. aureus, Serratia.

These organisms are all catalase positive.

Catalase decomposes H202 (2 H202 → 02 + 2 H2O).

Findings:
✦ Abnormal dihydrorhodamine (flow cytometry) test ( ↓ green fluorescence).

✦ Nitroblue tetrazolium dye reduction test is ⊝ (patient's neutrophils fail to turn blue
upon nitroblue tetrazolium testing this is the hallmark test for CGD)

✦ The nitroblue tetrazolium test is carried out by adding nitroblue tetrazolium to a

sample of patient neutrophils.
✦ Properly functioning neutrophils are able to produce reactive oxygen species such
as superoxide, and these chemicals are able to reduce nitroblue tetrazolium,
leading to formation of a dark blue pigment within the cells.
✦ Cells from patients with CGD are unable to reduce nitroblue tetrazolium because
they cannot produce reactive oxygen species due to a genetic defect resulting in
NADPH oxidase deficiency.

Note:
Glucose-6-phosphate dehydrogenase (G6PD) deficiency → There is deficiency of
essential enzymes in hexose monophosphate shunt → same symptoms as CGD with
associated anemia.

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N.B:
B-cell deficiencies tend to produce recurrent bacterial infections, whereas T-cell
deficiencies produce more fungal and viral infections.

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Transplantation Immunology
Transplantation is the process of taking cells, tissues, or organs (a graft) from one
individual (the donor) and implanting them into another individual or another site in
the same individual (the host orrecipient).

Several different types of grafts are used in medicine:

✦ Autograft: From self.
✦ Syngeneic graft (isograft):From identical twin or clone.
✦ Allograft: From nonidentical individual of same species.
✦ Xenograft: From different species.

Mechanisms of graft rejection

✦ The recognition of transplanted cells as self or foreign is determined by the

extremely polymorphic genes of the major histocompatibility complex, which are

expressed in a codominant fashion.

✦ This means that each individual inherits a complete set or haplotype from each
parent and virtually assures that two genetically unrelated individuals will have
distinctive differences in the antigens expressed on their cells.

✦ The net result is that all grafts except autografts are ultimately identified as foreign
invading proteins and destroyed by the process of graft rejection.

✦ Even syngeneic grafts between identical twins can express recognizable antigenic
differences due to somatic mutations that occur during the development of the
individual. For this reason, all grafts except autografts must be followed by some
degree of lifelong immunosuppression of the host to attempt to avoid rejection
reactions.

Four different classes of allograft rejection phenomena are classified according to

their time of activation and the type of effector mechanism that predominates:

1. Hyperacute rejection:
Onset: Within minutes.

Pathogenesis: Hyperacute rejection is an antibody-mediated reaction that is caused

by preformed antibodies (type I hypersensitivity reaction) within the recipient that are
directed against donor antigens and activate complement.

Examples of such mismatches include ABO blood group antibodies and anti-HLA
antibodies.

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Classically, this form of transplant rejection is diagnosed by the surgeon in the

operating room because upon anastomosis of the donor and recipient blood vessels
and initial perfusion of the organ, the organ immediately becomes cyanotic and
mottled.

Blood flow through the new organ ceases immediately due to fibrinoid necrosis of
the small vessels of the organ in addition to the rapid formation of extensive
thrombosis within the transplanted organ.

Features:
Widespread thrombosis of graft vessels (arrows within glomerulus) → ischemia/
necrosis.

Graft must be removed.

2. Acute rejection:
Onset: Weeks to months.

Pathogenesis:
• Cellular: CD8 T cells T and/or CD4 T cells activated against donor MHCs (type IV
hypersensitivity reaction).

• Humoral: similar to hyperacute, except antibodies develop after transplant.

Acute rejection occurs in approximately 2 of every 5 hearts transplanted and in the

large majority of cases occurs by the cell-mediated pathway.

In rare cases, acute rejection is due to anti-donor host antibodies, and cases of
humoral rejection are diagnosed by direct immunofluorescence.

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The clue that indicates acute rejection is the timeframe of symptoms because acute
rejection usually occurs one to four weeks following transplant and the
histopathology showing a dense infiltrate of mononuclear cells (this is typical
histopathology in acute rejection).

Features:

Vasculitis of graft vessels with dense interstitial lymphocytic infiltrate.

Treatment with immunosuppressive drugs is aimed primarily at preventing this form

of rejection.

3.Chronic rejection:
Onset: Months to years.

Pathogenesis:

• CD4+ T cells respond to recipient APCs presenting donor peptides, including

allogeneic MHC.

• Both cellular and humoral components (type Il and IV hypersensitivity reactions).

Features:
Recipient T cells react and secrete cytokines that induces proliferation of vascular
smooth muscle and parenchymal fibrosis and causes an obliterative intimal smooth
muscle hypertrophy and fibrosis of cortical arteries (obliterative vascular fibrosis).

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Dominated by arteriosclerosis.

4. Graft-versus-host disease (GVHD):

Onset: Varies.

Pathogenesis:

• Graft-versus-host disease (GVHD) is a condition that most commonly occurs after

allogeneic bone marrow transplantation, transplantation of organs rich in
lymphocytes (such as liver), or transfusion of non-irradiated blood.

• The host is generally severely immunodeficient due to the primary disease process
or as a result of immunosuppressive medications.

• Immunocompetent T-cells within the donor tissue recognize host MHC antigens as
foreign and attack them (Type IV hypersensitivity reaction). Both donor CD4 and
CD8 cells participate in destroying host cells.

• Any organ may be a target of GVHD, but the skin, liver, and Gl tract are generally
affected most severely:

1. Liver damage manifests with jaundice and increased levels of ALT, AST, alkaline
phosphatase, and bilirubin

2. Gl tract involvement causes diarrhea, intestinal bleeding, abdominal cramping,

and/or ileus.

3. In severe cases, there may be skin desquamation.

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Features:

• Maculopapular rash, jaundice, diarrhea, hepatosplenomegaly.

• Usually in bone marrow and liver transplants (rich in lymphocytes).

• Potentially beneficial in bone marrow transplant for leukemia (graft-versus-tumor

effect).

• Irradiate blood products prior to transfusion for immunocompromised patients to

prevent GVHD.

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Immunosuppressant drugs

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