Genetic Variation Of Immune Disorders

17.3.06

Disregulated, excessive or absent immune responses → pathology.

Excessive: allergies eg. asthma, hay fever.

Autoimmune diseases eg. diabetes, rheumatoid arthritis.

Immunodeficiencies.

Immunoproliferative disorders.

CD4+ helper T lymphocytes provide cytokines and growth factors that serve as (usually) essential costimulants for B cell (antibody) and CD8+ cytotoxic T cell responses.

2 types of antigen receptor
1. Surface immunoglobulin on B cells.
-Recognise intact antigens outside cell, where most bacteria found.
2. Antigen receptor on T cells: T cell antigen receptor (TCR).
-Detect peptide antigens generated inside cell eg. viral and bacterial peptides.

Function of HLA molecules
• Originally identified as histocompatibility antigens in context of transplantation and pregnancy.
• Now know: main function to sample antigenic peptides and present them for screening by T cells.

HLA molecules
• Encoded on short arm of chromosome 6.
• Human major histocompatibility complex (MHC) gene complex contains 264 genes/pseudogenes.

MHC
1. Class I HLA
• Expressed on virtually all nucleated cell types.
-Not trophoblast.
-Not sperm.
• 3 important genes - HLA - A, B, C; multiple "alleles."
• Binds small peptides (form cytosol) and "presents" them to CD8+ (cytotoxic) T cells.

2. Class II HLA
• Expressed on antigen - presenting cells (APC) - macrophages, dendritic cells and B cells.
• 3 gene products, HLA - DR, DP, DQ; multiple "alleles."
• Binds peptides (from intracellular vesicles) and presents them to CD4+ (helper) T cells.

CD4 activation necessary for virtually all immune responses, so APC play pivotal role.

Each HLA allele (tissue type) binds different repertoire of antigenic peptides fo presentation to T cells.

Frequency of immunogenic peptides
• Average-sized protein of 60,000 molecular weight contains ≈ 500 amino acids.
• From defined anchor residues for each class I/II HLA molecule in any individual, would be (at best) only a few peptides that could be bound.
• Hence, low frequency of immunogenic peptides in any typical protein - immunogenic peptides will vary between individuals.

How is HLA polymorphism maintained?
1. Non-pathogen-driven mechanisms
• Spontaneous mutation and gene conversion rates?
• Maternal-foetal incompatibilities??
• Mating preferences?

2. Pathogen-driven mechanisms
• Heterozygote advantage.
• Rare allele advantage.

HLA and HIV
• Frequently-exposed HIV-negative individuals:
-HLA-A2, -A28; -DR13.
-Higher occurrence of cervical IgA anti-HIV.
• Fast progressors:
-HLA-A1, -A9, -A11, -A23, -A24; -B8, -B-35.

HLA-B53 and malaria
• Frequency of allele is ≈ 1% in Caucasian populations, but >50% in Gambians.
• HLA-B53 can bind peptide from malaria parasite that is a target for cytotoxic T cells.
• Selective advantage of allele in malaria-endemic regions.

HLA-A11 and EBV
• European EBV strains recognised by HLA-A11 restricted CD8+ cytotoxic T cells.
• In New Guinea (where HLA-A11 more frequent), EBV has mutated - no longer recognised by HLA-A11-restricted CTL.
• Here, parasite one step ahead of host.

EBV, HSV and certain adenoviruses can persist harmlessly after primary infection (illness), because they interfere with the cellular mechanisms of production, processing or presentation of antigenic peptide fragments of viral proteins.

HLA polymorphism important in humans.