MHC.pptx

major histocompatibility

1. Major Histocompatibility Complex

2. Major Histocompatibility Complex The Major Histocompatibility Complex (MHC) is a set of molecules displayed on cell surfaces that are responsible for lymphocyte recognition and "antigen presentation".

3. The MHC molecules control the immune response through recognition of "self" and "non-self" and, consequently, serve as targets in transplantation rejection. In humans, MHC is also called human leukocyte antigen (HLA). Major Histocompatibility Complex

4. The major histocompatibility complex is encoded by several genes located on the short arm of human chromosome 6. Major Histocompatibility Gene complex:

5. Major Histocompatibility Gene complex: Class I MHC molecules Contains three loci A, B and C, each of which codes for α chain polypeptides of class I MHC antigenic surface molecules. Cla ss II MHC molecules encoded by DP, DQ, DR regions.

6. 3-Class III region It is not actually a part of the HLA complex, but is located within the HLA region, because its components are either related to the functions of HLA antigens or are under similar control mechanisms to the HLA genes. Class III region encodes for certain complement components (C2, C4, factor B,) and 2 cytokines TNF-α and β. They have no role in graft rejection.

7. A person usually inherits two copies of each gene locus so carries total of six Class I loci(E.g . 2 HLA – A, 2 HLA –B, 2 HLA –C) and six class loci II ( E.g. 2HLA- DR, 2HLA- DP, 2HLA- DQ) Multiple of each locus may persist in human population. There are at least 151 HLA –A alleles, 301 HLA- B alleles and 282 HLA- DRβ alleles. Diversity of this type is called Allelic polymorphism and the MHC genes are the most polymorphic gene. Inheritance of Major Histocompatibility Genes

8. The alleles are “ Codominantly expressed” Each set of allele is referred to as Haplotype. An individual inherits one haplotype from the mother and another haplotype from the father. The alleles are “ Codominantly expressed” that is both maternal and paternal gene products are expressed in the same cell . Inheritance of Major Histocompatibility Genes

9. MHC polymorphism benefits humanity ? Because it increases the likelihood that at least some individuals will be able to present antigens from any new pathogens , thus helping to ensure the survival of the whole population. MHC is also known as HLA as because they are found in high concentration on lymphocytes & other WBCs. Peptide antigens associated with class I MHC molecules are recognized by CD8+ cytotoxic T cells. Inheritance of Major Histocompatibility Genes

10. Regulation of Major Histocompatibility complex (MHC) expression Cytokines : IFN α,β,γ and TNF increases the expression of class I MHC on cells IL-4 increases expression of class II molecules by resting B cell MHC expression is decreased in some viral diseases like CMV, HBV, Adenovirus and in tumer cell.

11. Although the decrease in MHC class I expression decrease CD8+T cells response it may also act as a trigger of NK cells response to virus infected cells and tumor cells. MHC class I are negative regulators of NK cells activity i.e. MHC class I expressed on normal cells interact with killer inhibitory receptor (KIR) expressed on the surface of NK cells so preventing NK cells from killing the host cells. If the cell is MHC-I deficient, the KIR- MHC complex is not formed and the cell is a target for killing with NK cells.

12. A- Class I-MHC Molecules: Class I MHC molecules contain two separate polypeptide chains H eavy (44-47 KDa ) alpha chain Light (12 KDa ) beta chain known as β2-microglobulin . Both α chain and β2-microglobulin are members of the Ig superfamily . Structure of MHC Molecules :

13. 1- Alpha (α) chain: The carboxyl end of α chain resides inside the cell while the amino end projects on the surface of cell . α chain is coded by the MHC genes and has three globular domains α1, α2 and α3. The alloantigenic sites that carry determinants specific to each individual are found in the α1 and α2 domains.

14. The α1 and α2 domains bind T cell receptor (TCR) of CD8 T lymphocytes. α1 and α2 domains show marked variability (polymorphism). The greatest variability in amino acids occurs in the α1 and α2 sequences that line the wall and floor of the peptide binding groove (hyper variable region). α3 domain is constant . The importance of the highly conserved region of α3 is that CD8 molecules present on CD8 T lymphocytes binds to this region.

15. 2- Beta chain (β2-microglobulin): It is encoded by a gene on another chromosome away from MHC genes ( on chromosome 15). It is important for transport a nd expression of MHC-I on the cell surface . Individuals with defective β2 microglobulin gene do not express any class I MHC and hence they have a deficiency of cytotoxic T cells.

16. B- Class II Molecules: MHC class II molecules comprise two non-identical and non-covalently bound polypeptide chains (α and β). 1- α and β chains: These two chains have amino ends on the surface, a short transmembrane stretch and intracytoplasmic carboxyl ends. Both α chain (34 kDa ) and β chain (28 kDa ) are MHC-encoded by the D region .

17. Each polypeptide chain folds into two separate domains; alpha-1 and alpha-2 for the alpha polypeptide, and beta-1 and beta-2 for the beta polypeptide. With the exception of the α1 domain, all domains are stabilized by disulfide bridges .

18. α1 and β1show marked polymorphism while α2 and β2 are largely non-polymorphic. During antigen presentation , CD4 molecule of Helper T lymphocyte binds to β2 domain of the class II MHC molecules.

19. Similarities and differences between MHC class I and II: A- Similarities: 1- functions: They bind peptides and present them at the surface to T cell receptors. Are strong transplantation antigens. MHC molecules bind only one peptide at a time, and all peptides that bind to a particular MHC molecule share the same structural motifs .

20. Similarities and differences between MHC class I and II: 2- Structure: both have Two polypeptide chains. A transmembrane region and a cytoplasmic region. A single peptide binding groove. A polymorphic region (which includes the peptide binding region) and a constant region. 3- Both show genetic polymorphism with multiple alleles in the population.

21.   MHC I MHC II Nomenclature HLA- A, B, C HLA-DP, DQ, DR Found on all nucleated cells dendritic cells, macrophages, B cells and activated T cells Recognized by CD8 TC (CTLs) CD4 TH cells Peptides that are bound Endogenously synthesized in cytosol Exogenously processed in vesicles Bind peptides of 8-9 amino acids of 12-25 amino acids Functions Presentation of antigens to TC cells leading to elimination of abnormal or infected host cells. Presentation of antigen to TH cells which secrete cytokines. β2 micro-globulin Yes No Coded for on chromosome 6 but light chain β2 microglobulin is on chromosome 15 Entirely on chromosome 6. B- Differences:

22. Variability of MHC antigens or (HLA): MHC antigens differ from one individual to another. These differences are genetically determined. These differences in MHC molecules structure arise from 2 sources: 1- polygenecity: 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 and that for class II MHC products rarely exceed six. Thus, as each chromosome is found twice (diploid) in each individual, a normal tissue type of an individual will involve 12 HLA antigens .

23. 2- Polymorphism: It means that multiple stable forms of each MHC gene (multiple alleles) exist in population. Although MHC molecules are diverse within the population, each cell in a particular person expresses the same set of HLA class I and class II molecules.

24. Antigen Processing and Presentation Types of antigens Endogenous antigens are generated within a cell (e.g., viral proteins in any infected cell, tumor antigens ) Exogenous antigens (inhaled, ingested, or injected) are taken up by antigen-presenting cells (APCs) by endocytosis .

25. Antigen Processing and Presentation Intracellular peptides for MHC class I presentation are made by proteases and the proteasome in the cytosol, then transported into the endoplasmic reticulum via TAP (Transporter associated with Antigen Processing) to be further processed . They are then assembled together with MHC I molecules and travel to the cell surface ready for presentation.

26. a- Presentation of endogenous antigens in MHC-I pathway: Endogenous antigens are processed in the cytoplasm. They are degraded by proteasomes into fragments (peptides) within the cell. Class I histocompatibility molecules are synthesized by ribosomes on the rough endoplasmic reticulum (RER) and assembled within its lumen then move through the Golgi apparatus to the cell surface . Antigen Processing and Presentation

27. MCH Class II Molecules The route of processing for  exogenous  antigens for MHC class II presentation begins with endocytosis of the antigen. Once inside the cell, they are encased within endosomes that acidify and activate proteases, to degrade the antigen. MHC class II molecules are transported into  endocytic vesicles  where they bind peptide antigen, and then travel to the cell surface.

28.   Endogenous (cytosolic) Exogenous (vesicular) Types of cells in which antigen is processed then presented All nucleated cells Dendritic cells, Macrophages and B cells Source of protein antigen Mainly endogenously synthesized proteins in the cytosol e.g. viruses. Extracellular proteins or microbes internalized in vesicular compartment Site of processing Cytoplasm Vesicles Enzymes responsible for peptide generation Cytosolic proteasomes Endosomal and lysosomal proteases Site of peptide loading of MHC Endoplasmic reticulum (ER) Specialized vesicular compartment Peptides bind to MHC-I MHC-II Peptide/MHC complex is presented to CD8 cytotoxic T cells CD4 helper T cells Outcome Killing of presenting cells by CTLS Secretion of cytokines by TH cells activating macrophages and other cells.

29. Significance of MHC 1-Organ transplantation and graft rejection. 2-MHC is essential for antigen presentation: TC recognizes antigens only in association of MHC-I molecules and TH recognize antigens only in association of MHC-II molecules. 3-Paternity testing and forensic investigations.

30. 4-Disease association: certain HLA types are associated with some autoimmune diseases. E.g. HLA-B27 is associated with ankylosing spondylitis, Reiter's disease and post gonococcal arthritis. DR2 is associated with multiple sclerosis, B8 with myasthenia gravis, DR4 with rheumatoid arthritis, and DR5 with Hashimoto's thyroiditis. Significance of MHC