Module 3: Nature of Antigens MHC

Immunogen

A substance capable of stimulating an adaptive immune response.

Antigen

A substance specifically recognized by the immune system that does not always trigger an immune response.

Immunogen vs. Antigen Relationship

All immunogens are antigens, but not all antigens are immunogens.

Immunogen Molecular Size Requirement

Must be at least 10,000 daltons to be recognized, though most immunogens are over 100,000 daltons.

Degree of Foreignness

The more structurally unrelated a substance is to the host, the more effective it is as an immunogen.

Most Effective Immunogen Class

Proteins, due to their chemical composition and high molecular complexity.

T Cell Antigen Recognition

Recognizes short linear peptide fragments (primary amino acid sequences) presented by MHC molecules.

B Cell Antigen Recognition

Recognizes surface shapes and binds directly to 3D structures (tertiary and quaternary protein structures).

Epitope (Antigenic Determinant)

The specific part of an antigen recognized by a single B or T cell.

Linear Epitope

A sequential sequence of amino acids in a row on a single polypeptide chain.

Conformational Epitope

An epitope formed by protein folding that brings distant amino acids together on the surface.

T Cell Epitope Constraint

T cells recognize only linear epitopes that are revealed when proteins are broken down inside cells.

Hapten

A small, nonimmunogenic substance that cannot activate B cells alone but creates new antigenic determinants when bound to a carrier protein.

Why Haptens Cannot Activate B Cells Alone

Haptens are too small and usually have only one epitope, preventing them from cross-linking B cell receptors (BCRs).

Hapten Clinical Example

Catechols from poison ivy binding to tissue proteins to produce contact dermatitis.

Adjuvant

A substance delivered simultaneously with an antigen in vaccines to stimulate innate immune receptors and enhance the adaptive immune response.

Alum (Aluminum Salts) Mechanism

The most widely used human vaccine adjuvant; triggers local inflammation, recruits APCs, and slows antigen diffusion at the injection site.

Autoantigen

An antigen belonging to the host that usually does not evoke an immune response unless autoimmunity develops.

Alloantigen

An antigen originating from another individual of the same species, important in organ transplantation and blood transfusions.

Heteroantigen

An antigen originating from a different species (such as animals, plants, or microorganisms).

Heterophile Antigen

Heteroantigens in unrelated species that share closely related structures, causing antibodies produced against one to cross-react with the other.

Heterophile Antigen Example

Pneumococci bacterial antigen cross-reacting with human type A blood group antigen.

Major Histocompatibility Complex (MHC)

A gene cluster on chromosome 6 encoding cell-surface proteins (HLAs) that present peptide antigens to T cells and determine tissue graft compatibility.

MHC Class I Loci

Encoded by HLA-A, HLA-B, and HLA-C loci on chromosome 6.

MHC Class II Loci

Encoded by the D region (HLA-DR, HLA-DQ, and HLA-DP loci) on chromosome 6.

MHC Haplotype

A block of MHC genes on chromosome 6 inherited together as a single unit from one parent.

Codominant Expression of MHC

Both maternal and paternal MHC alleles are actively expressed on cell surfaces, doubling the variety of antigen-presenting molecules.

MHC Polymorphism Significance

Thousands of allele variants in the population ensure that at least some individuals can mount an immune response against any pathogen.

MHC Class I Cellular Distribution

Expressed on all nucleated cells (highest on lymphocytes and myeloid cells; lowest/undetectable on hepatocytes, muscle, neural, and sperm cells).

MHC Class I Structure

Glycoprotein dimer composed of one heavy alpha chain (3 domains) noncovalently linked to beta-2 microglobulin ($\beta_2$-microglobulin).

MHC Class I Antigen Source

Endogenous antigens (originating inside the cell, such as viral proteins or tumor antigens).

MHC Class I Target Cell Presentation

Presents endogenous peptides to CD8+ cytotoxic T cells (Tc).

MHC Class I Peptide Binding Cleft

Closed at both ends, binding short peptides of 8 to 11 amino acids.

MHC Class II Cellular Distribution

Expressed primarily on professional antigen-presenting cells (APCs: dendritic cells, macrophages, B cells) and thymic epithelial cells.

MHC Class II Structure

Glycoprotein dimer composed of one alpha chain (2 domains) and one beta chain (2 domains) encoded by separate MHC genes.

MHC Class II Antigen Source

Exogenous antigens (ingested from outside the cell, such as extracellular bacteria or toxins).

MHC Class II Target Cell Presentation

Presents exogenous peptides to CD4+ helper T cells (Th), which secrete cytokines to stimulate B cell antibody production.

MHC Class II Peptide Binding Cleft

Open at both ends, binding peptides of 13 to 18 amino acids.

CD4 / CD8 Rule of 8

:: CD8 binds MHC Class I ($8 \times 1 = 8$) and CD4 binds MHC Class II ($4 \times 2 = 8$).

HLA Matching Clinical Role

Performed prior to tissue transplantation to reduce donor-recipient mismatch and prevent graft rejection.

HLA-B27 Autoimmune Association

Strong association with Ankylosing spondylitis.

HLA-DQ2 / HLA-DQ8 Autoimmune Association

Associated with Celiac disease and Type 1 diabetes.

HLA-DR4 Autoimmune Association

Associated with Rheumatoid arthritis.

HLA-DR2 Autoimmune Association

Associated with Multiple sclerosis.