Chapter 3 - Nature of Antigens and the MHC

Antigen

a substance that is specifically recognized by the adaptive immune response

RECOGNIZED by adaptive, but doesn’t always invoke a response

*not all antigens are immunogens

Immunogen

a substance that is capable of causing an adaptive response

GOING to cause an adaptive immune response

*all immunogens are antigens

Factors that influence immune response

Age

• older individuals have a decreased response to antigenic stimulation

• neonates immune system not fully developed

Overall health

• malnutrition, fatigue, and stress dampen immune response

Genetics

• MHC genes exert an overall profound influence on how you respond to an infection

Dosage

• small # ag, innate takes care of it

• large # ag, adaptive activates

Route of Inoculation

Routes of inoculation

intravenous

intramuscular

intradermal

subcutaneous

oral

Traits of Immunogens that influence the immune response

(size, foreignness, composition)

macromolecular size must be at least 10,000 daltons to be recognized; most immunogens are >1000,000 daltons

the more foreign a substance is to a host, the more successful it is as an immunogen

proteins are the most effective immunogens, followed by polysaccharides

More complex protein induces a ____ immune response

stronger

Epitope definition and 2 types

part of immunogen that is recognized by lymphocytes

linear epitopes

• sequential

• AA following one another on a single polypeptide chain

conformational epitopes

• result from folding of one or more chains

• distant AAs brought close together

B cells recognize what types of epitopes and requires what

linear & conformational

require that the epitope be on the surface of cell

require more than one epitope so crosslinking can occur

T cells recognize what types of epitopes and require what

linear epitopes

must be presented by a MHC molecule

Haptens definition/function

small substances that are nonimmunogenic by themselves

create new antigenic determinants when combined with a carrier

Ex = Catechols from poison ivy bind to tissue proteins to produce contact dermatitis

Adjuvants definition/function

substances delivered simultaneously with an antigen to enhance the immune response; used in many vaccines

stimulate innate immune receptors

also prevent ag from diffusing away from the site of inoculation

longer response time attracts more immune cells to the injection site and increases protective immunity

trick the body into acting as if an infection is underway, even if Ag is harmless (i.e. flu vaccines)

Autoantigens

belong to the hose

do not usually provoke an immune response

if an immune response occurs, an autoimmune condition is likely

Alloantigens

from other members of the host’s species

Ags recognized in organ transplantation and blood transfusions

are capable of eliciting an immune response

Heteroantigens

from other species, such as animals, plants, or microorganisms

more foreign, more immunogenic

Heterophile antigens

exist in unrelated plants or animals, but are identically to or closely related in structure so that antibody to one antigen will cross-react with the other

Ex: Ag from pneumococci bacteria cross-reacting with type A blood group Ag

MHC molecules

determine whether transplanted tissue, found in all nucleated cells in the body, is histocompatible and accepted or recognized as foreign and rejected

linked to the genetic capability to mount an immune response

play a pivotal role in the development of humoral and cellular immunity

serve as carriers of peptide antigens for recognition by T cells

Genes coding for MHC molecules

found in humans on the short arm of chromosome 6

divided into 3 classes

• Class I: found on three different loci (designated as A, B, & C)

• Class II: found in the D region (designated as DR, DQ, & DP)

• Class III: found in a region between class I and II and codes for C4a, C4b, C2, & B

Class I, II, III MHC and things they code for overview

I) 1 gene that codes for each of the A, B and B

II) 1 gene for alpha chain and 1 gene for beta chain

III) codes for cytokines and TNF factor

T/F MHC genes are codominant

True

inherited together as a haplotype

the MHC system is the most ___ system in humans

polymorphic

MHC alleles #s

thousands of alleles - alternate forms of a gene that code for a slightly different variety of the same product are found:

• more than 4,600 different HLA-A alleles, 5,500 HLA-B alleles, and 4,300 HLA-C alleles

Each person has two HLA alleles of each type; linked genes are inherited (haplotype)

Class I MHC molecules

expressed on all nucleated cells

different levels of expression

• highest on lymphocytes and myeloid cells

• lowest or undetectable on liver hepatocytes, neural cells, muscle cells, and sperm

HLA-C expressed at lower levels than HLA-A/B

Class I MHC structure

glycoprotein dimers made up of two noncovalently linked polypeptides

• a chain with 3 domains

  • a-1/a-2 form together making peptide-binding cleft for Ag

    • cleft closed on both ends, so it binds smaller peptide chains (6-12 AAs long)

  • a-3 binds to cell surface and CD8+ cells

• b-2 microglobulin

Class I MHC-Peptide Interaction

Class I MHC molecules process endogenous Ags and present them to CD8+ cytotoxic T cells (Tc)

endogenous because peptide and MHC arise from inside the cell

healthy cell - self peptides bound to MHC

• patrolling T cells recognize self

tumor cells - foreign peptides bound to MHC

• patrolling T cells initiate immune response

CD8+ bind to the Ag-MHC Class __ complex on the target cell surface

class I

Tc releases enzymes that destroy the target cell

MHC class I provide Tc what

a means of surveying the interior of our cells throughout the body

Where are Class II MHC found

primarily on APS

• B lymphocytes

• Monocytes

• Macrophages

• Dendritic cells

  • most effective APC so they present high levels of MHC II

• Thymic epithelial cells

MHC II structure

DP, DQ, DR

2 noncovalently bound polypeptides that are encoded by separated genes in the MHC complex

• 1 gene codes for a chain with 2 domains

• another gene codes for b chain with 2 domains

peptide binding cleft open, bind larger peptides up to 30 AA long

Class II MHC-Peptide Interaction

Class II MHC process exogenous antigens and present them to CD4+ T helper cells (Th)

*Ag must be taken in my endocytosis or phagocytosis

Where is MHC I and II formed

formed and synthesized in ER

The Assist Antibody Production (what T cell)

CD4+ Th cells stimulate B cells (cytokines) to divide and differentiate into Ab-producing plasma cells

Table MHC I vs. II (in back of chapter around study section)

Cellular distribution

• MHC I = all nucleated cells

• MHC II = B cells, monocytes, macrophages, dendritic cells, thymic epithelial cells

Structure

• MHC I = One a chain and B2-microgloublin

• MHC II = an a chain and a b chain

Classes

• MHC I = A, B, & C

• MHC II = DP, DQ, DR

Size of peptides bound

• MHC I = 8-11 amino acids

• MHC II = 10-30 amino acids (12-16 optimally)

Nature of peptide binding cleft

• MHC I = closed at both ends

• MHC II = open at both ends

Interaction with T cells

• MHC I = presents endogenous Ag to CD8+ T cells

• MHC II = presents exogenous Ag to CD4+ T cells

Clinical significance of MHC

important in tissue transplant procedures

MHC I and II can induce graft rejection

Certain HLA types appear to play a role in development of autoimmune diseases

• HLA B27

Summary points