Immunology

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1. Kuby Immunology (5th ed. Goldsby, Richard A. et al. W. H. Freeman and Company 2003
2. Immunobiology: The Immune System in Health and Disease 6th ed. C. A. Janeway,
P.Toavers Current Biology Ltd 2005
3. Immunology 7th ed. I. M. Roitt, J. Brostoff, D. K. Male Mosby 2006

1~7 聯 8~14
臨 念 臨
1.The components of the immune system. 1
2.Innate and adaptive immunity.
3.The recognition of antigen. 2,3,4
4.The development of B- and T-lymphocytes.
5.Cell mediated immune responses.
6.Humoral immune responses. 5,6,7
7.Immunoregulation.
8.Host defense against infection Vaccination.
9. Allergy and hypersensitivity. 8,9
10. Immunodeficiency.
11.Autoimmune diseases. 10,11,12,13,14
12.Tumor immunology.
13.Transplantation.
臨 識

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1. The components of the immune system

Immune responses are mediated by: a variety of cells; and the soluble molecules that these cells secrete

1. Phagocytes and lymphocytes are key mediators of immunity. Phagocytes internalize pathogens
and degrade them. Lymphocytes (B and T cells) bear receptors that recognize specific molecular
components of pathogens and have specialized functions. B cells make Abs, cytotoxic T
lymphocytes (CTLs) kill virally infected cells, and helper T cells coordinate the immune
response by direct cell-cell interactions and release of cytokines.

2. Specificity and memory are two essential features of adaptive immune responses. As a result
the immune system mounts a more effective response on second and subsequent encounters with
a particular antigen. Non-adaptive (innate) immune responses are our first line against invader,
but they do not alter on repeated exposure to an infectious agent.

3. Antigens are molecules that are recognized by receptors on lymphocytes. B cells usually
recognize intact antigen molecules, whereas T cells recognize antigen fragments on the
surface of other cells Ag presenting cells .

4. An immune response occurs in two phases antigen recognition and antigen eradication. In
the first phase clonal selection involves recognition of antigen by particular clones of
lymphocytes, leading to clonal expansion of specific clones of T and B cells and differentiation
to effector and memory cells. In the effector phase, these lymphocytes coordinate an immune
response, which eliminates the source of the antigen.

5. Cytotoxic cells include cytotoxic T lymphocytes (CTLs), natural killer (NK) cells (large granular
lymphocytes; LGLs), and eosinophils.
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6. Complement is made primarily by the liver, though there is some synthesis by mononuclear
phagocytes.

7. Vaccination depends on the specificity and memory of adaptive immunity. Vaccination is

based on the key elements of adaptive immunity, namely specificity and memory. Memory cells
allow the immune system to mount a much stronger response on a second encounter with
antigen.

8. Inflammation is a response to tissue damage. It allows antibodies, complement system molecules,

and leukocytes to enter the tissue at the site of infection, resulting in phagocytosis and
destruction of the pathogens. Lymphocytes are also required to recognize and destroy infected
cells in the tissues.

9. The immune system may fail (immunopathology). This can lead to immunodeficiency,
hypersensitivity, or autoimmune diseases.

10. Normal immune reactions can be inconvenient in modern medicine, for example blood
transfusion reactions and graft rejection.

Cells, Tissues, and Organs of the Immune System

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1. Most cells of the immune system derive from hemopoietic stem cells.
2. Phagocytic cells are found in the circulation (monocytes and granulocytes) and reside in
tissues (e.g. Kupffer cells in the liver).
3. Eosinophils, basophils, mast cells, and platelets take part in the inflammatory response.
Mast cells are identifiable in all tissues.
4. The origin of the large granular lymphocytes with natural killer (NK) activity is probably the
bone marrow. NK cells recognize and kill virus-infected cells and certain tumor cells
through apoptosis.
5. Antigen-presenting cells APC link the innate and adaptive immune systems and are
required by T cells to enable them to respond to antigens.
6. B and T cells express antigen receptors, which are required for the antigen recognition.
7. T cells developing in the thymus are subject to positive and negative selection processes.
8. Mammalian B cells develop mainly in the fetal liver and from birth onwards in the bone
marrow. This process continues throughout life. B cells also undergo a selection process
at the site of B cell generation.
9. The diverse antigen repertoires found in mature animals are generated during
lymphopoiesis by recombination of gene segments encoding the T cell receptor (TCR) and
immunoglobulin.
10. Lymphoid organs and tissues protect different body sites - the spleen responds to
blood-borne antigens; the lymph nodes respond to lymph-borne antigens; and MALT protects
the mucosal surface.
11. Systemic and secondary lymphoid organs include the spleen and lymph nodes. Lymphocytes
migrate to, and function in, the secondary lymphoid organs and tissues.
12. Mucosa-associated lymphoid tissue (MALT) includes all the lymphoid tissues associated
with mucosae. Peyer's patches are a major site of lymphocyte priming to antigens crossing
mucosal surfaces of the small intestine.
13. Most lymphocytes recirculate around the body; there is continuous lymphocyte traffic from
the blood stream into lymphoid tissues and back again into the blood via the thoracic duct and
right lymphatic duct

2. Innate and adaptive immunity.

3. The recognition of antigen.
4. The development of B- and T-lymphocytes.

z Mechanisms of Innate Immunity

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1. Innate immune responses do not depend on immune recognition by lymphocytes, but have
co-evolved with and are functionally integrated with the adaptive elements of the immune
system.
2. The body's responses to damage include inflammation, phagocytosis, and clearance of
debris and pathogens, and remodeling and regeneration of tissues. Inflammation is a
response that brings leukocytes and plasma molecules to sites of infection or tissue damage.
3. The phased arrival of leukocytes in inflammation depends on chemokines and adhesion
molecules expressed on the endothelium.
4. Adhesion molecules fall into families : the cell adhesion molecules (CAMs) of the
immunoglobulin supergene family (which interact with leukocyte integrins), and the selectins
(which interact with carbohydrate ligands).
5. Leukocyte migration to lymphoid tissues is also controlled by chemokines.
6. Plasma enzyme systems modulate inflammation and tissue remodeling. The kinin system
and mediators from mast cells including histamine contribute to the enhanced blood supply and
increased vascular permeability at sites of inflammation.
7. Pathogen-associated molecular patterns (PAMPs) are distinctive biological
macromolecules that can be recognized by the innate immune system. Innate antimicrobial
defenses include molecules of the collectin, ficolin, and pentraxin families, which can act as
opsonins, either directly or by activating the complement system.
8. Macrophages also have surface lectins, which allow them to directly bind to pathogens. The
Toll-like receptors recognize various PAMPs and cause macrophage activation. Their signaling
systems and actions are closely related to those used by inflammatory cytokines TNFα and
IL-1.

z Antigens are molecules recognized by receptors on lymphocytes:

Antigens are not just components of foreign substances, such as pathogens. A large variety of
'self' molecules can serve as antigens as well, provoking autoimmune responses that can be
highly damaging, and even lethal

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APCs link the innate and adaptive immune systems

Specialized APCs are involved in

both innate and adaptive immunity
to bacteria and viruses by the
production of cytokines and for
presentation of antigens to T cells.
Innate immune system cells are
monocytes/ macrophages,
polymorphonuclear granulocytes, NK
cells, mast cells, and platelets.

B cells and T cells are responsible for the specific recognition of antigens

B CELLS E XPRESS ANTIBODY

1. B cells express the Ag receptor (immunoglobulin)

on their cell surface during their development and,
when mature, secrete soluble immunoglobulin
molecules (also known as antibodies) into the
extracellular fluids.

2. Antigen binds only to those B cells with the

specific antibody, driving these cells to divide
and differentiate into plasma cells and memory
cells, all having the same specificity as the
original B cell.

3. B cells are responsible for the humoral arm of

the adaptive immune system, and thus act
against extracellular pathogens.

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Antibodies The basic four-chain model for Ig molecules

Immunoglobulins are made up of a unit with four

polypeptide chains - two identical light chains and
two identical heavy chains. The N terminal domains
of each light and heavy chain are highly variable in
sequence, are referred to as the variable regions (Vl
and Vh, respectively), and form the antigen-binding
sites of the antibody. The C terminal domains of the
light and heavy chains together form the constant
regions (Cl and Ch, respectively), which determine
the effector functions of the immunoglobulin.

1. There are five classes of Ab: IgG (IgG1,IgG2,IgG3, IgG4), IgM, IgA (IgA1, IgA2), IgD, IgE

2. A vast repertoire of Ag-binding sites is achieved by random selection and recombination of

a limited number of V, D, and J gene segments that encode the variable (V) domains. This
process is known as VDJ recombination and generates the primary antibody repertoire.
3. Repeated rounds of somatic hypermutation and selection act on the primary repertoire to
generate antibodies with higher specificity and affinity for the stimulating antigen. The
class and subclass of an Ig are determined by its heavy chain type. Immunoglobulin class
switching combines rearranged VDJ genes with various C region genes so that the same antigen
receptor can serve a variety of effector functions.

4 Receptors for immunoglobulin constant regions (Fc receptors) are expressed by

mononuclear cells, neutrophils, natural killer cells, eosinophils, basophils, and mast cells. They

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interact with the Fc regions of different classes of immunoglobulin and promote activities such
as phagocytosis, tumor cell killing, and mast cell degranulation.

T Cell Receptors and MHC Molecules

1. Macrophages present Ag to TH1 cells,
which then activate the macrophages to
destroy intracellular or phagocytosed
pathogens.

2. B cells present Ag to TH2 cells, which

activate the B cells, causing them to
divide and differentiate.

3. Cytotoxic T cells (CTLs) and large

granular lymphocytes (LGLs) recognize
and destroy virally infected cells

4. T cells recognize antigen via cell surface

receptors (T cell receptors) and have a
wide range of biological functions

1. The T cell antigen receptor (TCR) is located on the surface of T cells and plays a
critical role in the adaptive immune system. Its major function is to recognize antigen
and transmit a signal to the interior of the T cell, which generally results in activation of T
cell responses.
2. TCRs are similar in many ways to immunoglobulin molecules. Both are made up of
pairs of subunits (α and β or γ and δ), which are themselves members of the Igs superfamily,
and both recognize a wide variety of antigens via N terminal variable regions. Both the αβ
TCR and the γδ TCR are associated with CD3, forming TCR complexes.
3. The two types of TCR may have distinct functions. In humans and mice, the αβ TCR
predominates in most peripheral lymphoid tissues, whereas cells bearing the γδ TCR are
enriched at mucosal surfaces. Critical signaling functions are performed by the invariant
chains of the TCR, the CD3 complex.
4. Like immunoglobulins, TCRs are encoded by several sets of genes, and a large
repertoire of TCR antigen-binding sites is generated by V(D)J recombination during T cell
differentiation. Unlike immunoglobulins, TCRs are never secreted and do not undergo
class switching or somatic hypermutation.
5. Recognition by the αβ TCR requires the antigen to be bound to a specialized
antigen-presenting structure known as a major histocompatibility complex (MHC)
molecule. Unlike immunoglobulins, TCRs recognize antigen only in the context of a
cell-cell interaction.
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6. Class I and class II MHC molecules bind to peptides derived from different sources.
Class I MHC molecules bind to peptides derived from cytosolic (intracellular)
proteins, known as endogenous antigens. Class II MHC molecules bind to peptides
derived from extracellular proteins that have been brought into the cell by phagocytosis or
endocytosis (exogenous antigens).
7. Class I and class II MHC present peptide antigens to the TCR in a cell-cell interaction
between an antigen-presenting cell (APC) and a T cell.
8. HLA-A, HLA-B, and HLA-C gene loci encode class I MHC molecules
9. HLA-DP, HLA-DQ, AND HLA-DR gene loci encode class II MHC molecules.
10. An individual's MHC haplotype affects susceptibility to disease.
11. CD1 is an MHC class 1-like molecule that presents lipid antigens.

Complement
1. Complement is central to the development of inflammatory reactions and forms one of
the major immune defense systems of the body.
2. Complement activation pathways have evolved to label pathogens for elimination. The
classical pathway links to the adaptive immune system. The alternative and lectin pathways
provide non-specific 'innate' immunity, and the alternative pathway is linked to the classical
pathway.

3. Each of the activation pathways generates a C3 cnvertase, which converts C3 to C3b, the
centralevent of the complement pathway. C3b in turn activates the terminal lytic membrane
attack pathway.

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4. The complement system is controlled to protect the host. C1 inhibitor controls the
classical and lectin pathways. C3 and C5 convertase activity are controlled by decay and
enzymatic degradation.
5. The membrane attack pathway results in the formation of a transmembrane pore.
Regulation of the membrane attack pathway reduces the risk of 'bystander' damage to
adjacent cells.
6. Many cells express one or more membrane receptors for complement products.
Receptors for fragments of C3 are widely distributed on different leukocyte populations.
Receptors for C1q are present on phagocytes, mast cells, and platelets The plasma
complement regulator fH binds leukocyte surfaces.
7. Complement has a variety of functions. Its principal functions are chemotaxis including
opsonization and cell activation, lysis of target cells, and priming of the adaptive immune
response.
8. Complement deficiencies illustrate the homeostatic roles of complement. Classical
pathway deficiencies result in tissue inflammation. Deficiencies of mannan-binding lectin
(MBL) are associated with infection in infants. Alternative pathway and C3 deficiencies are
associated with bacterial infections. Terminal pathway deficiencies predispose to
Gram-negative bacterial infections. C1 inhibitor deficiency leads to hereditary angioedema.
Deficiencies in alternative pathway regulators produce a secondary loss of C3.

5. Cell mediated immune responses.

6. Humoral immune responses.
7. Immunoregulation.

Antigen Presentation
1. T cells recognize peptide fragments that have been processed and become bound to major
histocompatibility complex (MHC) class I or II molecules. These MHC-antigen complexes
are presented at the cell surface.
2. MHC class I molecules associate with endogenously synthesized peptides, binding to
peptides produced by degradation of the cells' internal molecules. This type of antigen
processing is carried out by proteasomes (which cleave the proteins) and transporters (which
take the fragments to the endoplasmic reticulum [ER]).
3. MHC class II molecules bind to peptides produced following the breakdown of proteins
that the cell has endocytosed. The peptides produced by degradation of these external
antigens are loaded onto MHC class II molecules in a specialized endosomal compartment
called MIIC.
4. Cross-presentation allows APCs to acquire antigens from infected cells. A specialized
pathway allows the acquisition of antigens from infected cells by APCs. This pathway, called

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cross-presentation, allows the display of exogenous antigens by MHC class I molecules.

5. Co-stimulatory molecules are essential for T cell activation. Molecules such as B7
(CD80/86) on the APC bind to CD28 on the T cell to cause activation. Antigens presented
without co-stimulation usually induce T cell anergy. Intercellular adhesion molecules also
contribute to the interaction between a T cell and an antigen-presenting cell (APC). Interactions
between intercellular cell adhesion molecule-1 (ICAM-1) and leukocyte functional antigen-1
(LFA-1) and between CD2 and its ligands extend the interaction between T cells and APCs.
6. CD4 binds to MHC class II and CD8 to MHC class I molecules. These interactions increase
the affinity of T cell binding to the appropriate MHC-antigen complex and bring kinases to the
TCR complex.
7. The highly ordered area of contact between the T cell and APC is an immunological
synapse.
8. T cell activation induces enzyme cascades, leading to the production of interleukin-2
(IL-2) and the high-affinity IL-2 receptor on the T cell. IL-2 is required to drive T cell
division.
9. Antigen presentation affects the subsequent course of an immune response. The immune
system responds to clues that an infection has taken place before responding strongly to
antigens

Cell Cooperation in the Antibody Response

1. The primary development of B cells is antigen-independent. Pre-B cells recombine genes
for immunoglobulin heavy and light chains to generate their surface receptor for antigen.
2. T-independent (TI) antigens activate B cells without requiring T cell help. They can be
divided into two groups. TI-1 antigens can act as polyclonal stimulators, while TI-2 antigens
are polymers that activate by cross-linking the B cell receptor.
3. T-dependent (TD) antigens are taken up by B cells, processed, and presented to helper T
(Th) cells. T cells and B cells usually recognize different parts of an antigen.
4. B and T cell activation follow similar patterns. B cell activation requires signals from the B
cell receptor (BCR) and co-stimulation. CD40 is the most important co-stimulatory molecule
on B cells. Ligation of B cell co-receptor complex can lower the threshold of antigen needed to
trigger the B cell. Intracellular signaling pathways are analogous in B and T cells.
5. Cytokine secretion from CD4+ T cells is important in B cell proliferation and
differentiation. Activated B cells proliferate and differentiate into antibody-forming cells
(AFCs).
6. B cell affinity maturation takes place in the germinal centers. Mutation of immunoglobulin
genes followed by selection of high-affinity clones is the basis of affinity maturation.
7. B cells switch to another immunoglobulin class (class switching) by recombining heavy
chain genes. Differential splicing of long RNA transcripts is a second mechanism by which B

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cells can produce more than one type of antibody.

Cell-mediated Cytotoxicity
1. Cell-mediated cytotoxicity is an essential defense against intracellular pathogens,
including viruses, some bacteria, and parasites. CTLs recognize antigen presented on
MHC molecules. Most CTLs are CD8+ and recognize antigenic peptides presented on
MHC
2. class I molecules. NK cells react against cells that do not express MHC class I molecules.
They can interact with these cells using a variety of receptors.
3. NK cells express a variety of receptors. The lectin-like receptor CD94 interacts with
HLA-E. KIRs (killer immunoglobulin-like receptors) are members of the immunoglobulin
superfamily - those with short tails are activating, and those with long tails are inhibitory.
Immunoglobulin-like transcripts (ILTs) have a wider cell distribution than other NK cell
receptors.
4. Interactions with NK receptors determine NK cell action. NK cells use several different
receptors to positively identify their targets, and intracellular signaling pathways coordinate
inhibitory and activating signals.
5. Cytotoxicity is effected by direct cellular interactions, cytokines, and granule
exocytosis. Fas ligand and TNF can signal apoptosis to the target cell. Granules containing
perforin and granzymes contribute to target cell damage. Ligation of Fas or the type 1 TNF
receptor on the target cell leads to the activation of caspases, which are the ultimate
mediators of apoptosis in the target.
6. Macrophages, neutrophils, and eosinophils are non-lymphoid cytotoxic effectors.
Macrophages damage targets using their non-specific toxic effector systems or via
cytokines. Eosinophils mediate cytotoxicity by exocytosis of their granules

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8. Host defense against infection; Vaccination.

Immunity to Viruses

1. Entry of virus may be inhibited by Ab.

2. Following the initial infection, the virus may
spread to other tissues via the blood stream.
Interferon produced by the innate IFNα and
IFNβ and adaptive IFNγ immune
responses make neighboring cells resistant to
virus.
3. Interferon, NK cells, and macrophages
restrict the early stages of infection and
delay spread of virus.
4. Macrophages act at three levels to destroy
virus and virus-infected cells.

1. The initial defense against virus is the

integrity of the body surface. Once
breached, innate immune defenses IFN,
NK and macrophage become active.
2. As a viral infection proceeds, the
adaptive (specific) immune response
unfolds. Antibodies and complement can
limit viral spread or reinfection. T cells
mediate viral immunity in several ways -
CD8+ CTLs destroy virus-infected cells;
CD4+ T cells are a major effector cell
population in the response to many virus
infections.

1. Abs are important in controlling free virus, whereas T cells and NK cells are effective at
killing viral infected cells.
2. Viruses have evolved strategies to evade the immune response. Virus latency and antigenic
variation are the most effective mechanisms. Many viruses deviate the immune response by
the production of cytokine analogs and cytokine receptor analogs. Many DNA viruses have
strategies to control the expression of MHC molecules.
3. Responses to viral antigens can cause tissue damage from the formation of immune
complexes and by causing immunosuppression, immunodeficiency, or autoimmunity.

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Immunity to Bacteria and Fungi

1. Lymphocyte-independent bacterial recognition pathways have several consequences.

Complement is activated via the alternative pathway. Release of proinflammatory
cytokines increases the adhesive properties of the vascular endothelium. Pathogen
recognition generates signals that regulate the lymphocyte-mediated response.
2. Antibody provides an antigen-specific protective mechanism. Neutralizing antibody
may be all that is needed for protection if the organism is pathogenic only because of a
single toxin or adhesion molecule. Opsonizing antibody responses are particularly
important for resistance to extracellular bacterial pathogens. Complement can kill some
bacteria, particularly those with an exposed outer lipid bilayer, such as Gram-negative
bacteria.
3. Ultimately most bacteria are killed by phagocytes following a multistage process of
chemotaxis, attachment, uptake, and killing. Optimal activation of macrophages is
dependent on TH1 CD4 T cells. Persistent macrophage recruitment and activation can
result in granuloma formation, which is a hallmark of cell-mediated immunity to
intracellular bacteria.
4. Successful pathogens have evolved mechanisms to avoid phagocyte-mediated killing.
5. The response to bacteria can result in immunological tissue damage. Excessive
release of cytokines caused by microorganisms can result in immunopathological
syndromes, such as endotoxin shock and the Schwartzman reaction.

6. Fungi can cause life-threatening infections. Immunity to fungi is predominantly cell

mediated and shares many similarities with immunity to bacteria.

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Immunity to Protozoa and Worms

1. Parasites stimulate a variety of immune defense mechanisms.
2. Effector cells such as macrophages, neutrophils, eosinophils, and platelets can kill both
protozoa and worms. They secrete cytotoxic molecules such as reactive oxygen radicals
and (NO•). All are more effective when activated by cytokines. Worm infections are
usually associated with an increase in eosinophil number and circulating IgE, which
are characteristic of Th2 responses. Th2 cells are necessary for the elimination of
intestinal worms.
3. IgE antibodies play a critical role in defense against helminths. The biological role of
immediate hypersensitivity is to control helminth infections such as schistosomiasis,
hookworm, or ascariasis. However, it is likely to be a combination of effector TH2 cells,
basophils, and eosinophils, as well as IgE antibodies on mast cells, that control these
worms
4. Parasites have many different escape mechanisms. Evasion of the host's immune response
by parasites occurs in various ways. Some exploit the host response for their own
development. It is becoming clear that many parasites, in particular helminths, are able to
modulate the host immune response.
5. Inflammatory responses can be a consequence of eliminating parasitic infections.
6. Parasitic infections have immunopathological consequences. Parasitic infections are
associated with pathology, which can include autoimmunity, splenomegaly, and
hepatomegaly. Much immunopathology may be mediated by the adaptive immune
response.
7. Vaccines against human parasites are not yet available.

Vaccination
1. Vaccination applies immunological principles to human health. Active immunization is
known as vaccination.
2. A wide range of antigen preparations are in use as vaccines, from whole organisms to
simple peptides and sugars.

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3. Living vaccines being generally more effective.

4. Adjuvants enhance antibody production, and are usually required with non-living vaccines.
They concentrate antigen at appropriate sites or induce cytokines.
5. Passive immunization can be life-saving. The direct administration of antibodies still has a
role to play in certain circumstances, for example when tetanus toxin is already in the
circulation.

9. Allergy and hypersensitivity.

Four type of hypersensitivity

Immediate Hypersensitivity (Type I)

1. The severity of symptoms depends on IgE, the quantity of allergen, and also a variety of
factors that can enhance the response including viral infections and environmental pollutants.
2. Production of IgE in genetically predisposed (i.e. atopic) individuals occurs in response to
repeated low-dose exposure to inhaled allergens such as dust mite, cat dander, or grass pollen.
3. Mast cells and basophils contain histamine. IgE antibodies bind to a specific receptor,
FcεRI, on mast cells and basophils. When bound IgE is cross-linked by specific allergen,
mediators including histamine, leukotrienes, and cytokines are released.

Hypersensitivity (Type II)

1. Type II hypersensitivity is mediated by antibodies binding to specific cells. Type II
hypersensitivity reactions are caused by IgG or IgM antibodies against cell surface and
extracellular matrix antigens. The antibodies damage cells and tissues by activating
complement, and by binding and activating effector cells carrying Fcγ receptors.

2. Type II hypersensitivity reactions may target cells. Transfusion reactions to

erythrocytes are produced by antibodies to blood group antigens, which may occur
naturally or may have been induced by previous contact with incompatible tissue or blood

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following transplantation, transfusion or during pregnancy.

3. Hemolytic disease of the newborn occurs when maternal antibodies to fetal blood group
antigens cross the placenta and destroy the fetal erythrocytes.

4. Type II hypersensitivity reactions may target tissues. Damage to tissues may be

produced by antibody to functional cell surface receptors through Fab regions. In doing so,
they may enhance or inhibit the normal activity of the receptor. Examples include
myasthenia gravis, pemphigus, and Goodpasture's syndrome.

Hypersensitivity (Type III)

1. Immune complexes can trigger a variety of inflammatory processes. Fc-FcR interactions
are the key mediators of inflammation. Most importantly, Fc regions within immune deposits
within tissues engage Fc receptors on activated neutrophils, lymphocytes, and platelets to
induce inflammation. During chronic inflammation B cells and macrophages are the
predominant infiltrating cell type, and activation of endogenous cells within the organ
participates in fibrosis and disease progression.

2. Immune complexes are normally removed by the mononuclear phagocyte system.

Complement helps to disrupt antigen-antibody bonds and keeps immune complexes soluble.
Primate erythrocytes bear a receptor for C3b and are important for transporting
complement-containing immune complexes to the spleen for removal. Complement
deficiencies lead to the formation of large, relatively insoluble complexes, which deposit in
tissues.

3. Immune complex deposition in the tissues results in tissue damage. Immune complexes can
form both in the circulation, leading to systemic disease, and at local sites such as the lung.
Charged cationic antigens have tissue-binding properties, particularly for the glomerulus, and
help to localize complexes to the kidney. Factors that tend to increase blood vessel
permeability enhance the deposition of immune complexes in tissues.

Hypersensitivity (Type IV)

1. DTH reflects the presence of antigen-specific CD4 T cells.

2. There are three variants of type IV hypersensitivity reaction - contact, tuberculin,

and granulomatous.

3. Contact hypersensitivity occurs at the point of contact with an allergen. Langerhans'

cells internalize and process epicutaneously applied hapten and migrate to the draining
lymph nodes where they present it to antigen-specific T cells. Cytokines produced by
immune-competent skin cells (e.g. keratinocytes, Langerhans' cells, T cells) recruit
antigen-non-specific T cells and macrophages.

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4. Tuberculin-type hypersensitivity is induced by soluble antigens from a variety of

organisms. It is useful as a diagnostic test for exposure to a number of infectious agents.

5. Granulomatous hypersensitivity is clinically the most important form of type IV

hypersensitivity. Persistence of antigen leads to differentiation of macrophages to
epithelioid cells, and fusion to form giant cells. This pathological response is termed a
granulomatous reaction and it results in tissue damage. Granuloma formation is driven by
T cell activation of macrophages, and is dependent on TNF. Inhibition of TNF leads to
breakdown in granulomas.

6. Many chronic diseases manifest type IV granulomatous hypersensitivity. These

include tuberculosis, leprosy, schistosomiasis, sarcoidosis, and Crohn's disease.

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