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Lecture Notes By Dr.

Santosh Kumar

03/08/11

Lecture Notes By Dr.Santosh Kumar

03/08/11

Immune Response Is Antigen-driven

Lecture Notes By Dr.Santosh Kumar

03/08/11

Bacterial
O antigens of Salmonella
Flagellin Toxins

Viral
Viral capsid proteins Viral envelope glycoproteins

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Substance capable of binding specifically to immune components.

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Antigen
Any substance that can bind to an antibody or T cell receptor

Immunogen
Any substance that can elicit an immune response All immunogens are antigens Not all antigens are immunogens, i.e. haptens

Lecture Notes By Dr.Santosh Kumar

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What affects Immunogenicity ?

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Immunogenic?
Proteins Carbohydrates

almost always potentially usually poorly (Some glycolipids and phosopholipids can be immunogenic for T cells and illicit a cell mediated immune response)

glycoproteins
Lipids

Nucleic

Acids

poorly (single stranded/protein complex good)

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High molecular weight <1000D-Not Immunogenic (penicillin) 1000-6000D May or May not be immunogenic (insulin) >6000D-Generally immunogenic (albumin, Tetanus toxin) Chemically complex homopolymers not generally immunogenic Ex: Polylysine-30,000 D, Poly-D-Glutamic acid50,000D Degradable Foreignness

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Bovine albuminspecific Immature Lymphocyte Bovine


albumin

Response to Immunization

Apoptosis

NO

No Tetanus Toxoid Antigen

Yes

Toxoid-Specific Immature Lymphocyte

Mature Lymphocyte
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Response to Immunization

Bovine Albumin

Cow Sheep Chicken

NO Yes ++ Yes +++++

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Foreignness Size

Chemical Composition
Primary Structure Secondary Structure Tertiary Structure Quarternary Structure Sequence determinants Conformational determinants

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Foreigness Size Chemical Composition Physical Form

Particulate (more susceptible to processing) > Soluble Denatured > Native

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Foreigness Size Chemical Composition Physical Form Degradability

Ag processing by Ag Presenting Cells (APC)

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Genetics
Variation in genes coding for MHC, receptors & regulatory proteins

Species Individual
Responders vs Non-responders The species or individuals may lack or have altered genes that code for the receptors for antigen on B cells and T cells or they may not have the appropriate genes needed for the APC to present antigen to the helper T cells

Age
very young and the very old age poor response

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Dose (booster dosing increases immune response)


Low Zone Tolerance High Zone Tolerance

Route
Subcutaneous > Intravenous > Intragastric Alters the nature of response (e.g., i/v goes to spleen; s/c goes to regional lymph nodes)

Adjuvant
Substances that enhance an immune response to an Ag

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Low-Zone and High-Zone Tolerance

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Polysaccharides

Properties Polymeric structure (same antigenic determinant repeated many times ) Polyclonal B cell activation Yes -Type 1 (TI-1) No - Type 2 (TI-2) Resistance to degradation

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Induce IgM synthesis but not other adaptive immune responses (e.g., do not elicit IgG or memory cells) Human infants make poor responses to carbohydrate antigens, so early vaccinations with bacterial polysaccharide antigens employ protein carriers Examples Pneumococcal polysaccharide, lipopolysaccharide Flagella

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Structure - few copies of many different antigenic determinants recognized by different B cells and induce a polyclonal antibody response Activate helper T cells, consequently induce more B cell antibody production, synthesis of IgG or IgA, and generation of memory B and T cells Examples Microbial proteins Non-self or Altered-self proteins
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Proteins

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Low mw molecules. Antibiotics, drugs Not immunogenic (but which can react with the products of a specific immune response), unlessconjugated to high mw compounds (carriers) to gain immunogenicity

HAPTENS
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Not immunogenic, Have the property of antigenicity but not immunogenicity Uses anti-hapten Abs used to detect certain important biomolecules in the body (e.g., Home pregnancy kit contains Anti-HCG Abs to detect HCG in women's urine) Harmful effects drug allergies formation and deposition of IgE on the mast cells & basophils, against the hapten, e.g. allergic reactions against penicillin, streptomycin, certain sulpha drugs, some anaesthetics, etc.

CARRIER HAPTENS
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Portion of an antigen that combines with the products of a specific immune response Discrete immunologically active sites on immunogens recognized by antibodies or T cell receptors Macromolecules contain many epitopes with different immunogenicities Immunogenicity can vary between individuals and populations. Some epitopes are immunodominant

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Overlapping Non-overlapping

Allosteric Linear Conformational Neoantigen

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Composition
Proteins, polysaccharides, nucleic acids, haptens Sequence (linear) determinants (by the primary sequence of residues in the polymer ) Conformational determinants (by the secondary, tertiary or quaternary structure of the molecule ) Located on the flexible regions of an immunogen No MHC required Binds to soluble Ags

Size
4-8 residues
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Composition Size Number

Limited (immunodominant epitopes influenced by intrinsic topography of epitope & animals regulatory mechanism) Located on the external surfaces of the Ag (limited to those portions of the antigen that are accessible to antibodies )

Fe

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Composition

Proteins - primary sequence of amino acids & (some lipids) do not recognize polysaccharide or nucleic acid antigens Sequence determinants

Processed (need not be located on the exposed surface of the antigen since recognition of the determinant by T cells requires that the antigen be proteolytically degraded into smaller peptides ), APC processing MHC presentation (lipid presentation by MHC-like CD1)

Size

Number

8 -15 residues Limited to those that can bind to MHC


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Via Surface Immunoglobulin Recognize and bind FREE ANTIGEN SOLUTION B Cells bind Native Protein Antigen

IN

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Antigen Recognition By B Lymphocytes

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B Cell Antigen Recognition


Antigen BCR B Cell

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Portion

of Ag that binds receptor Antigenic determinant 5-22 amino acids Multideterminant Ags have many different epitopes on the same molecule

binding site
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Continuous/Linear-Single

polypeptide segment. Conformational/DiscontinuousAmino acids from different parts of the Sequence brought together by Protein folding.

binding site

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Administration of Protein in Adjuvants - a substance that, when mixed with an antigen and injected with it, serves to enhance the immune response to the antigen. Incomplete Freunds adjuvant-oil-in- water emulsion Complete Freunds adjuvant-oil-in-water emulsion plus dead Mycobacteria Aluminum hydroxide gel

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Delayed Release-Prolonged Antigen Persistence Increase the size of the antigen by causing aggregation Enhance Costimulatory Signals (costimulation enhancement of immune response that results when CD80 & CD86 on a macrophage interacts with CD28 on a responding T-cell) Induce Granuloma formation Stimulates Lymphocytes Nonspecifically

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Antibodies, Unlike TCRs, Bind Continuous (Linear) Or Conformational Epitopes


Usually antigens recognized by antibodies are in their native configuration. Antibodies bind on the surface of the antigen (e.g., amino acids that are buried in the center of a globular protein are not accessible by antibodies).. Antibodies bind linear and conformational epitopes. Antibodies can bind proteins, carbohydrates, lipids and nucleic acids (essentially any macromolecule). (most antibodies bind proteins or
carbohydrates)

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Unlike Antibodies, The TCR Binds Only Continuous (Linear) Epitopes


The TCR binds peptides from processed protein (proteins that have been chopped-up). Accordingly, TCRs can bind peptides that are derived from the surface of a proteins or peptides from the interior of the protein. Because of processing and presentation of peptides, the TCR binds only linear epitopes. TCRs can bind non-surface epitopes buried in the center of a big protein and can bind peptides from proteins from inside of bacteria and viruses. TCRs bind only peptides [not nucleic acids, not lipids and not carbohydrates (rare exceptions)] because MHC presents only peptides (not nucleic acids, not lipids, not carbohydrates).
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Conventional Antigen

Superantigen

Monoclonal/Oligoclonal T cell response 1:104 - 1:105

Polyclonal T cell response 1:4 - 1:10

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Superantigens

Bacterial enterotoxins Staphylococcal, Streptococcal and Mycobacterial Minor lymphocyte stimulating (Mls) antigen Endogenous mouse retroviral products Unidentified endogenous antigens

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Comparison of Superantigens and Convential Peptide Antigens


Conventional Antigens Frequency of responsive T cells Interaction with the TCR Interaction with MHC MHC restricted recognition Requirement for processing Binding to peptide groove in MHC 1 in 104 to 105 + + + + + Superantigens 1 in 4 to 20 + + -

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Definition Examples Staphylococcal enterotoxins Staphylococcal toxic shock toxin Staphylococcal exfoliating toxin Streptococcal pyrogenic exotoxins

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Diseases Caused by Superantigens

Toxin Staphylococcal enterotoxins (SE) A, B, C1, C2, C3, D and E Toxic Shock Syndrome Toxin (TSST1) Exfoliating Toxins A and B Pyrogenic exotoxins A, B, C M. arthritides mitogen

Organism S. aureaus S. aureus S. aureus S. pyogenes M. arthritides

Disease Food poisoning, Shock Toxic Shock Syndrome Scalded Skin Syndrome Fever, Rash, shock Shock

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Adaptive Immune System Discrete Determinants Reacts with a specific pathogen Innate Immune System Broad Molecular Patterns Reacts with a variety of pathogens PAMPs Pathogen Associated Molecular Patterns PRRs Pattern Recognition Receptors

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PAMP

PRR

Biological Consequence of Interaction Opsonization; Complement activation Opsonization; Complement activation Phagocytosis Macrophage activation; Secretion of inflammatory cytokines
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Microbial cell wall Complement components Mannose-containing Mannose-binding carbohydrates protein Polyanions Lipoproteins of Gram+ bacteria Yeast cell wall components Scavenger receptors TLR-2 (Toll-like receptor 2)

Lecture Notes By Dr.Santosh Kumar

PAMP Double stranded RNA TLR-3

PRR

Biological Consequence of Interaction Production of interferon (antiviral) Macrophage activation; Secretion of inflammatory cytokines Macrophage activation; Secretion of inflammatory cytokines

LPS TLR-4 (lipopolysaccharide of Gram bacteria

Flagellin (bacterial TLR-5 flagella)

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PAMP U-rich single TLR-7 stranded viral RNA

PRR

Biological Consequence of Interaction Production of interferon (antiviral)

CpG containing DNA

TLR-9

Macrophage activation; Secretion of inflammatory cytokines

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