MSB 103 MHC MOLECULES.pdf

Major Histocompatibility Complex (MHC) Rispah Torrorey Immunology Section Pathology Department 6/13/2024 1  Outline Major histocompatibility complex: - components - inheritance pa...

Major Histocompatibility Complex (MHC) Rispah Torrorey Immunology Section Pathology Department 6/13/2024 1  Outline Major histocompatibility complex: - components - inheritance patterns - characteristic features of MHC molecules - genetic control of an immune response. - roles of MHC in medicine 6/13/2024 2  Introduction Definition: Major Histocompatibility Complex (MHC) are glycoproteins encoded in a large cluster of genes located on the short arm of chromosome 6. These set of genes control Immunological self/ nonself recognition- also referred to as cell antigens The MHC is a large region of DNA, spanning about four million base pairs in humans, or about 0.1% of the human genome, and contains over 200 coding loci. 6/13/2024 3 Functions of MHC MHC genes encode cell surface proteins (class I and II MHC molecules) that present small peptide antigens to T cells. Class III MHC region encodes several genes involve in complement cascade, TNF-α,β etc. Through antigen presentation, MHC molecules control all specific immunological responses, both cell- and antibody-mediated. 6/13/2024 4  Role of MHC MHC genes play such a central role in the immune system, because they influence many important traits, ✓ including resistance to infectious diseases, ✓ autoimmunity, ✓compatibility of tissue transplants, ✓spontaneous abortion, 6/13/2024 5 Maps of Human and Murine MHC loci In humans MHC are known as human leukocyte antigens (HLA) antigens are found in chromosome 6 In mouse MHC are known as H-2 and are found in chromosome 17 In humans there class I loci (e.g. A, B and C) and class II loci (e.g. DP, DQ and DR), In mice there are class I ( K, D and L) and class II (O, A and E) loci. 6/13/2024 6  Immunogenetics of MHC System Location: Human MHC genes are located on chromosome 6 (HLA complex). Regions: Three regions - Class I, Class II, and Class III. Gene Clusters: Class I: HLA-A, HLA-B, HLA-C. Class II: HLA-DP, HLA-DQ, HLA-DR. Class III: Contains genes for components of the complement system and other immune-related genes. 6/13/2024 7 6/13/2024 8  MHC Genes The human Major Histocompatibility Complex (MHC) locus is located on the short arm of the chromosome 6 at 6p21.3. The chromosome 6 is estimated to be 150-180 Mb in size. The MHC locus spans about 4 Mb (Human Chromosome 6 Project Overview at Sanger, March 2002). MHC class I: HLA-A, HLA-B, HLA-C MHC class II: HLA-DRA, HLA-DRB3, etc MHC class III: C2, BF, C4B, CYP21A2 MHC class I like: HLA-E,F,G, MICA, MICB etc genes involved in the antigen processing: TAP1, TAP2, PSMB8 (LMP7), PSMB9 (LMP2), TAPBP cytokines: LTA, TNF, LTB 6/13/2024 9  MHC System Components Class MHC Loci Tissue distribution of MHC gene products I HLA-A,B,C All nucleated cells, lymphoid, epithelial and mesenchymal tissues II HLA-DP, HLA-DNA, Accessory antigen presenting cells like HLA-DOB, HLA-DQ monocyte-macrophage lineage cells, B-cells HLA-DR and activated T-cells III Central MHC C2,BF, C4b, C4a, and 21-hydroxylase region enzyme (21- Phase), tumour necrosis factor (TNF), lymphotoxin and heat shock proteins 6/13/2024 10  Structure of MHC Class I Antigens Comprised of 2 molecules  chain (45 kDa), transmembrane 2-microglobulin (12 kDa) Non-covalently associated with each other Association Of  Chain and 2 Is Required For Surface Expression  Chain Made Up Of 3 Domains (1, 2 and 3) 2-microglobulin Similar To 3 1 And 2 Form Peptide Binding Cleft Fits peptide of about 8-10 a/a long 3 Highly Conserved Among MHC I Molecules Interacts with CD8 (TC) molecule 3 domain & 2m have structural & amino acid sequence homology with Ig Constant domains Ig GENE SUPERFAMILY 6/13/2024 11  MHC Class I structure 6/13/2024 12  Structure of Class I MHC 6/13/2024 13  MHC class II molecules Human class II molecules are designated HLA-D and class II MHC region encodes several molecules including HLA-DP (α,β); HLA-DNA; HLA-DOB; HLA-DQ (α,β) and HLA-DR (α,β). Comprised of  and  chains  chain and  chain associate non-covalently  and  chains made up of domains - 1 and 2 ( chain) - 1 and 2 ( chain) 1 and 1 form antigen binding cleft CD4 Molecule binds 2/2 domains 2 & 2 domains have structural & amino acid sequence homology with Ig C domains Ig GENE SUPERFAMILY 6/13/2024 14  Structure of MHC class II molecules 6/13/2024 15  Structure of Class II MHC 6/13/2024 16  Class III MHC Region Class III MHC region is located in the central part of the MHC system and contains genes which code for complement components [Factor B (BF), C2, C4b and C4a]; tumour necrosis factor (TNF); lymphotoxin (LT); heat shock proteins (HSP 70-1 and HSP 70-2). The proteins produced also include 21 – hydroxylase enzyme (21-Ohase) which is deficient in patients with congenital adrenal hyperplasia. The three classes of MHC genes code for specific antigens distributed in various tissues as summarized in the Table below. 6/13/2024 17  Naming of MHC alleles HLA allele names consist of several parts that convey specific information about the gene and the allele. The general structure is: HLA-*:::: 6/13/2024 18  Example: HLA-A*02:01:01:02N HLA: Prefix indicating the gene is part of the Human Leukocyte Antigen system. Gene: Indicates the specific gene, such as HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA- DQB1, etc. *: Separator between the gene name and the allele group. Group: A two-digit number representing the major group of alleles that encode proteins differing by one or more amino acids. For example, "02" in HLA-A*02. Subgroup: A two-digit number indicating alleles that encode proteins differing by one or more amino acids within the group. For example, "01" in HLA-A*02:01. Specific Protein: A two-digit number indicating differences in the nucleotide sequence of the coding region that do not change the amino acid sequence. For example, "01" in HLA-A*02:01:01. Synonymous Mutation: A two-digit number indicating differences in the nucleotide sequence that do not change the protein (silent mutations) or in non-coding regions (introns, 5' and 3' untranslated regions). For example, "02" in HLA-A*02:01:01:02. Suffix: Indicates specific characteristics or modifications of the allele: N: Null allele (does not produce a functional protein). L: Low cell surface expression. S: Secreted protein only (not present on the cell surface). C: Cytoplasmic protein only. A: Aberrant expression. 6/13/2024 19  Nomenclature of HLA Alleles 6/13/2024 20  Major Characteristics of MHC Region High Allelic Diversity: The MHC genes are highly polymorphic, especially the classical class I and class II genes, which have many different alleles in the population. This polymorphism is essential for the variability of immune responses.Functional Implications: Different alleles can bind and present different peptide antigens, enhancing the ability of the immune system to recognize a wide range of pathogens. 6/13/2024 21  Class I HLA A locus 580 HLA B locus 921 HLA C locus 312 Allelic Polymorphism Class II HLA-DPα locus 23 HLA-DPβ locus 127 HLA-DQα locus 34 HLA-DQβ locus 86 HLA-DRα locus 3 HLA-DRβ locus 577 6/13/2024 22  2.Inherited as Haplotypes Histocompatibility genes are inherited as a group (haplotype), one from each parent. Thus, MHC genes are codominantly expressed in each individual. A heterozygous human inherits one paternal and one maternal haplotype, each containing three Class-I (B, C and A) and three Class II (DP, DQ and DR) loci. Each individual inherits a maximum of two alleles for each locus. The maximum number of class I MHC gene products expressed in an individual is six; that for class II MHC products can exceed six but is also limited. Thus, as each chromosome is found twice (diploid) in each individual, a normal tissue type of an individual will involve 12 HLA antigens. Haplotypes, normally, are inherited intact and hence antigens encoded by different loci are inherited together. However, on occasions, there is crossing over between two parental chromosomes, thereby resulting in new recombinant haplotypes 6/13/2024 23 Codominance Given a simple Mendelian pattern of inheritance, the distribution of MHC haplotypes in a family is 25% identical; 25% non-identical and 50% partially – identical 6/13/2024 24  Father Mother HLA-A3 HLA-B7 HLA-A69 HLA-A5 HLA- A1 HLA-Cw7 HLA-B45 HLA-B4 HLA-B8 HLA-DR15 HLA-Cw9 HLA-Cw3 HLA-Cw2 HLA-DQ6 HLA-DR17 HLA-DR2 HLA-DR4 HLA-DP4 HLA-DQ2 HLA-DQ7 HLA-DQ3 HLA-DP4 HLA-DP3 HLA-DP4 Offspring (Son) HLA- A1 HLA-A3 HLA-B8 HLA-B7 HLA-Cw2 HLA-Cw7 HLA-DR4 HLA-DR15 HLA-DQ3 HLA-DQ6 HLA-DP4 HLA-DP4 6/13/2024 25  The inheritance of HLA alleles and haplotypes within a family. 6/13/2024 https://clinicalgate.com/histocompatibility-hla-and-other-systems/ 26 3. Show Linkage Disequilibrium Genetic Linkage: The MHC region exhibits strong linkage disequilibrium, meaning certain alleles at different loci are inherited together more often than would be expected by chance. Haplotypes: Specific combinations of MHC alleles, or haplotypes, are often found together in the population due to this linkage. 6/13/2024 27 Examples of Strong Linkage Disequilibrium in the MHC Region HLA-DRB1 and HLA-DQB1 Linkage: HLA-DRB1 and HLA-DQB1 are part of the HLA class II region. These loci often exhibit strong LD, meaning specific alleles at HLA-DRB1 are frequently found with specific alleles at HLA-DQB1. Example: The HLA-DRB103:01 allele is commonly associated with the HLA-DQB102:01 allele. This haplotype is linked to an increased risk of autoimmune diseases like type 1 diabetes and celiac disease. HLA-B and HLA-C Linkage: HLA-B and HLA-C, both class I genes, also exhibit strong LD. Certain alleles at these loci are inherited together more often than by chance. Example: The HLA-B08:01 and HLA-C07:01 alleles form a common haplotype. This combination is part of the larger 8.1 ancestral haplotype, which is associated with various autoimmune conditions. HLA-A and HLA-B Linkage: Although HLA-A and HLA-B are physically further apart compared to other gene pairs in the MHC region, they still demonstrate significant LD. Example: The HLA-A01:01 and HLA-B08:01 alleles are often inherited together. This haplotype is also part of the 8.1 ancestral haplotype, showing a complex pattern of inheritance and disease association. 6/13/2024 28  MHC restriction first demonstrated by Peter Doherty and Rolf Zinkernagel from studies of virus specific toxic cells. Virus specific cytotoxic T cells generated in say MHC(A) type individual can not recognize and kill the same virus infected cells from an individual having MHC(B). Co-recognition of peptide and MHC molecule by TCR is known as MHC restriction. 6/13/2024 29  MHC Restriction of T cells T cells recognize antigen presented by MHC molecules in a highly restricted manner. T cells (e.g. from a HLA- B8+ individual) that recognize a particular pMHC combination (e.g. peptide/HLA-B8) (left panel) will not be able to recognize the same peptide bound by a different MHC molecule (e.g. HLA-B44) (middle panel), nor will they be able to recognize a different peptide bound to the same MHC (e.g. HLA-B8). 6/13/2024 J.K. Archbold et al. / Molecular Immunology 45 (2008) 583–598 30  Importance of MHC in Immune Response T Cell Activation: MHC molecules present antigens to T cells, initiating the adaptive immune response. Self vs. Non-self: MHC molecules help the immune system distinguish between self and non-self. Clinical Relevance: Importance in organ transplantation, autoimmune diseases, and vaccine development. 6/13/2024 31  Clinical Implications Transplantation: Autoimmunity: Vaccination: Role in graft rejection Certain MHC alleles are MHC molecules play a and matching donor- associated with role in how individuals recipient compatibility. autoimmune diseases. respond to vaccines. 6/13/2024 32  Anthropological studies HLA are closely linked and their distribution in the population is markedly restricted. Information derived from HLA polymorphism shows that sub-Saharan African populations are genetically most diverse and the founding human race was probably of the African descent. the migration patterns of certain peoples of these populations could be determined through HLA characterization. Liberians appear more closely related to a distinct Malawian population than to their West African neighbors. 6/13/2024 33  Forensic use of HLA typing Identification of Individuals: HLA Profiling: HLA genes are highly polymorphic, and their variability can be used to create a unique genetic profile for an individual, similar to DNA profiling but with greater variability. Missing Persons Cases: HLA typing can be used to identify individuals in cases where DNA profiling is not feasible or where there is no reference DNA sample available. Body Identification:Mass Disasters: In mass disaster situations, such as plane crashes or natural disasters, where traditional identification methods may be challenging due to body condition, HLA typing can aid in identification. Forensic Anthropology:Remains Analysis: HLA typing can complement anthropological and odontological methods in identifying human remains. Parentage Testing:HLA Matching: HLA typing can be used for parentage testing when the biological parents are unavailable, particularly in cases involving disputed parentage or where traditional DNA testing is not possible. Criminal Investigations:Trace Evidence: HLA typing can potentially be used to analyze trace evidence left at crime scenes, such as bodily fluids or tissues, to link suspects to the scene. 6/13/2024 34  HLA and disease association Type 1 Diabetes: HLA-DRB104 and HLA-DQB103 alleles are associated with an increased risk of type 1 diabetes. Rheumatoid Arthritis: HLA-DRB101 and HLA-DRB104 alleles are associated with susceptibility to rheumatoid arthritis. Celiac Disease: HLA-DQ2 (HLA-DQA105:01-DQB102:01) and HLA-DQ8 (HLA- DQA103:01-DQB103:02) are strongly associated with celiac disease. Infectious Diseases: HIV/AIDS: Certain HLA class I alleles, such as HLA-B57:01 and HLA-B27:05, are associated with slower disease progression and better control of viral replication. Hepatitis B: HLA-DPB1*05:01 is associated with chronic hepatitis B infection. Drug Hypersensitivity: Abacavir Hypersensitivity Reaction: HLA-B*57:01 is strongly associated with hypersensitivity to the antiretroviral drug abacavir. 6/13/2024 35  References 1. The Human Major Histocompatibility Complex: Evolution, Organization, and Expression" edited by Peter Parham. 2. IMGT/HLA Database: A comprehensive database of HLA sequences and allele information maintained by the International Immunogenetics Information System (IMGT). 3. HLA Genotype Frequency Database: Provides allele frequency data across different populations for various HLA loci. 6/13/2024 36  END 6/13/2024 37