MHC PDF

The Major Histocompatibility Complex (MHC) By Dr. Amany M. Tawfeik Medical Microbiology & Immunology department Teaching Objectives Definition of MHC Classes of MHC MHC genes MHC polymorphism Structure of MHC class I and II...

The Major Histocompatibility Complex (MHC) By Dr. Amany M. Tawfeik Medical Microbiology & Immunology department Teaching Objectives Definition of MHC Classes of MHC MHC genes MHC polymorphism Structure of MHC class I and II Function of MHC Differences between class I and class II MHC association with disease Antigen processing and presentation. How the antigen processed and presented to T cells by APCs. References: 1. First Aid for the USMLE Step 1 2018. Le Tao, BhushanVikas, Sochat Matthew, ChavdaYash, Zureick Andrew, KalaniMehboob and Kallianos Kimberly. New York: McGraw-Hill Education, 2018. page 100 2. First Aid for the USMLE Step 1 2018.Kaplan Page 1082  The Major Histocompatibility Complex (MHC) MHC is a collection of genes found in all mammals. In humans ,MHC is located on the short arm of chromosome 6. Its protein products are called HLA (human leukocyte antigens ) because they were first discovered on leukocytes.  MHC Genes The layout (design)consists of three major regions (classes): class I, II and III. Class I region contains a set of 3 independent genes (loci): A, B, C. Each encompasses one gene. Class II region contains 3 sets of genes (loci): DP, DQ, and DR. Each set encompasses 2 genes. Class III region contains multiple genes, lie between regions I and II.  Two major sets of MHC genes and products are involved in T cell response. MHC class I genes: A,B,C. MHC class II genes :DP,DQ,DR Products of class III region genes are soluble proteins e.g. some complement components, cytokine, some enzymes and heat shock proteins.  In the population, each MHC gene has a number of alternative forms ( alleles). The MHC variation in the human population is high. There are at least 350 alleles for HLA-A genes, 620 alleles for HLA-B, 400 alleles for DR, and 90 alleles for DQ. Any two individuals who are not identical twins will express differing MHC molecules. This is known as genetic polymorphism. This is population diversity (different individuals in the population express distinct MHC molecules). MHC polymorphism makes tissue matching between unrelated people very unlikely.  MHC polymorphism An allele is one of two or more versions of a gene. An individual inherits two alleles (for each gene, one from each parent). If the two alleles are the same, the individual is homozygous for that gene. If the alleles are different, the individual is heterozygous. Though the term "allele" was originally used to describe variation among genes.  MHC antigens (MHC molecules) Products of class I and class II genes are expressed as membrane proteins called MHC molecules. A diploid cell expresses up to 6 different class I and class II molecules from both paternal and maternal MHC gene products. The immune system of the individual is educated to recognize his set of MHC molecules as self; will not react against it.  Synthesis and Structure of MHC molecules Class I MHC molecules (A, B, C). Class I molecules are expressed on all nucleated cells and consist of 2 separate non-identical, non-covalently linked polypeptide chains. 1 – A long alpha (α) chain. Divided into: an extra cellular segment(α1,α2,α3), trans membrane segment and a short cytoplasmic segment. The groove between α1, α2 is the peptide binding site. Amino acid sequence forming this groove varies from allele to allele. 2 – A small β chain (β2 microglobulin). Amino acid sequence of this chain is constant in all class I molecules. It has no direct membrane attachment with the cell surface. The β2 microglobulin chain is required for expression and stabilization of class I molecules on cell surface.  Class II MHC molecules (DP, DQ, DR) Class II molecules are expressed on the professional antigen presenting cells(APCs). It consists of 2 separate, non-identical, non-covalently – associated α and β chains. Both chains are encoded by 2 different genes within the MHC locus and are polymorphic. Each chain is divided into distinct regions: an extra cellular segment (α1,α2, β1, β2), a transmembrane segment and a cytoplasmic segment.  Antigen Processing And Presentation The processing of antigen for the presentation to naive T lymphocytes. Endogenous Pathway of MHC I: The endogenous pathway of antigen-processing handles threats to the host which are intracellular. These might include viruses, altered /mutated genes (from tumors) Exogenous Pathway of MHC II : APCs include dendritic cells, macrophages, and B cells; their job is to load partially degraded peptides into the groove of the MHC class II molecules.  Endogenous Pathway of MHC I Intracellular proteins are targeted by ubiquitin and degraded in proteasomes. These proteins are transported through a peptide transporter known as the TAP complex (transporter of antigen processing) Bind to freshly synthesized MHC class I molecules. The peptide-MHC class I complexes are then transported to the cell membrane where they may be presented to CD8+ T lymphocytes (cytotoxic T lymphocyte).  Exogenous Pathway of MHC II When MHC class II molecules are produced in the APC, a protein called the invariant chain (Ii) is synthesized at the same time. Ii has a chain peptide (CLIP) that binds with high affinity to the peptide binding clef of newly synthesized MHC class II molecule. CLIP blocks the peptide-binding groove so no normal cellular peptides can accidentally be attached. The CLIP + Ii is transported in a vesicle to the location of endocytic vesicles containing the ingested, internalized peptides. Exchanged for the CLIP, the peptide is loaded on the MHC class II molecule and the complex is transported to the cell surface, where it will be accessible for interaction with any CD4+ T lymphocyte with a complementary TCR.  Functions of MHC molecules 1 – MHC molecules on cell surfaces act as antigen presenting molecules. They are involved in the process of antigen recognition. Class I molecules present processed antigens to CD8 T cells. Class II molecules present processed antigens e.g. bacterial peptides to CD4 T lymphocytes. 2 – MHC molecules are associated with self/non self discrimination. 3– MHC molecules are responsible for rejection of incompatible transplants.  MHC association with disease A number of human diseases were found to occur at a higher frequency in individuals with certain HLA alleles. These diseases are often inflammatory or autoimmune in nature. Examples: Disease HLA allele - Ankylosing spondylitis B27 - Insulin dependent diabetes mellitus DR3 - Multiple sclerosis DR2 - Systemic lupus erythematosus(SLE) DR3 - Rheumatoid arthritis DR4