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MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) BOND KING SWU
THE MHC• Is the gene region located on chromosomes 6 in humans and it encodes the antigen presenting cells molecules designated class I MHC and class II MHC.• In between the two region MHC I and MHC II are the class III MHC genes that encodes some of the complement proteins.• Both classes of MHC molecules consists of two polypeptide chains non covalently associated.
MHC• each class of MHC has three distinct forms:- Class I MHC- HLA-A, HLA-B and HLA-C Class II MHC – HLA-DP, HLA-DQ, HLA-DRClass II MHC genes Class I MHC genesHLA-DP,HLA-DQ,HLA-DR HLA-B,HLA-C,HLA-A00 00 00 0 0 0
MHC• The total set of MHC alleles class I and II inherited from one parent is haplotypes (seen genotype)• Each form MHC has several alleles(variants) in the population.• Each allelic variants can potentially bind a number of antigen peptides.• When a peptide binds to MHC molecules, the complex formed subsequently displayed in the cell surface, where it can be recognized by T cell
MHC• In effect ,these complex alert T cell that a foreign substance (micro-organism) is present.• Recognization of these complexes is required for T cells activation, which is a requirement for most adaptive immune responses.• The genes that determined the out come of the graft were referred as the histocompatibility genes and the proteins encoded to the genes histocompatibility antigen.
CLASS I MHC IN HUMAN• Three forms of class I MHC proteins can be identified in all human nuclear cells.• There molecule form a complex with antigen fragments within the cells and the complex is displayed on a cell surface.
DISCOVERY OF CLASS I MHC• Mouse was used in experiments (skin grafts)• Human blood transfusion was used ( graft) because cells are transfused from one individual to another.• Therefore ,individual who had received a foreign graft (blood transfusion) or mother who had several pregnancies (multiparous) were identified as graft recipients ( serum tested for anti-MHC antibodies).
• Individual who have received blood transfusions would have generated antibodies specific for the MHC antigens present on transfused blood cells.• For mothers who had several pregnancies is that lymphocytes from the fetus enter the maternal circulation during delivery.• Since fetal lymphocytes expresses paternal MHC antigens (as well as the mother MHC antigens)the fetal cells are foreign grafts.
• the mother’s immune system would be activated in response to the foreign MHC and would lead to the production of anti-MHC (paternal antibodies).• Because MHC molecules to which antibodies were generated were present in the human leukocytes these MHC molecules were called human leukocytes antigen and the gene locus that encoded them the HLA locus.• The HLA locus is synonym with MHC locus the genetic term for this region.
Description of class I MHC Two polypeptides• Polymorphic heavy chain MHC locus chromosome 6.• Non polymorphic light chain (B2 microglobulin)- chromosome 15
Class I MHC polymorphism and Nomenclature• Each HLA (A,B,C) gene has many allelic variant forms in the population (polymorphic)• HLA-A1 HLA-A2 HLA-A3 and so on.
Expression of class I MHC• Each of three forms of class I MHC are co-dominantly expressed.• The three class I alleles (variants)inherited from each parents are expressed on the cell. examples the child inherits the following alleles from one parent (HLA-A ,HLA-B8 and HLA-Cw4) and the following alleles from the parent( HLA- A2,HLA- B37 and HLA-Cw7) all six different molecules will be present on the child nucleated cells.
CLASS II MHC• Three forms of class II MHC can be identified on antigen presenting cells.• These molecules bind antigen fragments within a cystolic vacuole and the complex is then displayed on the surface of the antigen presenting.
Discovery of class II MHC• The human class II MHC gene region known as the HLA-D region was identified using the mixed leukocyte reaction (MLR)• MLR is a laboratory technique used as a predictive test for graft rejection.• This assay is used to determine whether T cells forms one individual will be activated when they interact with class II MHC protein present on another individual cells(allogenic MHC).
• HLA-D region consisted of three gene loci HLA-DP ,HLA-DQ, HLA-DRExamples In individual who are genetically identical (monozygotic twins)T cells will not be activated in MLR on the other hand. If two individuals are genetically desperate the CD4+ T cells recognizing the class MHC proteins as foreign and respond by proliferation.
Description of class II MHC• They are comprised of two poly peptide chains ( alpha and beta).each chain is polymorphic and the genes that encodes them are located within the MHC locus• For the most part, class II MHC molecules are normally Expressed on antigen presenting cells (B cells, monocytes, macrophases and dendrite cells)• Exposure to some cytokins can enhance the number of class II MHC molecules expressed on an antigen presenting cells.
Class II MHC polymorphism and Nomenclature• Each HLA-D (DP,DQ,DR) gene has many allelic variants or forms in a population and so the HLA-D genes are said to be polymorphic.• Each gene variant (allele) is given a number example HLA-DR alleles are numbered HLA-DR1 , HLA-DR2
Expression of class II MHC• Class II molecules are co-dominantly expressed.• Each class is different various combination of polypeptide are possible• When a child inherits two entirely different sets of alleles at least 12 different combination. (four for each HLA-DR,DP,DQ) are possible, however not all combinations will be represented equally because some combinations are more stable than others.
Examplesif a child inherits HLA-DR1 which is comprised of sigma(1) and beta(1) from the one parent and HLA-DR4 comprised of alpha(4) and beta(4) from the other parent, the number of possible combinations of HLA-DR on the cell surface would be (HLA-DR (1)/ (1) ,HLA-DR (4)/ (4) ,HLA-DR (1)/ (4) and HLA-DR (4)/ (1)
• The expression of so many different class II MHC molecules on an antigen presenting cells greatly increase the liklihood that an antigen peptide will form a complex with an MHC protein and be presented on the cell surface of the T cells to recognize.
Role of MHC in immune response• Based on the studies the MHC gene loci were aimed to identify those molecule that were involved in graft rejection.• Important molecules in host defense• In normal host immune response, antigenic peptides are displayed on cell surfaces complexed with MHC molecules.
• Cytotoxic T cells (CD8+ T cell) recognize antigen peptide complexed with a class I MHC molecules on the cell surface.• In contrast helper T cells ( CD4+ T cell) will recognize antigen peptide displayed with a class II MHC molecules
Importance• A sucessful immune response, demands that helper T cells (CD4+) are activated, and this can only occur if antigenic displayed on the cells surface in association with class II MHC• In turn, experiment of that complex requires that one of the inherited MHC alleles is capable of binding one of antigen peptides generated in the phagocytosis vacoule.
Transplantation immunology Transplantation• Is there process where by an individual (recepient) receives cells or tissues from a 2nd individual (donar)
classification• Isograft :-graft in which there is no genetic different between donar and receipent (genetically identical individual)• Allograft:- graft between the member of same species• Xenograft:-graft across a species• Autograft:-self tissue transferred from one body site to another in the same individual.
• For some part ,transplants are allografts are so there is a genetic disparity betwn the donar and receipent (MHC loci)• To some extent the MHC genetic disparity determine whether a graft will be accepted or rejected becoz the proteins( antigens) that they encode have been shower to induce the most vigrous rejection episodes.
Graft rejection• Immunologic response of a transplant receipent to the cells of the graft from a non- histocompatible donor.
classification 1.Hyperacute rejection• Occurs minutes to 1 hour following the engraftment.• Antibody mediated phenomenon and is associated with complement activator, blood clot formation and rapid graft failure.• Indicates that the recipient has been previously exposed to the donor MHC antigen• Graft removal
Acute rejection• Occurs week after tissue transplant and is caused by helper and cytotoxic T-cell activation (cell mediated)
Chronic Rejection• May occur weeks, months or years Post transplant.• Associated with a notable increase in the levels of non T cell derived non specific growth factors.• No treatment, graft must be removed• Humoral and cell mediated.
Rejection in bone marrow transplantation• Used to treat leukemias and lymphocytes• These types of transplants are unique in that the donor cells attack the receipent tissues.• Referred to as graft versus host disease(GVHD)• T cells present in the graft are stimulated becoz the recipient is recognized as foreign.• Recipients are seriously immunocompromised and so their immune system cannot attack the graft with the same intensity.
Immunosupressive therapies• Because acute rejection a T- cell mediated event, many of the therapies target the T-cells• Treatment for acute rejection consists of increasing dose of immunosuppressive drugs.• Commonly used drugs are cyclopshorin A and FK506 which block the production of a T cell growth factor• Prednisone is used as non specific anti- inflammatory agent, targets macrophages and reduced antigen presentation of T cells.
Screening to ensure compatibility• Recipients and potential donor, are pre- screened to ensure the best possible genetic match at MHC loci to minimize rejection.• The pre-transplantation screening test are based on serological cellular and molecular typing techniques• Pre-transplantation testing is more commonly referred as histocompatibility testing and includes tissue matching and tissue typing.
Histocompatibility testingA. TISSUE MATCHING• Also referred as cross-matching• To as certain donor-recipient compatibility.
serologic approach• Donor and recipient tissues are reacted separately with panels of antibodies for various MHC alleles and their relation are compared.• The problem with this approach is that allelic difference can be detected only if an antibody is available for the allele.
Cellular approach• Used mixed leukocyte reaction (MLR)• Donor and recipient cells are cultured together for several classes to allow T cells to be activated and proliferate in response to disparate MHC proteins.• The amount of proliferation can be measured and used to predict the magnitude of rejection.• Bone marrow transplant and cases of related donor.
Molecular approach• Used restriction fragment length polymorphism(RFLP) and the polymerase chain reaction (PCR)• RFLP- enzymes are used to cleave genomic DNA to obtain a pattern of fragmentation• The genetic disparity between the donor and recipient can be assessed by comparing pattern of fragmentation.
PCR• Directs amplification of a particular DNA sequence selected by use of primers (short nucleic acid sequence)that border the genes of interest.• The degree of disparity betwn the recipients and the donor for the selected sequences can be determined.
Tissue testing• Individuals HLA genotype• PCR is the method of choice.• Serologic approach- incubation of the individuals blood with panel of antibody of known specificity
Paternity and histocompatibility testing• Histocompatibility testing may also be used to determine paternity.• In this situation, paternity is not confirmed.• The test is based on exclusion.• If the child does not express any/ the same HLA alleles as the male being tested, paternity can be excluded.
• Organs – tissue that can be transplanted from human• Kidney liver heart skin lungs cornea pancreas blood bone marrow cord blood