Innate immunity vs Adaptive immunity

Innate immunity Adaptive immunity

Neutrophils, macrophages, T cells, B cells, circulating
monocytes, dendritic cells, antibodies
COMPONENTS natural killer (NK) cells
(lymphoid origin),
complement
Variation through V(D)J
MECHANISM Germline encoded recombination during
lymphocyte development
Resistance persists Microbial resistance not
through generations; does heritable
RESISTANCE not change within an
organism’s lifetime
Nonspecific Highly specific, refined over
RESPONSE TO Occurs rapidly (minutes to time
PATHOGENS hours) Develops over long
No memory response periods; memory response
is faster and more robust
PHYSICAL Epithelial tight junctions, —
BARRIERS mucus
Lysozyme, complement, C- Immunoglobulins
SECRETED reactive protein
PROTEINS (CRP), defensins
Toll-like receptors (TLRs): Memory cells: activated B
pattern recognition and T cells;
receptors that recognize subsequent exposure to a
KEY FEATURES pathogen-associated previously
IN PATHOGEN Molecular patterns encountered antigen 
RECOGNITION (PAMPs). Examples of stronger, quicker
PAMPs include LPS (gram immune response
⊝ bacteria), flagellin
(bacteria), and nucleic
acids (viruses).
Major Histocompatibility Complex (MHC) I and II
 MHC encoded by HLA genes. Present antigen fragments to T cells and
bind T-cell receptors (TCRs).

MHC I MHC II

LOCI HLA-A, HLA-B, HLA-C HLA-DP, HLA-DQ, HLA-DR

MHC I loci have 1 letter MHC II loci have 2 letters

BINDING TCR and CD8 TCR and CD4

STRUCTURE 1 long chain, 1 short chain 2 equal-length chains

EXPRESSION All nucleated cells, APCs, platelets APCs

Not on RBCs

FUNCTION Present endogenously synthesized Present exogenously

antigens (eg, viral or cytosolic proteins) synthesized antigens
to CD8+ cytotoxic T cells. (eg, bacterial proteins)
to CD4+ helper T cells.

ANTIGEN Antigen peptides loaded onto MHC I Antigen loaded following release
LOADING in RER after delivery via TAP of invariant chain in an acidified
(Transporter associated with antigen endosome.
processing).

ASSOCIATED β2-microglobulin Invariant chain

PROTEINS

STRUCTURE
Subtype Disease Mnemonics

A3 Hemochromatosis

B8 Addison disease, myasthenia gravis,

Graves’ disease

B27 Psoriatic arthritis, Ankylosing spondylitis, PAIR.

IBD-associated arthritis, Reactive arthritis
Also known as seronegative arthropathies.

B47 Congenital adrenal hyperplasia

B51 Bechet’s Disease

CW6 Psoriasis vulgaris

DQ2/DQ8 Celiac disease I ate (8) too (2) much

Gluten at Dairy Queen.

DR2 Multiple sclerosis, hay fever, Multiple hay pastures have dirt.
SLE, Goodpasture syndrome

DR3 Diabetes mellitus type 1, SLE,

Graves’ disease, Hashimoto thyroiditis, 2-3, S-L-E
Addison disease

DR4 Rheumatoid arthritis, There are 4 walls in a ―rheum‖ (room).

Diabetes mellitus type 1,
Addison disease

DR5 Pernicious anemia ---> vitamin B12 deficiency,

Hashimoto thyroiditis
 Stem cell

Pro-B cell
Addition of CD19, CD22 μ chain D-J gene arrangements

Pre-B cell
Addition of CD9, CD10 V-DJ-C gene rearrangements μchains appear

Immature B cell
 Addition of CD20, CD21, CD37
 Loss of CD9, CD10
 Appearance of membrane IgM and IgD receptors

Mature B cell
Antigen and T cell
Cytokines (IL-2, IL-4, IL-5, IL-6

Activated B cell

Plasma cells or Memory cells

• Secrete IgM antibody

• Ig switch to IgG, IgA, IgE
 Th1 cell Th2 cell
Secretes IFN-γ and IL-2 Secretes IL-4, IL-5, IL-6, IL-10, IL-13
Activates macrophages and cytotoxic T Recruits eosinophils for parasite defence
cells and promotes IgE production by B cells
Differentiation induced by IFN-γ and IL-12 Differentiation induced by IL-2 and IL-4

Inhibited by IL-4 and IL-10 (from Th2 cell) Inhibited by IFN-γ (from Th1 cell)

 Macrophage-lymphocyte interaction—dendritic cells, macrophages, and other

APCs release IL-12, which stimulates T cells to differentiate into Th1 cells. Th1
cells release IFN-γ to stimulate macrophages.
 Helper T cells have CD4, which binds to MHC II on APCs.
  APCs: B cells, dendritic cells, Langerhans cells, macrophages.
 Two signals are required for T-cell activation, B-cell activation, and
class switching.
T-cell activation
1. Dendritic cell (specialized APC) samples antigen, processes antigen,
and migrates to the draining lymph node.
2. T-cell activation (signal 1): antigen is
presented on MHC II and recognized by
TCR on Th (CD4+) cell. Endogenous or
cross-presented antigen is presented on
MHC- I to Tc (CD8+) cell.
3. Proliferation and survival (signal 2):
costimulatory signal via interaction of B7
protein on dendritic cell (CD80/86) and
CD28 on naïve T cell.
4. Th cell activates and produces
cytokines. Tc cell activates and is able to
recognize and kill virus-infected cell.

B-cell activation and class switching

1. Th-cell activation as above.
2. B-cell receptor–mediated endocytosis;
foreign antigen is presented on MHC II
and recognized by TCR on Th cell.
3. CD40 receptor on B cell binds CD40
ligand (CD40L) on Th cell.
4. Th cell secretes cytokines that
determine Ig class switching of B cell. B
cell activates and undergoes class
switching, affinity maturation, and
antibody production.
  Fab (containing the variable/hypervariable regions) consisting of light (L) and
heavy (H) chains recognizes antigens. Fc region of IgM and IgG fixes
complement. Heavy chain contributes to Fc and Fab regions. Light chain
contributes only to Fab region.
 Fab:
 Fragment, antigen binding
 Determines idiotype: unique antigen-binding pocket; only 1 antigenic
specificity expressed per B cell
 Fc:
 Constant
 Carboxy terminal
 Complement binding
 Carbohydrate side chains
 Determines isotype (IgM, IgD, etc)
Generation of antibody diversity (antigen independent)
1. Random recombination of VJ (light-chain) or V(D)J (heavy-chain) genes
2. Random addition of nucleotides to DNA during recombination by terminal
deoxynucleotidyl transferase (TdT).
3. Random combination of heavy chains with light chains
Generation of antibody specificity (antigen dependent)
4. Somatic hypermutation and affinity maturation (variable region)
5. Isotype switching (constant region)

Enzymatic Digestion
 Papin digestion: Papain cleaves the Ig molecule at a point the hinge
region, resulting in three fragments: Two Fab (Ag binding fragment) and
One Fc fragment (Crystallisable fragment).
 Pepsin digestion: Pepsin cleaves the Ig molecule at point below the
hinge region; resulting in formation of One F(ab’)2 fragment and many
smaller fragments.
 Mercaptoethanol digestion: Generates four fragments (Two Hand
Two L chains) as it cleaves only disulphide bonds sparing the peptide
bond.
 Heavy chain is coded by Chromosome No-14.
 Light chain Kappa is coded by Chromosome No-2.
 Light Chain lambda is coded by chromosome by-22.
Types Features
 Main antibody in 2° (delayed) response to an antigen.
IgG  Most abundant isotype in serum.
 Fixes complement, crosses the placenta (provides infants
with passive immunity).
 Opsonizes bacteria, neutralizes bacterial toxins and viruses.
 Prevents attachment of bacteria and viruses to mucous
membranes; does not fix complement.
 Monomer (in circulation) or dimer (with J chain when
secreted).
 Crosses epithelial cells by transcytosis. Produced in GI tract
(eg, by Peyer patches) and protects against gut infections (eg,
IgA Giardia).
 Most produced antibody overall, but has lower serum
concentrations.
 Released into secretions (tears, saliva, mucus) and breast
milk.
 Picks up secretory component from epithelial cells, which
protects the Fc portion from luminal proteases.
 Produced in the 1° (immediate) response to an antigen.
 Fixes complement but does not cross the placenta.
IgM  Antigen receptor on the surface of B cells.
 Monomer on B cell, pentamer with J chain when secreted.
 Pentamer enables avid binding to antigen while humoral
response evolves.
IgD Unclear function. Found on surface of many B cells and in
serum.
 Only heat labile Ig.
 Binds mast cells and basophils; cross-links when exposed to
allergen.
IgE
 Mediating immediate (type I) hypersensitivity through release
of inflammatory mediators such as histamine. Contributes to
immunity to worms by activating eosinophils.
 Lowest concentration in serum.
  System of hepatically synthesized plasma proteins that play a role in
innate immunity and inflammation. Membrane attack complex (MAC)
defends against gram ⊝ bacteria

ACTIVATION
 Classic pathway—IgG or IgM mediated. GM makes classic cars.
 Alternative pathway—microbe surface molecules.
 Lectin pathway—mannose or other sugars on microbe surface.
FUNCTIONS
 C3b—opsonization.
 C3a, C4a, C5a—anaphylaxis.
 C5a—neutrophil chemotaxis.
 C5b-9—cytolysis by MAC.
 C3b binds bacteria.
 Opsonins—C3b and IgG are the two 1° opsonins in bacterial defense;
enhance phagocytosis. C3b also helps clear immune complexes.
Opsonin (Greek) = to prepare for eating.
 Inhibitors—decay-accelerating factor (DAF, aka CD55) and C1
esterase inhibitor help prevent complement activation on self cells (eg,
RBCs).
Deficient Complement Disease
 Causes hereditary angioedema due to
unregulated activation of kallikrein  Increases
C1 esterase inhibitor bradykinin.
 Characterized by decreases C4 levels.
 ACE inhibitors are contraindicated.
C2 deficiency  Most common, no significant
C1, C2, C4  SLE and Collagen vascular disease
 Increases risk of severe, recurrent pyogenic
C3 deficiency sinus and respiratory tract infections.
 Increases susceptibility to type III hypersensitivity
reactions.
 Terminal complement deficiency increases
C5–C9 deficiencies susceptibility to recurrent Neisseria bacteraemia.
 Toxoplasmosis

Cell Surface
Receptor Microbial Activators Ligand
TLR1 Bacteria, mycobacteria Lipopeptides
Neisseria meningitidis Soluble factors
TLR2 Bacteria LTA, LPS, PG, etc.
Fungi Zymosan
Cells Necrotic cells
TLR4 Bacteria, parasites, host LPS, fungal mannans,
proteins viral glycoproteins, parasitic
Viruses, parasites, host Phospholipids, host
proteins heat shock proteins,
LDL
TLR5 Bacteria Flagellin
TLR6 Bacteria LTA, Lipopeptides,
Fungi zymosan
Lectins Bacteria, fungi, viruses Specific carbohydrates
(e.g., mannose)
N-Formyl Bacteria Bacterial proteins
methionine receptor
 Endosome
Receptor Microbial Activators Ligand
TLR3 Viruses Double-stranded RNA
TLR7 Viruses Single-stranded RNA
Imidazoquinolines
TLR8 Viruses Single-stranded RNA
Imidazoquinolines
TLR9 Bacteria Unmethylated DNA
Viruses (CpG)

Cytoplasm
Receptor Microbial Activators Ligand
NOD1, NOD2, Bacteria Peptidoglycan
NALP3
a) Cryopyrin b) Bacteria c) Peptidoglycan
d) RIG-1 e) Viruses f) RNA
g) MDA5 h) Viruses i) RNA
j) DAI k) Viruses, cytoplasmic l) DNA
DNA

Important Interleukins
 IL-1: fever (hot).
 IL-2: stimulates T cells.
 IL-3: stimulates bone marrow.
 IL-4: stimulates IgE production.
 IL-5: stimulates IgA production.
 IL-6: stimulates aKute-phase protein production
 Mnemonics: - “Hot T-bone stEAK”:
 IL-8: Major chemotactic factor for neutrophils.
 “Clean up on aisle 8.” Neutrophils are recruited by IL-8 to clear infections.
 IL-10: Attenuates inflammatory response. Decreases expression of
MHC class II and Th1 cytokines. Inhibits activated macrophages and
dendritic cells. Also secreted by regulatory T cells.
 TGF-β and IL-10 both attenuate the immune response.
 IL-12 Induces differentiation of T cells into Th1 cells. Activates NK
cells.
 APCs implies to cell that present the antigenic peptide along with
MHC-II to TH cells. They may be grounded into:-

Professional APCs Non-Professional APCs

 Macrophages  Fibroblast (Skin)
 Dendritic cells  Thymic epithelial cells
 B-cells  Pancreatic beta cells
 Vascular endothelial cells
 Glial cells (Brain)
 Thyroid epithelial cells

 CD1a, CD207: Langerhans cell, Histiocytosis cells

 CD2, CD3, CD4, CD5, CD7, and CD8: T cells
 CD2: Associated with T-antigen receptor/ "LFA2"
 CD3: Signal transduction complement of T-cells
 CD3-PAN T Cell marker
 CD4: Found on all Helper T-lymphocytes
 CD5: Mantle Cell Lymphoma
 CD8: Found on all Cytotoxic T-lymphocytes
 CD10: Early pre-B cells (immature B cells)
CALLA (Common Acute Lymphoblastic Leukemia Antigen)
Functions as a metalloendopeptidase (Zn dep)/
Deactivated by chellators.
 CD11c, CD25, CD103, CD123: Hairy cell leukemia cells
 CD13, CD33, CD117: Myeloid cells
 CD14, CD64: Monocytic cells
(Positive in AML-M4 and AML-M5)
 CD15: Reed-Sternberg cells, neutrophils
 CD16, CD56: Natural killer cells
 CD18: Leukocyte adhesion deficiency
 CD19, CD20, CD21, CD22: B cells
 CD19: PAN B Cell Marker
 CD 21: Receptor for the C3d component of complement
And EBV.
 CD23 and CD5: Chronic lymphocytic leukemia /
Small lymphocytic lymphoma
 CD23 negative and CD5 positive: Mantle cell lymphoma
Cells
 CD30 and CD15: Reed-Sternberg cells
 CD30 positive and CD15 negative: Anaplastic large cell
Lymphoma cells
 CD30: Hodgkin’s Disease
 CD31: (PECAM-1) Liver angiosarcoma
 CD33: Myeloid cells and precursors
 CD34: Hemopoetic Progenitor Cells /
Stem Cell Marker
 CD38: Plasma Cells /Multiple Myeloma Marker
 CD41, CD61: Megakaryocytes and platelets
(Positive in AML-M7)
 CD45: All leukocytes (except Reed-Sternberg cells!)
 CD45 RO: Memory T cells
 CD45 RA: Naive T cells
 CD68: Histiocytes
(Positive in malignant fibrous Histiocytosis)
 CD99: Ewings sarcoma cells
 CD117: Gastrointestinal stromal tumor (GIST) cells,
Mast cells (positive in mastocytosis),
Myeloid cells
 FIL 1: Ewings sarcoma cells
 DOG1: Gastrointestinal stromal tumour (GIST) cells.
 Four types: Anaphylactic and Atopic (type I),
Cytotoxic (antibody mediated, type II),
Immune complex (type III),
Delayed (cell mediated, type IV)
(ACID).

 Anaphylactic and atopic—free

antigen crosslinks IgE on
presensitized mast cells and
basophils, triggering immediate
release of vasoactive amines
that act at post capillary venules
(i.e., histamine). Reaction
develops rapidly after antigen
exposure because of preformed
antibody. Delayed phase results
from mast cells and basophils
releasing cytokines that induce
cellular inflammation.
 First (type) and Fast
(anaphylaxis).
 Types I, II, and III are all
antibody mediated.
 Test: skin test or blood test
(ELISA) for allergen specific IgE.
 Example:
Anaphylaxis (eg, food, drug, or bee sting allergies).
 Antibodies bind to cell-surface antigens --->cellular destruction,
inflammation, and cellular dysfunction.
 Direct Coombs test—detects
antibodies attached directly to the
RBC surface.
 Indirect Coombs test—detects
presence of unbound antibodies in
the serum.
 Cellular destruction: cell is
opsonized (coated) by antibodies,
leading to either:

 Phagocytosis and/or activation

of complement system.
 NK cell killing (antibody-
dependent cellular
cytotoxicity).
 Examples:
 Autoimmune-hemolytic anemia
 Immune thrombocytopenic
purpura
 Transfusion reactions
 Hemolytic disease of the new-
born
 Inflammation—binding of
antibodies to cell surfaces ---> activation of complement system and
Fc receptor-mediated inflammation.
 Examples:
 Good pasture syndrome
 Rheumatic fever
 Hyper acute transplant rejection
 Cellular dysfunction—antibodies bind to cell surface receptors --->
abnormal blockade or activation of downstream process.
 Examples:
 Myasthenia gravis
 Grave’s disease
 Immune complex—antigen-antibody (IgG) complexes activate
complement, which attracts neutrophils; neutrophils release lysosomal
enzymes. Can be associated with vasculitis and systemic
manifestations.
 In type III reaction, imagine an
immune complex as 3 things stuck
together: antigen antibody-
complement.
 Examples:
 SLE
 Polyarthritis nodosa
 Post streptococcal
glomerulonephritis
 Serum sickness—an immune
complex disease in which
antibodies to foreign proteins are
produced (takes 5 days). Immune
complexes form and are deposited
in membranes, where they fix
complement (leads to tissue
damage). More common than
Arthus reaction.
 Most serum sickness is now caused
by drugs (not serum) acting as
haptens. Fever, urticaria, arthralgia,
proteinuria, lymphadenopathy occur
5–10 days after antigen exposure.
 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.
 Antigen-antibody complexes cause the Arthus reaction.
 Two mechanisms, each involving T cells:
1. Direct cell cytotoxicity: CD8+ cytotoxic T cells kill targeted cells.
 Example:
 Type 1 diabetes mellitus
2. Delayed-type hypersensitivity:
sensitized CD4+ helper T cells
encounter antigen and release
cytokines ---> inflammation and
macrophage activation.
 Response does not involve antibodies
(vs types I, II, and III).
 Examples:
 Contact dermatitis (eg, poison ivy,
nickel allergy)
 Graft-versus-host disease
 Tests: PPD, patch test.
4T’s: T cells,
Transplant rejections,
TB skin tests,
Touching (contact dermatitis)

Fourth (type) and last (delayed).

 PATHOGENESIS: Type 1 hypersensitivity reaction against plasma proteins in
Transfused blood. IgA-deficient individuals must receive
Blood products without IgA.
CLINICAL PRESENTATION: Urticaria, pruritus, fever, wheezing, hypotension,
Respiratory arrest, shock.
TIMING: Within minutes to 2–3 hours.

PATHOGENESIS: Type II hypersensitivity reaction. Host antibodies against donor HLA

Antigens and WBCs.
CLINICAL PRESENTATION: Fever, headaches, chills, flushing.
TIMING: Within 1–6 hours

PATHOGENESIS: Type II hypersensitivity reaction. Intravascular hemolysis (ABO blood

Group incompatibility) or extravascular haemolysis (host antibody
Reaction against foreign antigen on donor RBCs).
CLINICAL PRESENTATION: Fever, hypotension, tachypnea, tachycardia, flank pain,
Haemoglobinuria (intravascular haemolysis), jaundice
(Extravascular).
TIMING: Within 1 hour

PATHOGENESIS: Donor anti-leukocyte antibodies against recipient neutrophils and

Pulmonary endothelial cells.
CLINICAL PRESENTATION: Respiratory distress and non-cardiogenic pulmonary
Edema.
TIMING: Within 6 hours
 Pathogen: Bacteria

 T CELLS ( ): Sepsis

 B CELLS ( ) Encapsulated (Please SHINE my SKiS):

 Pseudomonas aeruginosa,
 Streptococcus pneumoniae,
 Haemophilus
 Influenzae type B,
 Neisseria meningitidis,
 Escherichia coli,
 Salmonella,
 Klebsiella pneumoniae,
 Group B Streptococcus

 GRANULOCYTES ( )
 Staphylococcus
 Burkholderia cepacia
 Pseudomonas aeruginosa
 Serratia
 Nocardia

 COMPLEMENT ( )

 Encapsulated species with early

component deficiencies.
 Neisseria with late complement
(C5–C9) deficiencies
 Pathogen: Viruses
 T CELLS ( )
 CMV
 EBV
 JC virus
 VZV
 Chronic infection with respiratory/GI viruses
 B CELLS ( )
 Enteroviral encephalitis
 Poliovirus (live vaccine contraindicated)

 GRANULOCYTES ( )
 N/A
 COMPLEMENT ( )
 N/A
Pathogen: Fungi/Parasites
 T CELLS ( )
 Candida (local)
 PCP
 Cryptococcus
 B CELLS ( )
 GI giardiasis (no IgA)
 GRANULOCYTES ( )
 Candida (systemic)
 Aspergillus
 Mucor
 COMPLEMENT ( )
 N/A
Note: B-cell deficiencies tend to produce recurrent bacterial
infections, whereas T-cell deficiencies produce more fungal and
viral infections.
 AUTOANTIBODY ASSOCIATED DISORDER
 Anti-ACh receptor Myasthenia gravis
 Anti-glomerular basement membrane Good pasture syndrome
 Anti-β2 glycoprotein Antiphospholipid syndrome
 Anticardiolipin, lupus anticoagulant SLE,
Antiphospholipid syndrome
 Anticentromere Limited scleroderma
(CREST syndrome)
 Anti-desmoglein (anti-desmosome) Pemphigus vulgaris
 Anti-glutamic acid decarboxylase,
Islet cell cytoplasmic antibodies Type 1 diabetes mellitus
 Anti-hemidesmosome Bullous pemphigoid
 Antisynthetase (eg, anti-Jo-1), Polymyositis, Dermatomyositis
Anti-SRP, Anti helicase (anti-Mi-2)
 Anti-microsomal, anti-thyroglobulin, Hashimoto thyroiditis
Anti-thyroid peroxidase
 Ant mitochondrial 1° biliary cirrhosis
 Anti-parietal cell, anti-intrinsic factor Pernicious anemia
 Anti-phospholipase A2 receptor 1° membranous nephropathy
 Anti-Scl-70 (anti-DNA topoisomerase I) Scleroderma (diffuse)
 Anti-smooth muscle Autoimmune hepatitis type 1
 Anti-SSA, anti-SSB (anti-Ro, anti-La) Sjögren syndrome
 Anti-TSH receptor Graves’ disease
 Anti-presynaptic voltage-gated Lambert-Eaton myasthenic
Calcium channel syndrome
 IgA anti-endomysial, IgA anti-tissue transglutaminase Celiac disease
 MPO-ANCA/p-ANCA Microscopic polyangiitis,
Eosinophilic granulomatosis with
Polyangiitis (Churg-Strauss syndrome),
Ulcerative colitis
 PR3-ANCA/c-ANCA Granulomatosis with polyangiitis (Wegener)
 Rheumatoid factor (IgM antibody against IgG Fc region),
Anti-CCP (more specific) Rheumatoid arthritis
 Antinuclear (ANA) Nonspecific screening antibody,
Often associated with SLE
 Anti-dsDNA, anti-Smith SLE
 Anti-histone Drug-induced lupus
 Anti-U1 RNP (ribonucleoprotein) Mixed connective tissue disease