aditya

The Immune Response

Immunity: “Free from burden”. Ability of an

organism to recognize and defend itself
against specific pathogens or antigens.
Immune Response: Third line of defense.
Involves production of antibodies and
generation of specialized lymphocytes against
specific antigens.
Antigen: Molecules from a pathogen or foreign
organism that provoke a specific immune
response.
Line of Defense Against Infection
 Immune responses
Barriers Skin & Mucous membranes
rapidly regenerating surfaces, peristaltic
Invasion movement, mucociliary escalator,
& infection vomiting, flow of urine/tears, coughing

Innate immunity Cellular and humoral defences

+ lysosyme, sebaceous/mucous secretions,
stomach acid, commensal
organisms,complement proteins,
phagocytosis, NK cells

+ Inflammation
Cellular and humoral defences
Adaptive immunity Antibodies, cytokines, T helper cells,
cytotoxic T cells
Summary of the Immune Response
Immune system organs and
tissues
Lymphoid tissues
 Lymphoid tissues: the sites where
– the generation,
– maturation,
– habitation and
– activation of the immune cells take
place.
Lymphoid tissues
Cells of the Immune
System
Categories of Innate or
Nonspecific Immunity
Type of natural immunity
 Species immunity (B.anthracis infect human not chicken).
 Absence of specific tissue or cellular receptors for attachment
(colonization) by the pathogen.
 Temperature of the host and ability of pathogen to grow.
 Lack of the exact nutritional requirements to support the growth of the
pathogen.
 Lack of a target site for a microbial toxin.
 Individual immunity:
 Age.
 Sex.
 Stress.
 Diet, malnutrition..
 Intercurrent disease or trauma.
 Therapy against other diseases.
 Racial immunity: (sickle cell anaemia).
Type of defensive barriers
1. Anatomical Barriers
2. Microbial Antagonism

 Thisrefers to the protection of the

surfaces afforded by an intact normal flora
in a healthy animal.
 Competition with non-indigenous species
for binding (colonization) sites.
 Specific antagonism against non-indigenous
species.
 Nonspecific antagonism against non-
indigenous species. (fatty acids: lactate,
propionate, etc., peroxides and antibiotics).
3. Physiological Barrier
 Temperature
 pH
 Chemical mediators is two type:
 mediator released by the cells ie.
 Vasoactive amines (Histamine, 5-hydroxytryptamine /
serotonin),
 arachidonic acid metabolites ( via cyclo-oxygenase pathway
ie. Prostaglandins PGD2,PGE2 & PGF2-α , via lipooxygenase
pathway ie. 5-HETE – hydroperoxy eico-satetraenoic acid &
leukotrienes),
 Lysosomal components ( Neutrophilic origion:- lectoferrin,
lysozyme, alkaline phasphatase, collegenase, mylloperoxidase, acid
hydrolases, elastase, collagenase & proteinase etc),
 TNF, properdin, betalysin, Nitric oxide, leukins from leucocytes,
plakin from platlets. Chemokines , Interferons .
 The mediators released in plasma these are plasma proteases
derived from systems: Kinin system (bradykinin), Clotting system
(Fibrinopeptides), Complement system & fibrinolytic system
( plasmin).
4. Phagocytic/ endocytic barriers
 Mechanism; phagocytosis, receptor-mediated endocytosis & pinocytosis.
 Ex. Microphages: neutrophils, eosinophils. Macrophages: Monocytes,
histiocytes, reticulo-endothelial cells
 Non-specific Killer Cells: NK and LAK cells, ADCC (K) cell, Activated
macrophages.

Neutrophil Eosinophil

Neutrophil

Lymphocyte

Basophil
Monocyte
 Intracellular Killing Pathways

Intracellular Killing

Oxygen Oxygen
Dependent Independent

Myleoperoxidase Myleoperoxidase
Dependent Independent
5. Inflammatory barriers

 Celsus four cardinal sign of inflammation; - rubor

(redness), tumor (swelling), calor (heat), & dolor
(pain).Galen’s fifth sign: functio lasea(loss of fuction).
 Tissue damage and infection induce leakage of vascular
fluid, containing serum proteins with antibacterial activity,
and influx of phagocytic cells into the effected area.
 Inflammatory regulators:
 Acute phase protein ( α- anti trypsin, α 1-acid glycoprotein,
protease inhibitors, haptoglobin, C- reactive protein, serum
amyloid A, P- component etc.),
 corticosteroids,
 free cytokine receptors,
 suppressor T cells & anti-inflammatory chemical mediators
( PGE2 & prostacyclin).
Cytokine, Chemokines
Cytokines are small soluble proteins secreted by one cell that can alter the
behavior or properties of the cell itself or of another cell. They are released by
many cells in addition to those of the immune system.
 Cytokines, such as interferons (IFNs) and tumor-necrosis factor (TNF), induce
intracellular pathways that activate an anti-viral state or apoptosis
Chemokines are chemoattractant cytokines that regulate trafficking and
effector functions of leukocytes, and so have an important role in inflammation
and immune surveillance
 Chemokines: divided into 4 classes, CC-, CXC-, C-, CX3C-
 Expression of specific chemokines, together with differential expression of
respective chemokine receptors by leukocytes, determines which immune cells
migrate during inflammation

HIV utilizes chemokine receptors CCR5, CXCR4 for entry into target cells
Effecter mechanism of Innate
Immunity
Recognition mechanisms of innate immunity

 Toll-like receptors:
 bacterial cell wall components, viral nucleic acids
 Collectins, mannose receptor:
 distinctive cell surface polysaccharides
 Alternative pathway of complement:
 cell surfaces lacking protective anti-complement proteins
 Anti-microbial peptides:
 acidic phospholipids on outside of membrane
 Interferon-induction:
 double-stranded RNA (replication of viral genome)
 Virus replication-induced cell stress:
 induction of apoptosis, expression of stress-
 induced molecules that alert NK cells
Recognition mechanisms of innate
immunity
 Microbes evolve rapidly, so innate immunity
must focus on broadly expressed molecules
characteristic of broad groups of microbes
(“pathogen-associated molecular patterns”
PAMPs); “pattern recognition receptors”
 Molecules recognized tend to be structural
elements that are common to broad classes of
microbes and are very hard to change (only
useful to think of them as “patterns” in some
cases)
 The Epithelial Layer: The initial barrier to
infection
1. Physical barrier of the epithelial layer (toughness of barrier varies by
location due to other functions: air exchange, nutrient uptake, etc.)
2. Mucus/cilia to remove particles (lung, intestines)
3. Acid pH of the stomach
4. Anti-microbial peptides secreted by some epithelial cells (small
intestines, small airways of lungs)
5. Commensal bacteria (compete with pathogenic bacteria)
6. Secretory IgA (adaptive immunity)
7. Intraepithelial lymphocytes (adaptive immunity)
Anti-Microbial Peptides
 Made by neutrophils and some
epithelial cells (small intestines, small
airways)
 Short, cationic peptides (most 29-35
amino acids long)
 Interact strongly with acidic
phospholipids and thought to form
pores in membrane (eucaryotic
membranes often have negative charge
on carbohydrate rather than on
phospholipid of outside of bilayer; may
account for greater effect of peptides on
microbes )
 Differentially active against different
micro-organisms.
 They are classified into three major
groups: (i) peptides with an α-helical
conformation (insect cecropins,
magainins, etc.), (ii) cyclic and open-
ended cyclic peptides with pairs of
cysteine residues (defensins, protegrin,
etc.), and (iii) peptides with an over-
representation of some amino acids
(proline rich, histidine rich, etc.).
 Defensins link innate and adaptive immunity

TLR

LPS, etc. β−defensins Cathelicidins

CCR6 CCR6 FPRL1

MIP­3α
(CCL20)
Immature DC Memory T Cells PMNs
(Ag Sampling)
Recognition of an infection once it gets past the
epithelial barrier

 Soluble innate immune recognition elements (collectins,

ficolins, complement)

 Sentinel innate immune cells of tissues:

tissue macrophages, mast cells and immature dendritic
cells, which induce inflammation (1st two) and trigger
adaptive immunity (DCs)
Soluble innate recognition and complement
activation
•Soluble: C1q (complement cascade),
Collectins (Mannose binding lectin ,
ficolin/P35, SP-A, SP-D), Pentraxins
(CRP, SAP), LBP, sCD14
MBL •Receptors: Toll-like receptors (10),
CD14, Scavenger receptors (11), C-
type lectin receptors (47), Complement
receptors (22), Integrins (24a, 9b), Ig
Superfamily/DAP12

“pattern recognition receptors”;

particularly pattern of terminal sugars
on cell surfaces

Role: Direct or indirect

(complement) opsonization

Deficiency: Infections
Pentraxins
Acute phase serum proteins;
C-reactive protein (CRP): binds C-
polysaccharide of S. pneumoniae; promotes
phagocytosis of apoptotic cells;
noninflammatory clearance via C1q/factor H
Serum amyloid P (SAP): binds chromatin; KO
phenotype - anti-DNA Ab’s and less sensitive to
some bacteria 2o increased inflammation
 Proteins of the complement
system (nomenclature)

• C1(qrs), C2, C3, C4, C5, C6, C7, C8, C9

• factors B, D, H and I, properdin (P)
• mannose binding lectin (MBL), MBL associated
serine proteases (MASP-1 MASP-2)
• C1 inhibitor (C1-INH, serpin), C4-binding
protein (C4-BP), decay accelerating factor
(DAF), Complement receptor 1 (CR1), protein-
S (vitronectin)
Biological effects of C5a
Sentinel innate immune cells of tissues

Induction of
Inflammation
following
recognition of or mast cell

pathogens

Inflammatory mediators:
Cytokines, chemokines
and lipids
TNF
NOD (nucleotide-binding oligomerization domain) 1 & NOD2
recognize peptidoglycan substructures and promote innate
immune responses

NOD1 and NOD2 are

intracellular molecules and
resemble some plant disease
resistance proteins;

Mutations in the NOD2 gene

increase susceptibility to
Crohn’s disease (a form of
inflammatory bowel disease)
 Toll-like receptors and recognition of
pathogens

LRR (leucine-rich repeats) extracellular domain

TIR (Toll/Interleukin-1 receptor) domain inside
 Toll-like
receptor
signaling
pathways

MyD88(Myeloid
differentiation primary
response protein)
pathway and
TRIF pathway;
Transcription
factors and
MAP kinases
 Pathways of NF (Nuclear Factor)-kB
activation •B-Cell Activation Factor

Inhibitor of kB kinase

Classical Alternative
pathway Pathway
(some TNF
receptor
family
members)
Genes regulated by NF-kB
 Inflammation
 Pro-inflammatory cytokines (TNF, IL-1) signal to
endothelial cells to make them:
 Leaky to fluid (influx of plasma; containing antibodies,
complement components, etc.)
 Sticky for leukocytes, leading to influx of neutrophils first,
then monocytes, lymphocytes
 Systemic effects: fever, acute phase response

ACUTE PHASE RESPONSE: cytokines induce

production of particular proteins by the liver,
response to severe infection
Leukocyte recruitment to sites of inflammation
 FUNCTION OF COMPONENTS AND CELLS IN THE INFLAMMATORY EXUDATE

Component Function

Bradykinin, histamine, leukotrienes, Inflammatory Agents (IA) which act on the vascular
serotonin, prostaglandins system to produce increased blood flow and permeability

Fibrin: (formed from fibrinogen in

coagulates and may localize an invading pathogen
plasma)
Lysozyme causes lysis of bacterial cell walls
various activities increase the inflammatory response and
Complement lead to increased phagocytosis and complement-mediated
lysis of cells
block colonization by pathogens; neutralize microbial
Antibodies (in immune individuals) toxins or viruses; opsonize pathogens making them more
susceptible to phagocytosis; activate complement
cause fever acting on the thermo-regulatory control
Pyrogens, including endogenous centers in the hypothalamus. (Interleukin-1, which is
pyrogen (Interleukin 1) produced by macrophages, also promotes activation and
mitosis of B-cells and T-cells)
migrate to focus of infection and ingest and destroy
Neutrophils
foreign agents by phagocytosis

engulf and destroy infective agents, process antigenic

Macrophages
components and convey them to lymphocytes

Immunocompetent lymphocytes (B-cells for direct participation in immunological responses (AMI

and T-cells) and CMI)
 Sepsis Syndrome
 Bacterial septicemia leads to activation of TLRs on
monocytes in the blood
 Systemic release of TNF and IL-1 leads to
“inflammation” all over the body
 Shock from loss of blood pressure (vasodilation and
leakage of fluid into tissues)
 TLRs also induce coagulation (via tissue factor)
 The combination of effects can lead to multi-organ failure
and death
Sepsis syndrome - a systemic
response to infection

Fever, tachycardia,
tachypnea, hypotension,
organ dysfunction due to
widespread endothelial
injury

Gram negative bacilli >

Gram positive cocci > fungi
> viruses
 Septic shock

SR Mφ HPCR
TNF
IL-1 PROCOAGULANT
IL-6 APC
LPS IL-8
CD14 MyD88 NFκB
LPS

TLR4 Lipoproteins

LPS
LB
P
LBP
LPS
sCD14 IL-1, IL-6, IL-8
SELECTINS
TLR
NFκB
Inflammation: Neutrophils vs. Monocytes

 Acute inflammation is initially characterized as rich in

neutrophils; later it is more monocytes. This is
controlled by which chemokines are expressed by the
endothelial cells.
 Neutrophils are dedicated to killing bacteria and are
short-lived. They often damage host tissue as a
byproduct.
 Monocytes are multi-potential, depending on cytokine
signals:
+IFN-g: assume a vigorous killing phenotype similar to
neutrophils
+IL-10: assume a wound-healing type phenotype (to
clean up after infection is cleared)
+GM-CSF: assume a dendritic cell phenotype and
propagate adaptive immune priming
Opsonins and Phagocytic receptors

Opsonins
Complement components (C3b)
Collectins (mannose-binding lectin)
Antibodies

Phagocytic receptors
Receptors for opsonins (complement
receptors, Fc receptors)
Pattern recognition receptors
(mannose receptor, etc.)
Receptors for apoptotic cells
Phagocytosis
and killing

Primary granules:
Antimicrobial peptides
Lysozyme
(degrades peptidoglycan)
Proteases (elastase,etc.)

Secondary granules:
phagocyte oxidase

Lysosomes:
Digestive enzymes
 Phagocytosis and killing
•Phagocyte oxidase (=NADPH oxidase): makes reactive
oxygen intermediates (superoxide anion, hydrogen peroxide)
+Myeloperoxidase: hypochlorous acid

•Inducible Nitric oxide synthase (iNOS): makes reactive

nitrogen intermediates (NO)

phagolysosome
Chronic granulomatous
cytoplasm disease: genetic defect in
phagocyte oxidase (most
commonly gp91,
which is X-linked)
Production of interferon by infected cells

RIG-I, MDA-5: have RNA helicase domain and CARD

domain
Anti-viral effects of interferon a/b
 Plasmacytoid dendritic cells
 Many cell types produce small amounts of type
1 interferons upon infection
 There is a dendritic cell subtype (“plasmacytoid
dendritic cell”; “natural interferon-producing
cell”) that produces 100-1000x more interferon
upon contact with viruses, does not need a
productive infection.
 Also produces a large amount of TNF
 Recognition mechanism: probably TLR7, TLR9
 Mechanisms of killing
virus-infected cells
•Virus replication can induce apoptosis of cell
–p53 for DNA viruses (unscheduled DNA replication);
Caspase 12 (ER perturbation)
•Virus inhibition of cell protein synthesis makes cell sensitive
to TNF-induced apoptosis
•Virus replication can induce stress-activated proteins to
induce killing by natural killer (NK) cells
•Peptides from viral proteins are displayed on cell surface for
killing by CTL (adaptive immunity)
•NK cells recognize and kill cells lacking MHC molecules (to
avoid viral evasion of CTL)
Antigens
Factors Influencing Immunogenicity
Contribution of the Immunogen
 Foreignness
 Size
 Chemical Composition
 Primary Structure Sequence determinants
 Secondary Structure
 Tertiary Structure Conformational
 Quarternary Structure determinants
 Physical Form
 Particulate > Soluble
 Denatured > Native

 Degradability
 Ag processing by Ag Presenting
Cells (APC)
Chemical Nature of Immunogens
 Proteins
 Polysaccharides
 Nucleic Acids
 Lipids
 Some glycolipids and phosopholipids can be
immunogenic for T cells and illicit a cell
mediated immune response
 Types of Antigens

 T-independent  T-dependent
 Polysaccharides  Proteins
 Properties • Structure
 Polymeric structure
 Polyclonal B cell
 Examples
activation  Microbial proteins
 Yes -Type 1 (TI-1)  Non-self or Altered-self
 No - Type 2 (TI-2) proteins
 Resistance to degradation
 Examples
 Pneumococcal
polysaccharide,
lipopolysaccharide
 Flagella
Antigenic Determinants
Recognized by B cells and Ab F
e

 Composition
 Proteins, polysaccharides, nucleic acids,
haptens
 Sequence (linear) determinants
 Conformational determinants
 Size
 4-8 residues
 Number
 Limited (immunodominant epitopes)
 Located on the external surfaces of the Ag
Antigenic Determinants
Recognized by T cells
 Composition
 Proteins
(some lipids)
 Sequence determinants
 Processed

 MHC presentation (lipid presentation by MHC-like

CD1)
 Size
8 -15 residues
 Number
 Limited to those that can bind to MHC
 Immunoglobulins:
Structure and Function
Immunoglobulins:Structure and Function

 Definition:Glycoprotein molecules that are

produced by plasma cells in response to an
immunogen and which function as antibodies
 Ag binding
 Can result in protection
 Valence
 Effector functions
 Fixation of complement (Usually require Ag binding)
 Binding to various cells
Clinical Implications of Human
Immunoglobulin Classes -IgG
 1. Increases in:
 a) Chronic granulomatous infections
b) Infections of all types
c) Hyperimmunization
d) Liver disease
e) Malnutrition (severe)
f) Dysproteinemia
g) Disease associated with hypersensitivity granulomas, dermatologic
disorders, and IgG myeloma
h) Rheumatoid arthritis
 2. Decreases in:
 a) Agammaglobulinemia
b) Lymphoid aplasia
c) Selective IgG, IgA deficiency
d) IgA myeloma
e) Bence Jones proteinemia
f) Chronic lymphoblastic leukemia
Clinical Implications of Human
Immunoglobulin Classes-IgM
 1. Increases (in adults) in:
 a) Waldenström's macroglobulinemia
b) Trypanosomiasis
c) Actinomycosis
d) Carrión's disease (bartonellosis)
e) Malaria
f) Infectious mononucleosis
g) Lupus erythematosus
h) Rheumatoid arthritis
I) Dysgammaglobulinemia (certain cases)
 In the newborn, a level of IgM above 20 ng./dl is an indication of in utero
stimulation of the immune system and stimulation by the rubella virus,
the cytomegalovirus, syphilis, or toxoplasmosis.
 2. Decreases in:
 a) Agammaglobulinemia
b) Lymphoproliferative disorders (certain cases)
c) Lymphoid aplasia
d) IgG and IgA myeloma
e) Dysgammaglobulinemia
f) Chronic lymphoblastic leukemia
Clinical Implications of Human
Immunoglobulin Classes- IgA
 1. Increases in:
 a) Wiskott-Aldrich syndrome
b) Cirrhosis of the liver (most cases)
c) Certain stages of collagen and other autoimmune disorders such as
rheumatoid arthritis and lupus erythematosus
d) Chronic infections not based on immunologic deficiencies
e) IgA myeloma
 2. Decreases in:
 a) Hereditary ataxia telangiectasia
b) Immunologic deficiency states (e.g., dysgammaglobulinemia,
congenital and acquired agammaglobulinemia, and
hypogammaglobulinemia)
c) Malabsorption syndromes
d) Lymphoid aplasia
e) IgG myeloma
f) Acute lymphoblastic leukemia
g) Chronic lymphoblastic leukemia
Clinical Implications of Human
Immunoglobulin Classes -IgD

 1. Increases in:
 a) Chronic infections
b) IgD myelomas
Clinical Implications of Human
Immunoglobulin Classes-IgE

 1. Increases in:
 a) Atopic skin diseases such as eczema
b) Hay fever
c) Asthma
d) Anaphylactic shock
e) IgE-myeloma
 2. Decreases in:
 a) Congenital agammaglobulinemia
b) Hypogammaglobulinemia due to faulty
metabolism or synthesis of immunoglobulins
Antigen Presentation and MHC Molecules
 Functions of T lymphocytes
 Primary defense against intracellular microbes
 Activation of other cells (phagocytes, B cells)
 Killing of infected cells (i.e., CTL)

Key features:
 Mediated by interactions with other cells
 Allows surface molecules, cytokines to act at short 
range (enhances specificity)
 Different classes of T lymphocytes are most 
effective against different types of microbes
 Phagocytosed (extracellular) microbes: helper T cells 
stimulate antibody production, macrophages
 Cytoplasmic (endogenous microbes): CTLs kill infected 
cells and eliminate reservoirs of infection
 The challenge for T lymphocytes

 Very few lymphocytes in the body are specific for 
any one microbe (or antigen)
 Specificity and diversity of antigen receptors: the immune 
system recognizes and distinguishes between 107 ­ 109 
antigens
 The frequency of antigen responsive lymphocytes is 
typically 1 in 105 to 106

 Lymphocytes must be able to locate microbes that 
enter anywhere in the body
APCs are Required to Present Antigenic Peptide 
Fragments to T cells
Mannose receptors, and expression of
C­type Lectin receptors CCR7, and upregulation of 
and Toll­like receptors MHC I & II, and coreceptors
Why are dendritic cells the most efficient APCs 
for initiating immune responses
 Location
 At sites of microbe entry (epithelia), tissues
 Express receptors (CCR1,2, and 5) that recognize 
inflammatory cytokines
 Receptors for capturing microbes
 Such as mannose and C­type lectin receptors and Toll­
like receptors (TLRs) which function as pattern 
recognition receptors and have very active endocytic 
machinery
 Migration to T cell zones of lymphoid organs
 Role of CCR7 (ligands are Mip­3β and SLC)
 Co­localize with naïve T cells
 Maturation during migration
 Increase levels of MHC molecules, induce costimulators 
(B7 molecules, CD40) and decrease endocytic capacity
 Conversion from cells for antigen capture into cells for 
antigen presentation and T cell activation
 Dendritic cell subsets
 Immature dendritic cells capture antigens from 
sites of entry 

 Mature (activated) DCs present antigen to and 
activate naïve T cells in lymphoid organs

 DC1, DC2 subsets may stimulate differentiation to 
different T cell subsets (Th1, Th2)

 Some DCs (i.e., immature) may induce tolerance

 Problems:
 Lack of definitive markers

 Most studies based on culture derived DCs
Maturation of Dendritic Cells

MHC
Functions of Different Antigen Presenting Cells
 MHC
 A genetic locus discovered on the basis of 
transplantation
 Different individuals express products of different MHC 
alleles and reject grafts from one another
 Human MHC: HLA (human leukocyte antigens)
 Mouse MHC:H2
 The peptide display molecules of the immune 
system
 Different alleles of MHC molecules display distinct 
but overlapping sets of peptides
 Determines which protein antigens are recognized in 
different individuals
 MHC molecules determine how antigens in different 
cellular compartments are recognized by different 
classes of T cells
 MHC (major histocompatibility complex)­restricted 
antigen recognition by T cells
 A T lymphocyte recognizes an antigen on an antigen­
presenting cell (APC) that also expresses an MHC allele 
that the T cell sees as “self”
 First indication that T cells recognize complex of protein 
(peptide) antigen bound to MHC molecules

 Antigen receptors of T cells have dual specificities: 
 1. For peptide antigen (responsible for specificity of immune 
response), and 
 2. For polymorphic residues of self MHC molecules (responsible 
for MHC restriction)

 T cells learn self MHC restriction during maturation in the 
thymus: only T cells that “see”  MHC molecules in the thymus 
(can only be self MHC molecules) are selected to survive
 Features of Class I and Class II MHC Molecules
Feature Class I MHC Class II MHC

Polypeptide chain α (44­47 kD) α (32­34 kD)

β2­microglobulin (12kD)  β (29­32 kD)

Polymorphic residues α1 and α2 domains α1 and β1 domains

Coreceptor α3 domain binds CD8 β2 domain binds CD4

Source of peptide Cytosol (biosyntheic pathway) Endocytic/lysosomal 

pathway

Peptides bound 8­11 residues 10­30 residues

Nomenclature
Human HLA­A, ­B, or C HLA­DR, ­DQ, ­DP
Mouse H­2K, H­2D, H­2L I­A, I­E

Types of APCs All nucleated Cells DCs, Macrophages, 

B cells
 Some important properties of MHC molecules
 MHC molecules are the immune system’s mechanism 
for displaying peptide antigens to T lymphocytes
 Highly polymorphic genes: large number of alleles in the 
population
 Co­dominantly expressed: each cell has six class I 
molecules (3 from each parent) and 10­20 class II molecules 
(3 from each parent + some hybrid molecules)
 Class I MHC molecules are expressed on all nucleated cells
 Class II MHC molecules are expressed on few cells types 
(specialized APCs, e.g. dendritic cells; B lymphocytes, 
macrophages)
 Stable expression of MHC molecules on cell surfaces 
requires the peptide cargo
 MHC molecules present foreign and self peptides
 Expression of Class II MHC molecules, in particular, is up­
regulated by activation of the innate immune response (IFNs, 
etc.)
Enhancement of Class II MHC Expression by IFNγ

Similar effects
on class I MHC and 
the activation of 
CD8 T cells.
Presentation of Extracellular and Cytosolic Antigens
 Antigen processing

 Conversion of native antigen (globular protein) 
into peptides capable of binding to MHC 
molecules

 Occurs in same cellular compartments as 
synthesis and assembly of MHC molecules
 Determines which source of antigen generates 
peptides that are displayed by class I or class II 
MHC
 Uses cellular organelles that serve basic 
“housekeeping” functions in most cells
The class II MHC pathway of processing of
internalized vesicular protein antigens
 The class I MHC pathway of processing
of endogenous cytosolic protein antigens
How class I­ and class II­associated antigen presentation
influence the nature of the host T cell response
 Functions of APCs
 Capture antigens and take them to the “correct” 
place
 To peripheral lymphoid organs, through where naïve 
lymphocytes circulate

 Display antigens in a form that can be recognized 
by specific lymphocytes
 For T cells: MHC­associated peptides (cytosolic peptides 
to class I, vesicular peptides to class II)
 For B cells: native antigens; APCs include macrophages, 
follicular dendritic cells in germinal centers

 Provide “second signals” for T cell activation
 Costimulators and cytokines induced by microbes; ensure 
that T cells respond best to microbial antigens
B cell mediated immune
response
 B - LYMPHOCYTE
•Production of antibody in response to
infection is the main contribution of B
(Bursa of Fabricius)
Fabricius cells to adaptive
immunity
•Each B cell is programmed to make one
specific antibody
•Stimulation by specific antigen is required
for secretion of antibody
GENERATION AND SELECTION OF
B CELLS
1. Pro – B cells
Rearrangement of heavy-chain immunoglobulin
2. Immature B cell
IgM molecule expressed on cell surface, Both pro-B and immature B
cells-independent of antigen
3. Selection for self tolerance
B cells (newly expressed surface IgM) stimulated by self antigens
are:Eliminated or inactivated
they are prevented from developing further and secreting antibodies
that bind self cells or tissues
4. Survival in periphery
consequence of competition ,most B cells die by apoptosis
5. Mature B cells (or naïve B cells) express IgM
6. Activated B cells- cells that encounter their specific antigen
B-Cell Subtype
 Plasma B cells (also known as plasma cells) are large B
cells that have been exposed to antigen and are
producing and secreting large amounts of antibodies,
 Memory B cells are formed from activated B cells that
are specific to the antigen encountered during the
primary immune response.
 B-1 cells express IgM in greater quantities than IgG and
its receptors show polyspecificity, found predominantly in
the peritoneal and pleural cavities.
 Recirculating follicular B cells (aka “conventional B
cells”, B2 cells): circulate between LN follicles and blood
conventional B cells most texts refer to.
 Marginal zone B cells: reside in marginal zone of
spleen where they can respond to particulate antigen in
blood (bacteria, etc.)
B cells mediated immune response

Humoral immunity(HI) or antibody mediated

immunity:
The total immunological reaction that B cells
recognize antigen, then activate, proliferate,
differentiate into plasma cells and produce Ab.

 B2 cells mediated immune response to TD-Ag

 B1 cells mediated immune response to TI-Ag
 Immune response of B2 cell to TD-Ag

Characteristics of TD-Ag:
 Possess T cell epitope and B cell epitope
 Need Th cells participation
 Both CMI and HI
 Produce several types of antibodies: IgG
 Produce immune memory
 B cells recognize antigen

BCR directly recognize the

conformational determinant, capture Ag
and present Ag signal to Th cells
No APC , no MHC restriction
Specificity
 B cells activation, proliferation and
differentiation

B cell activation: double signals

 First signal : antigen signal
BCR--conformational determinant on the
surface of Ag
Igα/Igβtransduct first signal
CD19/CD21 (co-receptor) binds to C3d on Ag
 Second signal: co-stimulatory signal
The CD40 on B cells binds to CD40L on
activated T cells
 Antigen

CD40
B T helper TCR
B MHC II
cell cell
cell
1. Antigen presentation to
Th cell B7 CD28

CytokiImmunoglobulin 2. B7 expressed
receptor 3. Th cell is
ne
recep activated
tor and
expresses
CD40
CD40 ligand,
ligan Cytokines
d secreted
B B B B T helper
cell cell cell cell cell
5. B cell activated
Cytokine
ells proliferate, differentiate, secrete Ig
Interaction between Th cell and B cell

B cells act on Th cells:

 B cells present Ag to Th cells
 B cells provide B7 for Th cells

Th cells act on B cells:

 Activated Th cells provide co-stimulatory molecule
for B cells: CD40L—CD40
 Activated Th produce Cks （ IL-4 、 IL-5 、 IL-
6 、 IL-10 、 IL-13 ） which help B cells proliferate
and differentiate
 B cell Th cell

Th cell

Ag processing activation

B cell
activation

Interactions between B cell and Th cell

 Cytokines

Memory B cell

Activation Proliferation Differentiation

 Stage of effect----the function of Ab

1. Neutralization
2. ADCC—NK,macrophage
• Opsonization – macrophage
• Activate complement system
5. Participate in hypersensitivity-I,II,III
1. Neutralization:
* to neutralize microbial toxins and animal venoms
* to prevent viruses and bacteria from infecting cells
2. ADCC—NK

Antibody-coated target cells can be killed by natural killer cells(NK cell) in

antibody-dependent cell-mediated cytotoxicity, that is called ADCC.
3.Opsonization – macrophage
Fc receptors on phagocytes trigger the uptake of antibody-coated bacteria.
As a result, this action enhance phagocytosis of the bacterium.
4.Activation of complement
Complement can be activated to directly lyse bacteria by the presence of
antibodies bound to the bacteria.

Complement proteins bind to antibodies.

5. Participate in hypersensitivity
IgE binds to high-affinity Fc receptors on mast cells and basophils, and leads to
the rapid release of granules containing inflammatory mediators into surrounding
tissue, cause hypersensitivity
Rules of humoral immunity

1. Primary response

2. Secondary response
 ____________________________________________
Primary IR Secondary IR
____________________________________________
 latent phase long short
 peak concentration low high
 maintaining time short long
 Ab type mainly IgM mainly IgG
 Ab titer low high
 affinity low high
____________________________________________
Primary and secondary antibody responses to protein
antigens differ qualitatively and quantitatively
Cell-mediated cytotoxic
responses
Humoral and cellular immunity

 The cell mediated and humoral responses play

different roles in protecting host.
 The humoral responses mediated by antibodies can
bind and neutralize antigens on the surface of cells
and in the extracellular spaces.
 Thus primary domain of antibodies lies outside the
cells.
 The principal role of cell-mediated immunity is to
detect and eliminate cells that harbor intracellular
pathogens such as viruses and mycobacteria, or
altered-self cells such as tumor cells.
Cell-mediated Immunity (CMI)

 Just as B cells differentiate into plasma cells

to become “effective”, so resting T cells
differentiate into memory/effector cells.
 Effects of cells involved in CMI include
cytokine secretion (help) and direct
cytotoxicity to affected cells (CTLs)
 These effector T cells may be
 (a) Helper T cells
 (b) Cytotoxic Cells
 Bothantigen specific and antigen-
nonspecific cells can contribute to the cell-
mediated immune response.
Cells of CMI

 Antigen specific cells of cellular immunity

 – Cytokine-secreting CD4+ TH cells which mediate
delayed type hypersensitivity .
 – CD8+ cytotoxic T lymphocyte (TC cells or CTLs)
 Antigen-nonspecific cells of cellular immunity
 Natural Killer (NK) Cells
 Nonlymphoid cell types such as macrophages,
neutrophils, and eosinophils .
 Cellular immune responses are not completely
independent of antibodies as macrophages,
neutrophils and eosinophils use antibodies in
Antibody-Dependent Cell-Mediated Cytotoxicity
(ADCC).
Helper T cells (TH cells) TH1, TH2, TH17,TFH Cytokines secretion, regulate or
"help" the immune response or
one of other subsets.

Cytotoxic T cells (TC cells, or CD8+ T cells destroy virally infected cells and
CTLs). tumor cells, implicated in
transplant rejection, transformed
into regulatory T cells

Memory T cells central memory T cells (TCM quickly expand to large numbers
cells) and effector memory T of effector T cells upon re-
cells (TEM cells). exposure to their cognate antigen

Regulatory T cells (Treg cells naturally-occurring Treg cells maintenance of

or suppressor ) (CD4+CD25+FoxP3+ Treg cells) immunological tolerance
and the adaptive Treg cells Tr1
cells or Th3 cells

Natural Killer T cells (NKT bridges the adaptive immune

cells) system with the innate immune
system. Th and Tc cells

γδ T cells (intraepithelial Vγ9/Vδ2 T cells & γδ T cells are not MHC

lymphocytes- IELs) Non-Vδ2 γδ T restricted

Autoaggressive T cells TCR revision. Revision can

(CD40) be responsible for expanding
the T cell repertoire, but also
could result in the generation
of autoaggressive T cells.
Generation of effector CTLs
Stages in CTL-mediated killing

 After antigen specific

recognition, LFA-1 on
CTL binds to ICAMs on
the target cell
membrane forming a
conjugate.
 Antigen mediated CTL
activation converts
LFA-1 from a low- •Sequence of events:
avidity state to a high- •1. Conjugate formation
avidity state and persist •2. Membrane attack
in this stage for only 5- •3. CTL dissociation
10 minutes. •4. Target cell destruction
Cell Death induced by CTLs
 • Effector CTLs induce target cell death in 2 ways
 Directional delivery of cytotoxic proteins (perforin &
granzymes) by CTLs to target cells
 Fas mediated cytotoxicity
 • Cell death by locally secreted granules:
 Perforin-which forms complement-like pores in the
membranes of target cells
 Granzymes/Fragmentins – serine proteases which digest
the intracellular contents of the target cell and induce
apoptosis/DNA fragmentation in the target.
 Note: CTL-Ps lack cytoplasmic granules (granzymes
& perforins); They appear in effector CTL only after
activation of CTL-Ps .
Perforin & granzyme mediated killing
 Perforin exihibits some  Perforin mediates granzyme entry in
sequence homology with the 2 ways
terminal C9 component of  1. Pore formation in the cell

complement system. membrane of the target

 2. Perforin assisted pathway:
 The membrane pores formed by
Perforin is necessary for release of
perforin are similar to those granzyme B from the vesicle into
observed in complement- the cytoplasm of target cell
mediated lysis.
Fas mediated cytotoxicity of CTLs

 Some CTL lines lack perforin and granzymes. In

these, cytotoxicity is mediated by Fas.
 Fas is a transmembrane protein present on the
target cells.
 Fas can deliver a death signal (apoptosis of target
cells) when crosslinked by its natural ligand called
‘Fas ligand’ (FasL) present on the membrane of
activated CTLs.
 A feature of cell death by apoptosis is the
involvement of the ‘caspase’ family of cysteine
proteases.
 CTLs use ‘perforin/granzymes’ and ‘Fas ligand’ to
initiate ‘caspase’ cascade in their targets to induce
apoptosis.
Target cells apoptosis stimulated by
CTLs
Natural Killer Cells
 NK cells are specialized cells which nonspecifically
kill tumor & intracellular pathogen or virally-infected
cells.Are lymphoid cells derived from bone marrow
& make up 5-10% of the circulating lymphocyte
population.
 NK cells produce a number of cytokines which play
important role in both innate and adaptive immunity
 IFN-γ production by these cells can influence the innate
immunity by activation of macrophages.
 IFN-γ by NK cells enhance TH1 cell development via
induction of IL-12 by macrophages & dendritic cells.
 contain perforin and granzymes and express FasL.
 Despite some similarities with CTL, they do not
express CD3 and TCR.
 NK-cell response generates no immunologic
memory.
Opposing-signals model of NK cells

 NK cells employ 2 different

categories of receptors:
 Inhibitory receptors: deliver
inhibition signals to NK cells
 Activating receptors: deliver
activation signals to NK
cells
 According to current theory
of ‘opposing signals model’,
there are many different cell
receptors for activation
signals and for inhibitory
signals.
 The balance between
activating and inhibitory
signals enable NK cells to
distinguish healthy cells
from infected or cancerous
cells.
NKT cells
 Recently discovered cells. Have characteristics
common to both the CTL and the NK cells. Role in
immunity remains to be defined.
 NKT cell has TCR complexes on its surface but few
other qualities common to T cells.
 NKT cells considered part of the innate immune
system based on the following properties
 TCR on the human NKT cells is invariant with α and β
chains encoded by specific gene segments. Sometime
referred as invariant or iNKT cells.
 TCR does not recognize MHC-bound peptides but rather a
glycolipid presented by nonpolymorphic CD1d molecule.
 Do not form memory cells.
 Do not express a number of T cell markers but do express
characteristic of NK cells.
Antibody-Dependent Cell mediated
Cytotoxicity (ADCC)
 This type of cell killing is dependent on Fc receptors
on the surface of cytotoxic cells, which recognize
the antibody bound to the target cell.
 This antibody binding to Fc receptor triggers
degranulation of these cells and subsequently cause
lysis of the target cells. This is why it is called
ADCC.
 ADCC is a characteristic of NK-cells, monocytes,
macrophages, eosinophils & neutrophils.
 Although these cytotoxic cells are non-specific for
antigen, the specificity of the antibody directs them
to specific target cells.
 Mechanisms of ADCC

 •ADCC appears to
involve a number of
different
mechanisms, but
not complement
mediated lysis.
 •Important in killing
virus infected cells
and helminths.
 Sources: All the material from internet.