The Major Histocompatibility Complex PDF

The Major Histocompatibility Complex Dr Felix N. Toka Associate Professor, Veterinary Immunology & Virology Department of Biomedical Sciences Objectives of the topic Know the general characteristics of the mammalian MHC, and distinguish between class I and class II MHC molecules Understand the role...

The Major Histocompatibility Complex Dr Felix N. Toka Associate Professor, Veterinary Immunology & Virology Department of Biomedical Sciences Objectives of the topic Know the general characteristics of the mammalian MHC, and distinguish between class I and class II MHC molecules Understand the role of the MHC molecules in immunity Know the expression profile of MHC molecules on cells Know the structure of MHC class I and II Explain why certain MHC genes may predispose animals to some diseases. Activation of T cells The main function of T cells is to protect the body against intracellular pathogens and to activate other cells such as macrophages and B lymphocytes T cells require activation before functioning as effector cells Activation is achieved through interaction of T cells with antigen presenting cells such as dendritic cells, macrophages or B cells Activation of T cells - cont’d Interaction is mediated by receptors on T cells and special proteins found on the surface of antigen presenting cells The role of presenting antigen to T cells is performed by specialized proteins called MHC molecules expressed on antigen presenting cells Discovery of the MHC - History The MHC was discovered as a locus containing genes responsible for graft rejection There are two possible outcomes to a skin graft from one animal to another 1. the graft will survive and function 2. the graft will be rejected The Nobel Prize in Physiology or Medicine 1980 Baruj Benacerraf Jean Dausset George D. Snell Prize motivation: “for their discoveries concerning genetically determined structures on the cell surface that regulate immunological reactions" Grafts exchanged between inbred animals survive Grafts exchanged between outbred animals are rejected Therefore, recognition of a graft as “self” or “foreign” is an inherited trait The genes responsible for survival or rejection of a graft were called tissue or histo-compatibility genes The region that controlled graft rejection or survival was called the major histocompatibility complex (MHC) MHC History – cont’d Similarly, animals with certain MHC haplotypes may not respond to stimulation with particular antigens All animals have histocompatibility molecules Each MHC cluster of genes has at least 3 classes of the gene loci A typical mammalian MHC Arrangement of genes within the major histocompatibility (MHC) of the mouse Class I MHC molecules Class I loci code for MHC molecules that are expressed on all nucleated cells Class I loci MHC molecules are highly polymorphic (Class Ia, Ib, Ic) Class Id are less polymorphic and are located outside the MHC on a different chromosome H-6, c-7, hor-20, p-7 The number of class Ia loci is different in different species Mice – 30 Rats – 60 Humans – 20 Cattle – 13-15 Pigs – 11 Not all are functional, e.g., in mice only 2 or 3, and humans A, B, and C are functional. The rest are pseudogenes. Class II MHC molecules Class II loci encode MHC molecules found only on antigen presenting cells A complete class II region contains 3 paired loci In primates these are DPA and DPB, DQA and DQB, DRA and DRB The genes for α chains are A, for β chains are B Some but not all are polymorphic Class III MHC molecules The class III genes encode proteins that have many different functions Class III loci code for various proteins which do not function as antigen presenting molecules Class III proteins have other functions in the innate immunity e.g., complement proteins MHC molecules were originally found on white blood cells, so almost every MHC name contains the words leukocyte antigen Hence: Humans - HLA (Human leukocyte antigen) Monkeys - RHA (Rhesus leukocyte antigen) Rabbit - RLA (Rabbit leukocyte antigen) Cattle - BoLA (Bovine leukocyte antigen) Dogs - DLA (Dog leukocyte antigen) Horses - ELA (Equine leukocytes antigen) Swine - SLA (Swine leukocyte antigen) The MHC of mice is called H-2 and the MHC of rats is called RT1 Major Histocompatibility Complex Genetics The basic gene structure of the MHC is similar in all mammals Genetics - cont’d Each individual animal (humans too) has 2 complete sets of MHC molecules, one on each of the paternally and maternally derived chromosomes The MHC genes are co-dominantly expressed Therefore, each individual has six MHC I genes (A, B and C) Genes are transcribed such that each nucleated cell expresses six different class I antigens Class II genes give greater diversity because different α and β chains may pair to give distinct class II products Chromosomal DNA containing the MHC is inherited in its entirety Rarely, minor combinations may occur Because of this “en bloc” MHC inheritance, molecules are inherited within a family by simple Mendelian genetics Within a family theoretically, there is a 1 in 4 chances that 2 of the offsprings might share the same MHC type Summary Most MHC genes are highly polymorphic MHC genes are co-dominantly expressed A set of MHC alleles present on a chromosome is called a haplotype Role of MHC in adaptive immunity Apart from transplantation the MHC plays an immense role in antigen presentation MHC class I and MHC class II are the main antigen presenting molecules MHC class I molecules are expressed on all nucleated cells They are not usually found on red blood cells, gametes, neurons or trophoblast They present peptide antigens to CD8+ T lymphocytes MHC class II molecules are expressed on professional antigen presenting cells such as dendritic cells, macrophages and B cells They present antigens to CD4+ T lymphocytes (helper T lymphocytes) MHC class III do not participate in antigen presentation Structure of MHC class I molecule The whole MHC class I molecule is a heterodimer consisting of an α (α1, α2, α3) chain, β2-microglobulin chain and a bound peptide Stable expression of the MHC class I requires all the three components MHC I structure- cont’d Each MHC I molecule has: an extracellular domain which makes up the antigen binding groove an immunoglobulin-like extracellular domain transmembrane region cytoplasmic domain MHC I structure- cont’d The binding groove is the most variable part of the MHC class I molecule Variable region CD8 binding region The T cell co-receptor CD8 binds to the non-variable region α3 of MHC class I CD8 co-receptor binding to α3 of MHC class I molecule Cleft geometry a-chain Peptide -M MHC class I accommodates peptides of 8-10 amino acids Structure of MHC class II molecule The MHC class II molecule is similarly structured It consists of α (α1, α2) and β (β1, β2) chains The peptide binding grove is made up by the α1 and β1 parts of the appropriate chains Stable expression requires assembly of the 3 components: the 2 chains and a bound peptide Cleft geometry a-chain Peptide -chain MHC class II accommodates peptides of >13 amino acids Outcomes of antigen presentation through MHC molecules Characteristics of peptide-MHC interactions Each class I or class II MHC molecule has a single peptide-binding cleft that binds one peptide a time But each MHC molecule can bind different peptides Therefore, MHC molecules have a broad specificity for peptide binding Characteristics of peptide-TCR interactions Each T cell receptor (TCR) has a single peptide-binding cleft that binds one peptide a time But each TCR can bind one peptide and ONLY that peptide Therefore, TCRs have fine specificity for peptide binding Example A T cell recognizes a peptide presented by one MHC molecule An excess of a different peptide that binds to the same MHC molecule competitively inhibits presentation of the peptide that the T cell recognizes Characteristics of peptide-MHC interactions cont’d The peptides that bind to MHC molecules share structural features that promote this interaction (e.g., peptide length) MHC molecules of an individual do not discriminate between microbial peptides and peptides derived from the proteins of that individual Question: if self peptides are continuously being presented, why do all individuals not develop autoimmunity? Regulation of MHC expression Expression of MHC molecules increases in the presence of cytokines during innate and adaptive immune responses IFNα, IFNβ or IFNγ increase expression of MHC class I IFNγ increases expression of MHC class II on macrophages and dendritic cells Recognition of pathogens by dendritic cells (PAMPs) through Toll-like receptors increases expression of MHC class II Cytokines secreted by CD4+ helper T cells increase expression of MHC class II Macrophages increase expression of MHC class II in the presence of IFNγ secreted by NK cells MHC molecules and disease The MHC regulates the immune response A foreign antigenic peptide that does not fit the MHC molecule will not stimulate an immune response MHC I and II are polymorphic, each allele can bind a set of different antigenic peptides MHC molecules and disease – cont’d The more variety in an animals MHC the more antigens it can respond to Heterozygous animals will express more alleles and bind more antigenic peptides Homozygous animals will have less variety and more likely not to generate an immune response to certain antigenic peptides MHC molecules and disease – cont’d Examples African cheetahs are genetically very homogeneous and at risk for decimation by infectious pathogens Infectious peritonitis causes 60% mortality in Cheetahs compared to 1-2% in domestic cats MHC molecules and disease – cont’d Examples All of the Florida panthers alive in the twentieth century appear to have come from a single female Five Texas pumas were introduced into panther habitat (1995), and the resulting hybrids appear to be doing well However, scientist are sceptical whether the these populations will survive the next few decades MHC molecules and disease – cont’d The optimal number of MHC genes is a balance between the need to respond to microbial antigens and the need to avoid autoimmune disease Disease associations Animal Species Cattle Cattle Cattle Cattle Cattle Cattle Cattle MHC BoLA-Aw7 BoLA-Aw12 Outcome Resistance to bovine leukemia virus Susceptibility to bovine leukemia virus BoLA-A*16 Resistance to mastitis BoLA-DRB3.2*23 Increased incidence of severe coliform mastitis BoLA-DRB3*3 Lower risk of retained placenta BoLA-DRB3*22 Lower risk of cystic ovarian disease BoLA-DR locus Resistance to Dermatophilus Animal Species Horse Horse Horse Swine MHC Outcome ELA-Aw7 Allergic reactions to Culicoides midges ELA-A3, A15, Dw13 Development of sarcoid tumors ELA-A9 Equine recurrent uveitis Serum antibodies, ovulation rate, number of larvae of the parasite Trichinella spiralis are affected by the SLA MHC Summary CLASS I Loci Distribution Function Result CLASS II A, B, and C DP, DQ, and DR B cells, Macrophages, Most nucleated cells and DC Present antigen to T Present antigen to cytotoxic T cells helper cells T cell mediated toxicity T-cell mediated help Can the MHC molecule be used in diagnostics? Changes in expression of MHC proteins during disease e.g., idiopathic inflammatory myopathies (humans and dogs) MHC typing of cattle It is now possible to define polymorphism in both the class I and class II regions in cattle (microlymphocytotoxicity test) In order to determine resistance/susceptibility to disease Why might a particular MHC allele make an animal more or less susceptible to a certain disease, e.g., CAEV infection in goats and Be1 and Be14 MHC alleles? Possible explanation 1 Disease might arise in an animal that was unable to present a critical antigen and mount a protective immune response For example, a protective immune response against pathogen X occurs only if the host animal recognizes antigenic epitope of X If an animal expresses MHC alleles whose protein products do not bind and present antigen X, then that animal will succumb to the infection. Possible explanation 2 The disease might result from an overreaction or cross-reaction of the immune system. Let’s say pathogen X also carries an antigenic epitope Z that looks a lot like one found in a protein on synovial cells. If an animal infected with pathogen X carries a certain MHC allele and the product of that allele binds to the antigenic epitope Z, then when this animal’s immune system reacts to epitope Z on pathogen X, it may inadvertently also strike the synovial cells and cause a progressive arthritis. Examples of autoimmune diseases in dogs related to MHC proteins Autoimmune thyroiditis (hypothyroidism) Autoimmune hemolytic anemia (AIHA), Immune-mediated thrombocytopenia (IMTP or ITP) Hypoadrenocorticism (Addison's disease) Myasthenia gravis Systemic lupus erythematosus (SLE) Rheumatoid Arthritis (RA)