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Lecture

Lecture. Major histocompatibility complex MHC. Introduction. Every mammalian species studied to date possesses a tightly linked cluster of gen e s – the major histocompatibility complex – whose products (MHC antigenes) are associated with self/nonself discrimination .

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Lecture

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  1. Lecture Major histocompatibility complexMHC

  2. Introduction Every mammalian species studied to date possesses a tightly linked cluster of genes – the major histocompatibility complex – whose products (MHC antigenes) are associated with self/nonself discrimination. The MHC copmplex plays a central role in the development of both humoral and cellular immune response.

  3. Basic terms • MHC – major histocompatibility system, system of genes whichproducts determine the discrimination of self and nonself • major histocompatibility (transplantation) antigenes • -products of MHC genes • HLA – human leukocyte genes or antigens (human MHC) • H-2 – MHC of mice • haplotype – a group of MHC genes on single chromosome • allele – one of the several alternate forms of a gene at a single locus that control a particular characteristic • polymorphism – the existence of multiple alleles of single gene in population

  4. Major histocompatibility complexMHC Structure

  5. Structure of MHC molecules MHC class I MHC class II

  6. MHC I and binding of Ag fragments Top view Antigen fragment (green) is trapped by MHCI molecule in endoplasmic reticulum and transported to the surface of the cell. The Ag fragment spans for 8-10 amino-acid residues. Alfa helices of 1 and 2 domain (red) bind Ag fragment.

  7. Structure MHC I and peptide binding Side view

  8. MHC and TCR Antigens and superantigens Antigens are processed by APC cells and presented in the frame of MHCII molecules. Ag fragments are localized in the cleft between 1 and 1 domains of MHCII. APC`s activate just Ag specific clone of T cells. (right side of picture) Superantigens bind out of MHC cleft and activate many clones of T cells. The response is nonspecific, produce a lot of mediators (interleukines) that can lead to shock reaction. (left side of picture)

  9. Antigen processing and presentation MHC II molecules • Exogenous antigens (Ag) are presented by APC cells. • MHCII is synthesized in endoplasmic reticulum. Transported to Golgi system and released to cytoplasma in primary lysosome. • Ag is endocytosed and transported in early edosome. • After fusion of early endosome and primary lysosome the Ag is degradated to Ag fragments by lysosmal enzymes. • Fragments of Ag are trapped by MHCII molecules and expressed on cell surface where recognized by Th cells. APC cell

  10. Activation of Th cells MHC II molecules Th cells recognize Ag fragments by TCR (T cell receptor). The response of Th cells depend on the affinity between TCR and MHCII+Ag. 1) low affinity (usually self Ag) -> T cells are not activated 2) high affinity (usually foreign Ag) - > T cells accept the interaction as THE FIRST SIGNAL, but the T cells are still not fully activated. After delivery of SECOND SIGNAL represented by cytokine IL-1 (produced by macrophages) Th cells became ACTIVATED and provide HELP for : 1) Tc cells via IL-2 ( Tc became cytolytic) 2) B cells via IL-4, IL-5 (proliferation, diferentiation, class switching)

  11. Activation of Th cells MHC I molecules Endogenous antigenes (foreign as well as self) are presented by all nucleated cells. MHCII molecules are synthesized in endoplasmic reticulum. Endogenous Ag is cleaved in cytoplasm by proteasome and Ag fragments are transported to endoplasmic reticulum via TAP transporters. Ag fragments are then trapped by MHCII molecules and transported to surface of cell membrane, where recognized by Tc cells.

  12. Activation of Tc cells MHC I molecules Tc cells recognize Ag fragments by TCR (T cell receptor). The response of Tc cells depend on the affinity between TCR and MHCI+Ag. 1) low affinity (usually self Ag) -> T cells are not activated 2) high affinity (usually foreign Ag) - > T cells accept the interaction as THE FIRST SIGNAL, but the T cells are still not fully activated. After delivery of SECOND SIGNAL represented by cytokine IL-2 (produced by Th cells) Tc cells became ACTIVATED- cytolytic and lyse cells which present the Ag which was recognized during the first signal delivery.

  13. Major histocompatibility complexMHC Genetics

  14. Genetics • MHC genes are: • verypolymorphic • inherited according Mendelian rules • expressed codominantly on the cells

  15. The MHC complex

  16. Simplified organization of MHC complex

  17. Major histocompatibility complexMHC Functions

  18. Transplantation

  19. Biological roles of MHC molecules T cell maturation Transplantation MHC molecules Susceptibility to infection Autoimmunity Legal medicine

  20. Graft versus host reactionGvHR Common manifestations (figure 4) of GVH reaction are diarrhea, erythema, weight loss, malaise, fever, joint pains, etc. and ultimately death.

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