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HLA and more Ilias I.N. Doxiadis Geneva – 03/04/2012 www.ebmt.org HLA and more HLA and more / Doxiadis 2 Topic of the day Compatibility testing is a type of testing used to ensure compatibility of the system/application/website built with various other objects such as other web browsers, hardware platforms, HLA and more… KISS = Keep It Short and Simple What is HLA? • Human Leukocyte Antigens • Expressed on almost all nucleated cells (red cells have remains of some HLA molecules (Blood group BG = HLA-B7; platelets express HLA (megakaryocytes ) • Plays a key role in immune response (navel of the immune world) and in some other things What is immunogenetics? • Polymorphic (variable) genes involved in immune action • Mendelian inheritance (green peas story of the Czech monk) Scientists on this field are enthusiastic! HLA • Originally detected as blood groups present on white blood cells (Human Leuk(c)ocyte Antigens) but present on almost all nucleated cells and platelets. • More polymorphic than red blood groups: ABO system: 4 possible combinations (A,B,AB, O) HLA system: >1 million combinations (linkage disequilibrium) HLA antigens (leading to an antibody production) ABO natural antibodies HLA only antibodies after confrontation (!) with foreign HLA antigens i.e. pregnancy, blood transfusion and transplantation (* post SCT problems) 1954: antibodies can cause leukocyte agglutination HLA: Human Leukocyte Antigens Complement-dependent cytotoxicity Negative reaction Positive reaction CDC Serological difference between HLA-B35 and B53 B*35:01 = B35 (Bw6) AA pos. 77 80 81 82 83 B*35:01 Ser Asn Leu Arg Gly B*53:01 Asn Ile Ala Leu Arg B*53:01 = B53 (Bw4) Human Leucocyte Antigens DNA Typing: DNA (from any suitable source) is amplified using specific primers. The needed level of resolution defines the method to be used. Allelic difference between HLA-B*35 and B*53 N B*35:01 77 80 81 82 83 AGC AAC CTG CGC GGC B*53:01 AAC ATC GCG CTC CGC Polymorphism of the HLA system A Specificities: C B DR DQ A*01 B*51 DR*01 A*02 B*07 DR*15 A*03 B*08 DR*03 A*11 B*44 DR*04 A*69 B*15 DR*07 etc etc etc DP Chromosome 6 A C B Chromosome 15 HLA class I molecules present on all nucleated cells and platelets Beta-2 microglobulin Chromosome 6 DR αβ DQ αβ DP αβ HLA class II molecules, mainly expressed on antigen presenting cells: dendritic cells, monocytes, B-cells and activated T cells A1 B8 DR3 A2 B12 DR4 A3 B7 A9 B60 A1 B8 A3 B7 DR2 DR5 DR3 DR2 Genetics of HLA: mendelian inheritance; codominant expression Haplotype: set of HLA genes on one chromosome Phenotype: set of antigens expressed on the cells Genotype: set of genes on the DNA cd ab ac 25 % ad bc HLA haploidentical 50 % HLA different HLA identical ac bd 25 % The HLA system >7,000 HLA alleles monomorphic sites T cell recognizes target cell T cell starts to destruct target cell Function Lysis of target cell Role of HLA in the immune response patient APC HLA I IgG HLA II antibodies CD8+ B CD4+ T T cytotoxic T cell helper T cell HLA class I /self peptide No recognition CD8+ T cell Viral protein virus HLA class I /viral peptide Recognition CD8+ T cell Self protein APC HLA class II Not recognized CD4+ T cell virus APC HLA class II Activation CD4+ T cell Clinical consequence of HLA polymorphism Viral protein Viral peptide HLA-A1 + HLA-A2 + HLA-A3 + HLA-A11 -- Polymorphism HLA is clinically relevant • Different HLA molecules bind different peptides presented to T cells • HLA associations with infectious diseases (e.g. B53) • HLA associations with auto-immune diseases i.e. ankylosing spondylitis (B27), diabetes, rheumatoid arthritis Characteristics of MHC molecules: Enormous polymorphism Consequence: differential binding of antigenic peptides and differential immune response to pathogens. Increased incidence of heterozygosity Consequence: more possibilities for peptide binding and broader immune response Question: How and why did MHC polymorphism evolve? Analysis of HLA alleles in different populations New HLA class I alleles in Amerindians Variation is induced in the groove Hypothesis viral pressure leads to selection new alleles Gene frequencies HLA class I alleles survivors versus controls 16 14 12 10 survivors controls 8 6 4 2 0 A30 B7 B12 B17 Gene frequencies HLA class II alleles survivors versus controls 30 25 20 survivors controls 15 10 5 0 DR2 DR4 DR12 DR13 mismatches / matches / incompatibilites What is a mismatch? P: HLA-A1, A2; B7, B8; DR2, DR3 D: HLA-A1, A2; B7, B15; DR2, DR3 MM ? P: HLA-A1, A2; B7, B8; DR2, DR3 D: HLA-A1,-; B7, B8; DR2, DR3 MM ? P: HLA-A1, A2; B7, B8; DR2, DR3 D: HLA-A3,-; B7, B8; DR2, DR3 MM ? What is a mismatch? P: HLA-A1, A2; B7, B8; DR2, DR3 D: HLA-A1, A2; B7, B15; DR2, DR3 D>P MM ? no P: HLA-A1, A2; B7, B8; DR2, DR3 D: HLA-A1,-; B7, B8; DR2, DR3 D>P MM ? yes P: HLA-A1, A2; B7, B8; DR2, DR3 D: HLA-A3,-; B7, B8; DR2, DR3 D>P MM ? yes SCT • T cell mediated response • By introduction of incompatibilties humoral response possible • Post transplantation treatment of the patient requires the control of HLA specific antibodies in the donor and the patient Immunogenetics and .. fun Rhodents prefer partners with dissimilar MHC Different H-2 80% Recognition based on odour: H-2 identical 20% similar results when urine is used Yamazaki et al., 1979 Do the MHC genes play a role in partner choice? MHC-dependent mating preferences in man (Wedekind et al., 1995) •Female (N=49) and male students (N=44) were typed for HLA-A,-B and –DR. •The male students had to use neutral soap and no after-shave etc. •Each male student wore a T-shirt for two consecutive nights. •Next the T shirts were collected but not washed T-shirts are put in a box and females are asked to smell Each women is asked to judge the odour of 7 T-shirts: • 3 of man with a similar HLA type. • 3 of man with a dissimilar HLA type. • 1 control (fresh) T shirt. Females prefer odour of males with dissimilar HLA types very nice Pill using women 6 5 4 3 2 1 terrible 0 HLA dissimilar HLA similar HLA dissimilar HLA similar Wedekind et al.,1995 Females prefer odour of males with dissimilar HLA types very nice Pill using women 6 5 4 3 2 1 terrible 0 HLA dissimilar HLA similar HLA dissimilar HLA similar Wedekind et al.,1995 Summary and conclusions • To work in the field of immunogenetics is really rewarding • The function of the molecules is the immune surveillance towards pathogens • Transplantation reflects all attributesof immunity • Among all these factors is HLA one of the major components. Stem cells and diseases…. The end ! Thank you