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Immunogenetics Marie Černá Lecture No 635-T Immune system • belongs to basic homeostatic mechanisms of organism • Its function is maintaining the integrity of organism by recognition of harmful from harmless, and by this way it protects organism against injurious matter of external and internal origin. Immunogenetics Study characters of heredity laws of antigen recognitions. An antigen is any substance: biological / chemical, natural / artificial, self / nonself • that elicits an immune response. Immunity • Innate immunity – First line – integrity of the skin and the mucosa – Second line – nonspecific defense itself - cellular components - humoral components • Acquired immunity - cellular components - humoral components Innate immunity First line – integrity of the skin and the mucosa – defense mechanisms: mechanical (movement of cilia) chemical (fatty acids, pH 3-5, lysozyme) microbial (normal microbes) Innate immunity Second line – nonspecific defense itself - cellular components: phagocytic cells natural killer (NK) cells - humoral components: complement system interferons Acquired immunity Specific defense only in vertebrates - cellular components: T - lymphocytes B - lymphocytes - humoral components: antibodies produced by B - lymphocytes Induction of immunological memory Acquired immunity antibodies plasma cells T effector cells foreign antigen B lymphocytes humoral immunity lymphoblasts T lymphocytes cell immunity Acquired immunity • Vertebrates react selectively against a broad spectrum of foreign antigens. • Large variability of specific immune reactions is encoded in the genome. • Specific selective respond results from somatic recombination and rearrangement of genes (antigen receptors – TCR and Ig) and also huge gene polymorphism (antigen-presenting molecules – HLA). Accessory chains Antigen receptors Immunoglobulins (Ig) – humoral (cellular) • L – light chain – 2 isotypes + • H – heavy chain – 5 isotypes μ, δ, γ, ε, α T cell receptors (TCR) – cellular • α chain (or δ chain) • β chain (or γ chain) Each chain contains: - constant region C - variable region with V, (D), J subregions - region for antigen binding chromosome No: Immunoglobulins (Ig) 2 heavy, 2 light chains Genetic Diversity Genes are rearranged, during activation of lymphocytes, differently and specifically for every cell – somatic recombination Allelic exclusion: Each antibody (receptor of T lymphocyte) contains the combination of 2 chains (H+L, α+β) of one type - active genes only on 1 chromosome (transcription from 1 allele/haplotype) Genetic Diversity • The combinations of V, D and J segments: V 1-100 variable segment D 1-20 diversity segment J 1-10 joining segment • Inaccuracy in lining these segments • Random insertion of nucleotides at the joints between the segments • Somatic mutations in the J segment Somatic recombination IgH locus: V-D-J combinations C- for M,D,G,E,A constant region - defines Ig class V1 V100 D1 D20 IgL locus: V-J combinations Ig L kappa Ig L lambda J1 J2 J3 J4 J5 V D V100 J1 J2 J3 J4J5 V100 J1-10 C1-10 J C1 C C T cell receptors (TCR) T cell receptors (TCR) α chain and δ chain loci: V-J combinations β chain locus: V-D-J combinations (IgH locus) γ chain locus: V-J combinations locus: Genetic diversity in Ig and TCR genes Mechanism Variable domains Immunoglobulin H chain L chain 250 – 1 000 a TCR b 250 75 25 Number of D segments 12 0 0 2 Number of J segments 4 4 50 12 Segment Combinations 65 000 - 250 000 1 825 Total diversity 1011 1016 Antigen presenting system binding to TCR Major histocompatibility complex (MHC): a group of genes on one chromosome. This gene complex was discovered after observation that histocompatibility, i.e. the ability to accept graft (transplant), depends on fact if the donor and recipient share the same MHC haplotype. MHC antigens of man: Human leukocyte antigens - first detected on leukocytes HLA complex • contains three classes of genes (I, II, III) • one of the most polymorphic loci in human genome (5 500 alleles) • is inherited en bloc as a haplotype HLA complex 6 HLA class I and class II transmembrane proteins presenting antigens to TCRs on T- lymphocytes - TCRs recognize antigens only in context with MHC molecules part of cellular immune response class I - serologicaly defined antigens contains genes, each gene encodes one alpha chain – classical: A, B, C – on all nucleated cells recognized by cytotoxic CD8+ T-lymphocytes – non-classical: E, F, G – on certain tissues (placenta) recognized by NK cells (inhibition effect on NK cells) class II = region D - cellularly defined antigens loci: DP, DQ, DR, each locus contains alpha + beta chains on antigen-presenting cells (macrophages, B lymphocytes) recognized by helper CD4+ T-lymphocytes HLA class III mostly serum proteins part of humoral immune response + other genes without any function in immune responsiveness • • • • Complement system molecules: C2, C4, Factor B Cytokines: tumor necrosis factor (TNF) Heat shock proteins (HSP) Enzyme: 21-hydroxylase (mutation cases congenital adrenal hyperplasia) • The gene for hemochromatosis HLA class I The extracellular part of the alpha chain contains 3 domains: a1 a2 a3 (β2 microglobulin is coded on chromosome 15) Polymorphic a1 and a2 domains bind antigenic peptides. HLA class II The extracellular parts of the beta and alpha chains contain 2 domains: β1 β2 and a1 a2 Polymorphic β1 and a1 domains bind antigenic peptides. Allele polymorphism of HLA complex region class I classical gene No of alleles A B class II nonclassical C 965 1543 626 G DR D R A E F 9 21 46 3 DR B DQ DP DR DQ DQ DP B1 A1 B1 A1 855 762 35 107 28 DP B1 138 • One haplotype = haploid genotype = group of alleles on one chromosome - each parent has two haplotypes and transmits one of them to his child • Genes are closely linked => alleles are transmitted together • Alleles are codominant JEAN DAUSSET (1916-2009) 1980 Nobel Prize for HLA discovery in Physiology and Medicine 1952 - white cell agglutination induced by serum antibodies 1958 - the first leukocyte antigen the cardinal words of HLA: • transplantation • cellular immunology • predictive medicine • anthropology Transplantation and MHC MHC match - graft is accepted donor + recipient have the same MHC antigens/alleles MHC mismatch - graft is rejected donor + recipient have different MHC antigens/alleles Graft versus host reaction (in bone marrow transplantation with MHC mismatch) Immunosuppression of recipient => T lymphocytes of donor react against cells of recipient Transplantation laws • 1. H1H1 H1H1 • 2. H1H1 X H2H2 • 3. H1H1 x H2H2 X F1: X H1H2 Transplantation and HLA Organs or tissue Immunology examination: • virology (HIV,HBV,CMV) • ABO and Rh compatibility crossmatch testing – antibody detection: - recipient’ HLA antibodies (after transfusions or deliveries) against donor’ HLA molecules Transplantation and HLA Bone marrow • full HLA match for all genes (A,B,C, DR,DQ,DP) Kidney (and pancreas) • crossmatch - negative • half HLA match for 3 genes (class I - A, B, class II - DR) Liver, lung, heart • crossmatch - negative Transplantation and HLA • Register of bone marrow donors • Waiting list of kidney recipients Predictive Medicine HLA association with autoimmune diseases Anthropology Population studies American Indians have remarkable degree of restriction of the HLA polymorphism • • • • North American Caucasians - 27 DR alleles North American Indians - 20 DR alleles Argentinean Indians - 8 DR alleles Brazilian Indians - 5 DR alleles Blood groups systems Blood groups : A, B, AB, O chromosome 19 - antigen H = precursor (hh Bombay allele) chromosome 9 - antigens A, B group genotype agglutinin in serum A AA, Ai anti B B BB, Bi anti A AB AB - 0 ii anti A, anti B subgroups A 1-5 subgroups B 1-2 Blood Group Antigens Antibodies Donor for Recipient from AB A and B none AB AB, A, B, 0 A A B A and AB A and 0 B B A B and AB B and 0 0 none A and B AB, A, B, 0 0 Rh system chromosome 1 Rh antigens DD, Dd, dd (C, E) Rh + 83% Rh - 17% Maternal-fetal incompatibility mother Rh- (dd) father Rh+ (DD, Dd) baby Rh+ (Dd) Antibodies (IgG) from maternal serum cross the placenta and lyse the red cells of fetus! MN system Blood groups: M N MN genotypes: MM NN MN Literature Genetics in Medicine, sixth edition, revised reprint Thompson & Thompson Saunders, 2004 Chapter 14: Genetics of the Immune System The Major Histocompatibility Complex, Immunoglobulins, The T-Cell Antigen Receptor pages 277 – 285 Literature Medical Genetics at a Glance, second edition, Dorian J. Pritchard & Bruce R. Korf Blackwell Publishing, 2008 Part 2: Medical genetics 42 pages 102 – 103