Major Histocompatibility Complex (MHC) Dr. Mohammad Odibate

1. Major Histocompatibility Complex (MHC) Dr. Mohammad Odibate

2. Introduction Definition of the MHC Is a set of cell surface molecules encoded by a large gene family which controls a major part of the immune system in all vertebrates MHC molecules play a major role in three lines Antigen presentation Autoimmune diseases Transplantation

3. MHC molecules MHC nomenclature MHC were formerly called Human Leukocyte Antigens (HLA) because they were discovered at first on the human leukocytes (WBCs). Later on they called MHC molecules because of their important function in tissue compatibility

4. MHC Molecules MHC genes in humans are found on the short arm of chromosome 6 and are divided into three categories or classes. • Class I molecules are coded for at three different locations or loci, termed A, B, and C. • Class II genes are situated in the D region, and there are several different loci, known as DR, DQ, and DP. • Class III genes, which code for complement and TNF proteins

5. MHC-encoded -chain of 43kDa 2 1 2m -chain anchored to the cell membrane 3 Peptide antigen binds in a groove formed From a1 and a2 domains 2-microglobulin, 12kDa, non-MHC encoded, non-transmembrane, non covalently bound to -chain Class I MHC Molecule Overall structure of MHC class I molecules

6. Why do we have millions of different versions of MHC molecules? APC can express a huge number of MHC molecules that eventually react with Antigens in the phagolysosome searching for antigens specific to the MHC binding site APC

7. MHC genes (alleles) Inheritance of MHC genes • Multiple allele are present at each of MHC gene MHC- I MHC- I MHC- III MHC- III MHC-I I MHC-I I Chr.6

8. Human MHC Class 1 and 2 genes are highly polymorphic 921 580 312 • Each MHC locus has many alleles. • The difference in the inheritance of MHC molecules among individuals is due to the presence of a big number of MHC alleles

9. MHC-I Inheritance of MHC-I Ali Omar Ahmad A13 A19 A4 A18 A3 A8 B16 B2 B5 B24 B6 B4 C10 C3 C2 C10 C7 C8 A3 A13 A19 B2 B16 B6 A18 C8 C7 C10 C10 C3 B24 B5 B4 A4 A8 C2

10. MHC-encoded, -chain and a -chain 1 1 a and b chains anchored to the cell membrane 2 2 Peptide antigen binds in a groove formed From a1 and ß1domains MHC-II Overall structure of MHC class II molecules No b-2 microglobulin

11. MHC class I MHC class II Peptide Peptide binding groove Cell Membrane MHC-II MHC-I vs. MHC- II

12. MHC-II Ali Omar Ahmad Inheritance of MHC-II DP7 DP9 DP3 DP13 DP1 DP19 DQ5 DQ1 DQ12 DQ11 DQ3 DQ2 DR7 DR4 DR14 DR12 DR6 DR4 DP19 DP7 DP3 DQ12 DQ2 DQ5 DR12 DR6 DR4 DR7 DR14 DR4 DQ1 DQ3 DP1 DP9 DQ11 DP13

13. Expression of MHC molecules All nucleated ells express MHC1 APC can express both MHC1 & MHC2

14. Functions of MHC molecules • Its products play role in discriminating self/non-self • Participant in both humoral and cell-mediated immunity • MHC act as Antigen Presenting Structures • Genes Of MHC Organized In 3 Classes • Class I MHC genes • Glycoproteins expressed on all nucleated cells • Major function to present processed Ags to TC • Class II MHC genes • Glycoproteins expressed on APC such as M, B-cells, DCs • Major function to present processed Ags to TH • Class III MHC genes • Products that include secreted proteins that have immune functions. Ex. Complement system, inflammatory molecules

15. Functions of MHC-I molecules Types of endogenous proteins synthesized in the human cells including: The normally synthesized cellular proteins The mutated cellular proteins The viral proteins (antigens) A small amount of these proteins are directed to the proteosome in which these proteins are degraded into short peptides in order to be complexed with the MHC-I molecules. Then these proteins with MHC-I are expressed on the surface of the cell to be presented to the cytotoxic T-cells ( CTLs) Normal self protein Mutated self protein Viral protein

16. Functions of MHC-I molecules MHC-I molecules • Antigen presentation Proteasome Secretory vesicle Golgi Small peptides Newly synthesized protein Endoplasmic reticulum Nucleus Synthesized MHC-I protein

17. Functions of MHC-I molecules MHC-I molecules 1. Antigen presentation to CTL to check the normal expression of cellular proteins No TCR for Normal self protein Tc Tc Tc Perforin Perforin Viral protein Normal self protein Mutated self protein Cell Death Cell survive Cell Death Normal self protein Mutated self protein Viral protein Proteosome

18. Functions of MHC-I molecules MHC-I molecules 1. Antigen presentation Nucleus

19. NK cells and MHC-I Natural killer cells • Are a type of cytotoxic lymphocyte critical to the innate immune system • NK cells provide rapid responses to viral-infected cells and respond to tumor formation. • Typically, immune cells detect MHC presented on infected cell surfaces, triggering cytokine release, causing lysis or apoptosis. • They were named “natural killers” because of the initial notion that they do not require activation to kill cells that are missing “self” markers of MHC class 1. • This role is especially important because harmful cells that are missing MHC 1 markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

20. NK Cells can sense normal, abnormal, and downregulated MHC-I molecules Tumor cell Normal cell Transplanted tissue Viral infected cell Stimulatory ligand MHC-I Inhibitory receptor Stimulatory receptor - + + + + NK NK NK NK NK cells don not Respond to normal cells expressed normal MHCI Molecules. NK will not recognize the new MHC-1 and it will mount a destructive immune response NK recognizes and destructed cells lack or have downregulated MHC-I molecules NK recognize tumor cells lack MHC-I molecules and mount destructive immune response

21. Functions of MHC-II molecules MHC-II molecules • Antigen presentation: • For extracellular antigens • Such as engulfed bacteria B cell Th2 cvcv cv Phagolysosome Phagosome Nucleus Golgi ER APC

22. MHC I versus MHC II • The MHC-I and MHC-II molecules also show preferential restriction to T cells of the CD8- or CD4-bearing subsets. • This is related to the observation that CD8 binds to the nonpolymorphic a3 domain of MHC-I molecules, while CD4 interacts with membrane proximal domains of MHC-II.

23. Biological Importance of MHC MHC molecules play a major role in three lines Antigen presentation Autoimmune diseases Transplantation

24. Functions of MHC molecules 2- Transplantation DP7 DP3 DQ5 DQ12 DR7 DR14 DP9 Ahmad Omar DQ1 DP13 DR4 DQ11 A19 A3 DR12 B2 B6 C8 C7 C3 B5 C10 A4 B4 A8 Kidney from Omar to Ahmad Will be rejected because of MHC molecules incompatibility Rejected

25. Functions of MHC molecules 2- Transplantation Methods of Transplantation: • May take place between: • different parts of the same organism (autografting) • different organisms of the same species (allografting) • different species (xenografting)

26. Matching and cross-matching Matching: finding a donor who shares the HLA antigens of the recipient, to minimize antigen disparities requires donor and recipient antigens to be identified Cross-matching: testing the SERUM of the recipient for antibodies against the donor antigens

27. MHC and associated diseases

28. Association of Human MHC Alleles and Risk for Diseases DiseaseAssociated HLA AlleleRelative Risk** Ankylosing Spondylitis* B27 90 Hereditary Hemochromatosis A3/B14 90 Insulin Dependent Diabetes* DR4/DR3 20 Multiple Sclerosis* DR2 5 Myasthenia Gravis* DR3 10 Rheumatoid Arthritis* DR4 10 Systemic Lupus Erythromatosis* DR3 5 Narcolepsy DR2 130 * Autoimmune Disease **Percent of Patients with Allele Divided by Percent of Non-Affected Persons with this Allele

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