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MAJOR HISTOCOMPATIBILITY SYSTEM (MHC) AND ITS IMMUNOBIOLOGICAL RELEVANCE

MAJOR HISTOCOMPATIBILITY SYSTEM (MHC) AND ITS IMMUNOBIOLOGICAL RELEVANCE. HLA genes: - app. 60 genes located on the 6 th chr. - HLA I class - HLA II class - HLA III class  POLYMORPHISM: - alteration of many allels on particular locus  HAPLOTYPE:

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MAJOR HISTOCOMPATIBILITY SYSTEM (MHC) AND ITS IMMUNOBIOLOGICAL RELEVANCE

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  1. MAJOR HISTOCOMPATIBILITY SYSTEM (MHC) AND ITS IMMUNOBIOLOGICAL RELEVANCE

  2. HLA genes: - app. 60 genes located on the 6th chr. - HLA I class - HLA II class - HLA III class  POLYMORPHISM: - alteration of many allels on particular locus  HAPLOTYPE: HLA genes are linked sets of maternal and paternal HLA genes are inherited individual is heterozygous in out-bred population

  3. HLA SYSTEM: - MHC H. sapiens - Human Leukocyte Antigens (transplantation Ag) is a group of tightly linked genes is highly polymorphic products of HLA genes are expressed on the surface of cells is necessary for the specific recognition in the immune system is necessary for distinguishing of „self“ and „non-self“ is responsible for the individual resistance (susceptibility) to infection is responsible for increased individual susceptibility to autoimmune, immunopathological diseases

  4. ORGANISATION OF HLA SYSTEM, GENE POLYMORFISM HLA II class HLA III class HLA-DP HLA-DQ hsp HLA-DR TAP 1,2 LMP TNF- C4 B C2 A B A B A B 19 89 20 45 2 323 number of allels HLA I class HLA-C HLA-J HLA-H HLA-G HLA-F HLA-B HLA-E HLA-A number of allels 395 93 2 2 195 2 2

  5. EXPRESSION: HLA I: nuclear cells, platelets HLA II: antigen-presenting cells (macrophages, B cells, activated T cells, others) HLA III: component of complement, TNF, LMP, TPA, hsp

  6. 1 2 3 2 3 1 2M 2M HLA -I MOLECULE HLA -II MOLECULE DNA - 6th chromosome DNA - 6th chromosome 5' L Tm C ´3' 5' L 1 2 Tm C ´3' 1 2 S S S S H2N S S S S COOH COOH S H2N S S S H2N COOH 1 2 L 1 2 Tm C 5' ´3' 5' ´3' DNA - 15 th chromosome DNA - 6th chromosome

  7. FUNCTION: T cells can recognize only processed antigenic peptides that are bound to self HLA I or II molecules HLA restriction ANTIGENIC PEPTIDE: is bound to the polymorphic part of HLA weak chemical interactions between AAs PROCESSING AND PRESENTATION OF ANTIGENS TO T CELLS T cells recognize antigen through TcR T cells recognize antigenic peptides (processed) antigens are processed in antigen-presenting cells antigenic peptides have to be bound to self HLA

  8. EXOGENOUS ANTIGENS: - are bound to HLA II molecules - are recognized by helper inducer T cells - interaction between HLA II and CD4 PRESENTATION OF EXOGENOUS ANTIGENS exogen. protein Endocytosis Ag HLA II   Fusion GOLGI apparatus Endosome Endoplasmic reticulum Exocyt vacuole   HLA II Ii (invariant chain) mRNA

  9. - are bound to HLA I molecules - are recognized by suppressor cytotoxic T cells - interaction between HLA I and CD8 - polymorphism in TAP and proteasome molecules ENDOGENOUS ANTIGENS: Presentation of endogenous antigens HLA I b2M CALNEXIN HLA I. TAP Endog. protein Ag peptides DEGRADATION UBIQUITINATION Proteasome

  10. ASSOCIATION OF HLA SYSTEM AND DISEASES Certain haplotypes predispose to susceptibility or resistance to: infections autoimmune immunopathological disorders MOLECULAR BASIS: unique AAs composition of binding site for Ag on polymorphic part of HLA molecule different intensity of antigenic peptide binding different intensity of antigen presentation

  11. BINDING OF ANTIGENIC PEPTIDES TO HLA I MOLECULES 1 antigennic peptide 8 leu 4 7 3 5 val 2 6 9 HLA-A2 4 5 1 arg 7 8 6 3 HLA-B 27 9 2

  12. HLA SYSTEM TYPING There are two approaches: - analyses of HLA genes - analyses of HLA molecules HLA GENES: - PCR - DNA fingerprinting - most modern - most reliable - most rapid  HLA MOLECULES: - antigenic differences - serotypisation (HLA I molecules) - mixed-cultures (HLA II molecules) 

  13. CLINICAL SIGNIFICANCE OF HLA SYSTEM: transplantation immunology association with diseases paternity population study criminalistic investigations

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