MAJOR HISTOCOMPATIBILITY COMPLEX

MHC A very important topic to the point of view for immunology here you will be able to learn about the detailed information of it

1. P R E S E N T E D B Y : PRADDUM KUM A R NAMDE V BSc (Hons) ZOOLOGY 6 th sem. M A J O R HISTOCOMPATIBILITY C O M P L E X 1

2. This presentation include s : What are MHCs? What do MHC do Types of MHC MHC class І MHC class ІІ MHC class ІІІ MHC molecules and antigen presentation Features of MHC class I and II Peptides of MHC class I and II Important aspects of MHC 2

3. What are MHCs? Discovered by Peter Gorer in 1930 Major histocompatibility complex (MHC) is tightly linked cluster genes present in every vertebrate species, the product of which play in intercellular recognition and in discrimination between self and nonself . MHC is located on chromosome 6 in humans and chromosome 17 in mice (HLA – Human leukocyte antigen) complex and H-2 (histocompatibility- 2) respectively. 3

4. Contd… MHC genes are organized 3 classes Class І MHC genes Glycoproteins expressed on all nucleated cells Major function to present peptide Ags to Tc cells Class ІІ MHC Glycoproteins expressed on M ф , B cells, DCs Major function to present processed Ags peptide to T H cells Class ІІІ MHC Class III molecules are not membrane proteins, are not related structurally to class I and class II molecules, and have no role in Ag presentation, although most play some role in immune response. e.g. C2, C4a, C4b, factor B21-hydroxylase enzymes, TNF α , TNF β , heat shock proteins (HSP). 2

5. What do MHCs do? MHCs bind to peptide fragments (parts of chopped up through phagocytosis by APCs) and display/present them on the surface of the cell. The T cells monitor the MHCs for evidence of an invasion of a cell or for foreign cell. B cells do not interact with MHCs directly but come into action after stimulation by T cells. 5

6. Types of MHCs… CLASS І MHC molecules Molecular weight 45KD Found on almost all nucleated cells (except RBCs) Bonds to portions of antigens (peptide fragments ) Presents them on the cell surface. Cytotoxic T cells can recognize and begin specific defense . 6

7. Contd… It is membrane spanning molecule approx. 350 amino acids in length, 75 amino acids comprising the transmembrane and cytoplasmic portions. The remaining 270 amino acids are divided into three globular domains α -1, α -2 and α -3 The alpha chain is trans membrane glycoprotien encoded by A,B and C regions of human HLA complex and within the K and D regions of mouse H-2 complex T he second portion of the molecule is globular protein called β -2 microglobulin associactes with the α -3 domain and is necessary for MHC stability. Microglobulin is a protein encoded by highly conserved gene located on different chromosomes. 7

8. Contd… the β 2 microglobulin is non covalently associated with the α 3 domain. The α 1 and α 2 domains interact to form 8 antiparallel β strands spanned by 2 long α helical regions. The region is capable of binding (via non-covalent interactions) as small peptide of 10 amino acids. This small peptide is “presented” to a T-cell and defines the antigen “epitope” that the T-cell recognizes . The peptide-binding cleft is located on the top surface of the MHC class І molecule and it is enough to bind a peptide 8 to 10 amino acids. 8

9. Structure of MHC І 9 Fig.1 MHC I molecules are composed of a polymorphic chain non covalently attached t a non polymorphic microglobulin ( β 2m). The α -chain is glycosylated

10. Contd… Between the α -1 and β -2 domains lies a region very similar to that seen in the class І molecule. This region, bounded by a β - pleated sheet on the bottom and two alpha- helices on the sides, is capable of binding (via non-covalent interactions) a small peptide of about 10 amino acids, this small peptide is presented to a T-cell and defines the antigen “epitope” that the T-cell recognise. 10

11. Class ІІ MHC molecule Class ІІ molecules are composed of two polypeptide chains. These polypeptides (alpha and beta) are about 230 and 240 amino acids long respectively, and are glycosylated, giving molecular weights of about 33 kDa 28 kDa. The polypeptides fold into two separate domains; α 1 and α 2 for the alpha polypeptide, and β -1 and β -2 for the beta polypeptide. 11

12. Structure of MHC ІІ molecule 12 Fig.2 MHC II molecules are composed of a polymorphic α -chain non-covalently attached to a polymorphic β -chain. Both are glycosylated

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14. MHC Class ІІ І molecule These are heterogeneous molecules Include complement component C2, C4 and factor B (components responsible for formation of C3 convertase) They also include heat shock proteins and tumour necrosis factor. 14

15. MHC molecules and antigen presentation Both type of membrane glycoproteins (class I and class II MHC) function as highly specialised antigen-presenting molecules. The class I and class II MHC molecule present antigen to T-cells. Antigen recognition is mediated by αβ or γδ T-cell antigen receptors (TCR). T-cell recognize only combined with MHC molecules. Class I molecule present processed endogenous Ag to CD8 T-cells . Class II molecule present processed exogenous Ag to CD4 T-cells . Exogenous antigens are those antigens that originate outside the organism or cell whereas endogenous antigens originates within the organism or cell. 15

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17. Features of class І & class ІІ MHC 17

18. Peptides of MHC I & MHC II Class I MHC molecule present a peptide of 8-10 amino acids and are endogenous. Peptide bind MHC due to presence of specific a/a found at the ends of peptide. e.g. Gycine @ position 2. Class II MHC molecules bind and present slightly longer peptides of 13-18 amino acids, processed through endocytic pathway. Non peptide antigens (such as glycolipid, phospholipid) are presented by members of the CD1 family related to non classical class MHC I. 18

19. Important aspects of MHC MHC molecules (class I and class II) are membrane bound; recognition by T- cells requires cell-cell contact. Because each MHC molecule can bind to many different peptide, binding id termed degenerate. Although there is high degree of polymorphism for a species, an individual has maximum 6 different class I MHC products and only slightly more class II MHC products (considering only the major loci). Each MHC molecule has only one binding site. The different peptides can bind to a given MHC molecule to the same site, but only at a time. MHC polymorphism determined only in the germline. There are no recombination mechanism for generating diversity, 19

20. Contd… Alleles for MHC genes are codominant. Each MHC gene product is expressed on the cell surface of an individual nucleated cells. Cytokines (especially interferon- γ ) increase level of expression of MHC. Endogenous peptide associate with class I MHC are recognised by T C cells. Exogenous peptide associate with class II MHC are recognised by T H cells . 20

21. LIFE SCIENCES FUNDAMENTALS AND PRACTICES -1 (PATH FINDER PUBLICATION) BY- PRANAV KUMAR www.slideshare.com www.immunologynotes.com 21 References

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