Major Histocompatibility Complex (MHC) 2025 PDF

Major Histocompatibility Complex Dr. Eman Muhammad Majeed INTRODUCTION  Major Histocompatibility Complex (MHC) also called Human leukocyte antigen (HLA) include many genes responsible for coordinating the immune response.  It is a group of tissue antigens, controlled by chromosomal reg...

Major Histocompatibility Complex Dr. Eman Muhammad Majeed INTRODUCTION  Major Histocompatibility Complex (MHC) also called Human leukocyte antigen (HLA) include many genes responsible for coordinating the immune response.  It is a group of tissue antigens, controlled by chromosomal region, bearing a no. of genetic loci, each with multi alleles, that have relevance to transplantation rejection reaction & other immunological phenomena.  The MHC are membrane-bound glycoproteins that are closely related in both structure and function.  HLA antigens are the major determinants used by the body 's immune system for recognition of self from non- self antigens. Histocompatibility complex  The name histocompatibility complex is derived from the fact that a success of tissue and organ transplants depends on the similarities between the donor’s and recipient’s HLA genes(In other words, individuals who are identical at their MHC locus will accept grafts from one another, and individuals who differ at their MHC loci will reject such grafts).  These HLA proteins are alloantigens (i.e., they differ among members of the same species).  The genes of the major histocompatibility complex (MHC), located on the short arm of chromosome 6. In 1980 Nobel Prize has been awarded to Snell for his work that discovered the importance of MHC in transplantation and organ rejection. Classes of MHC complex genes Meaning of locus, alleles and gene Classes of MHC complex: 1. Class I MHC: include 3 main loci: A B C 2. Class II MHC: include 3 main loci: DP DQ DR 3. Class III genes named as a complement region.  This locus contains several immunologically important genes, encoding two cytokines (tumor necrosis factor and lymphotoxin) and two complement components (C2 and C4). HLA Ag expression on cells:  Class I HLA: These antigens are expressed on cell membrane of all nucleated cells including leukocytes except the sperms & RBCs.  ClassII HLA: molecules present on cell membrane of APC (monocytes, macrophages, dendritic cells, B- lymphocytes, some endothelial cell), & activated T-cells. Inheritance of HLA- antigens:  It follows Mendelian Rule of heredity.  Each person has two haplotypes (i.e., two sets of HLA genes: one on the paternal and the other on the maternal chromosome 6).  These genes are very diverse (polymorphic) (i.e., there are many alleles of the class I and class II genes).  Any individual inherits only a single allele at each locus from each parent and thus can make no more than 2 allels at each gene locus.  In human, each HLA allele is given a numerical designation, e.g: an HLA haplotype of an individual could be HLA- A2, HLA-B5, HLA- DR3, and so on. 25% chance that 2 siblings will share both haplotypes (e.g. ac & ac) » Identical 50% share one haplotype (e.g. ac & ad) » semi- identical 25% share no haplotype (e.g. ac & bd) » non-identical Co-dominant expression of HLA genes The minor antigens  There are minor antigens (normal body protiens) that have one or more amino acids differences from one person to another (i.e., they are “allelic variants”).  These minor antigens can induce a weak immune response that can result in slow rejection of a graft.  There are no laboratory tests for minor antigens. Molecular structure of MHC antigens MHC Class I molecule structure:  It is composed of 45-kDa α chain and 12-kDa β2- microglobulin molecule.  The α chain has three external domains, which are α1, α2, and α3 and transmembrane segment followed by short intracellular tail.  The α1and α2 (variable) domains interact together to form the peptide-binding groove. Both α1 and α2 domains have disulphide bonds (S-S bond).  The antigen binding groove can bind to 8 – 10 amino acids peptide derived from endogenous antigens.  α3 is the constant region that bind CD8 cells. MHC Class I molecule structure MHC class II structure:  It contains 2 different polypeptide chains, which are 33-kDa α chain, and a 28-kDa β chain, they associate together by non covalent bonds. They consist of variable region & constant region.  Both α and β chains have a trans-membrane segment and have two external domains which are α1 and α2 for α chain and β1 and β2 domains for β chain, each chain has trans- membrane portion and tail (cytoplasmic part).  α1 and β1 (variable) domains interact together to form the peptide-binding groove which binds to 13 – 18 amino acids derived from exogenous antigens.  β2 is the constant region that bind CD4 cells.  Note: Due to the similarity between the structures of Ig & HLA antigens, the latter are called Histoglobulins. MHC class II structure Functions of MHC  The main function of both class I and class II MHC molecules is to bind peptides derived from self or non- self antigens and then traffic to the cell surface, where these peptides can be displayed, or presented, for recognition by T-cells via the T-cell receptors (TCR).  The role of MHC molecules in antigen display ensures that T cells only recognize cell-associated protein antigens and that the correct type of T cell (helper or cytotoxic) responds to the type of microbe the T cell is best able to combat. (The ability of T cells to recognize antigen is dependent on association of the antigen with either class I or class II proteins). T cells role in accordance with MHC complex  MHC I presents endogenous peptide antigens to CD8+ T-cells (become cytotoxic and can kill the cells that present the pathogen-derived peptides).  MHC II primarily presents exogenous antigenic peptides to CD4+ T-cells (that can stimulate B cells to produce antigen-specific antibodies).  Function of HLA Ags: Both class I & class II MHC molecules are important in controlling immunological responses by a process known as MHC restriction. Properties of MHC Genes and Proteins  MHC genes are highly polymorphic, meaning that many different alleles (variants) are present among the different individuals in the population, (The polymorphism of MHC genes is so great that any two individuals in an outbred population are extremely unlikely to have exactly the same MHC genes and molecules.  MHC genes are co-dominantly expressed, meaning that the alleles inherited from both parents are expressed equally. Class I and II molecular polymorphism  Several hundred different allelic variants of class I and class II MHC molecules have been identified in human.  There is a possibility of 1/ 2,000,000 for a person to have another identical individual. Tables of variant alleles:  Number of variant alleles at class I and II loci according to the IMGT*-HLA database, last updated July 2014 MHC class I  HLA A 2,884.  HLA B 3,589.  HLA C 2,375.  Number of variant alleles at class II loci ( DP, DQ, and DR): MHC class II  DP- 16,036.  DQ- 34,528.  DR- 11,431. *IMGT®, the international ImMunoGeneTics information system® MHC alleles and susceptibility to certain diseases Some HLA alleles occur at a much higher frequency in people suffering from certain diseases than in the general population. The diseases associated with particular MHC alleles include:  Autoimmune diseases.  Susceptibility or resistance to certain viral diseases.  Disorders of complement system.  Different allergies. Examples of disease associated with HLA genes  Systemic lupus erythematous (SLE): HLA-DR3.  Rheumatoid arthritis : HLA-DR4.  Myasthenia gravis : HLA-B8.  Type I insulin dependant diabetes mellitus: DR3/DR4.  Ankylosing spondylitis: HLA-B27 allele have about 90 times relative risk to get ankylosing spondylitis than general population.  Celiac disease: It is an allergy to gluten. People who carry HLA-DQ2 allele have 50 times relative risk to get celiac disease. Indications of HLA typing : 1. Transplantation. 2. HLA typing is used primarily for determination of HLA compatibility between donor & recipient prior to transplantation. Disease association. 3. Paternity testing. 4. Anthropological studies (races & nations). Methods used for HLA-Typing 1. Serology:  It is an antibody-antigen reaction based method using monoclonal antibodies against the MHC antigens.  It is quick and cheap, but not that specific. Examples: 1. Microlymphocytoxicity test. 2. Mixed leukocyte reaction (MLR). 2. Molecular(DNA-based typing technique)  PCR-based techniques: They depend on amplifying specific piece of DNA.  They are more precise and specific but needs well trained workers and highly sophisticated molecular techniques and machines.