Major Histocompatibility Complex

Introduction:

Cellular interactions are very important for recognition and presentation of antigens to the immune system by antigen presenting cells. The primary component of this interaction is the T cell antigen receptor (TCR) and the Major histocompatibility complex (MHC) / human leukocyte antigens (HLA) molecule interaction. The major function of the TCR is to recognize antigen in the correct context of MHC and to transmit an excitatory signal to the interior of the cell.

MHC classes:  

The MHC is highly polymorphic from individual to individual and segregates in families in a Mendelian codominant fashion.

  • Genes for HLA are clustered in MHC located on short arm of Chromosome 6: 6p21.
  •  The class I gene complex contains three loci A, B and C, each of which codes of α chain polypeptides.
  • The class II gene complex also contains at least three loci, DP, DQ and DR; each of these loci codes for one α and a variable number of β chain polypeptides.
  • Class III region 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 antigens are associated with proteins in serum and other body fluids (e.g.C4, C2, factor B, TNF) and have no role in graft rejection.

For these proteins each individual has haplotypes i.e. one set of genes is inherited from each parent. These chains are very diverse (polymorphic)i.e. there are many alleles of  class I and class  II .We have more than 47 alleles for HLA –A, 88 for HLA –B, 29 for HLA –C AND 300 for HLA-D genes. An individual inherits only single alleles from each locus and can make only one MHC -1, MHC-II protein. Expressions of these genes are co-dominant i.e. are expressed. Each person can have 12 HLA proteins – 3 for class I and 3 for class II from each parent. In addition to HLA genes which are encoding major antigen there are several minor antigens encoded by several genes other than HLA. These genes cannot be identified by laboratory procedures. These genes lead to a slow antigen reaction i.e. slow graft rejection .But a cumulative effect of these genes can produce more rapid graft rejection. Between class I and Class II there is   third locus called as class III. It encodes for two cytokines (TNF and Lymphotoxins) and two components (C2 and C4) but it does not have any gene encoding for histocompatibility Antigen.

Simplified map of HLA region

Class I MHC:

These are glycoproteins which are found on the surface of virtually are all nucleated cells. Proteins encoded for MHC-I, are 20 on allelic genes of A locus, 40 at B locus and 8 at C locus. Class I MHC molecules contain two separate polypeptide chains, the heavier (44-47 KDa) alpha chain and the lighter (12 KDa) beta chain. The heavy chain is identical to immunoglobulin. It has hypervariable region in its N-terminal region. These regions are responsible for recognition of self and non-self. The carboxyl end of α chain resides inside the cell while the amino end projects on the surface of cell with a short intervening hydrophobic segment traverses the membrane.If all MHC-1 should have been similar our acceptance to allografts would have been more. These also have constant region where the CD8 protein of cytotoxic CD8 cells bind.

Structure of Class I MHC molecules:

Two polypeptide chains, a long α chain and a short β chain called β2-microglobulin. The α chain has following four regions:

  • A cytoplasmic region, containing sites for phosphoylation and binding to cytoskeletal elements. 
  • A transmembrane region containing hydrophic amino acids by which the molecule is anchored in the cell membrane.
  • A highly conserved α3 immunoglubilin-like domain to which CD8 binds. 
  • A highly polymorphic peptide binding region formed from the α1 and α2 domains.  The β2- microglobulin associates with the α chain and helps maintain the proper conformation of the molecule. 

Diagram showing structure of Class I and Class II MHC molecules 

Structure of Class I and Class II MHC molecules

Class II MHC:

These are glycoproteins found on surface of certain cells such as macrophages, B cells, dendritic cells, cells of spleen, langerhan’s cells of the skin. MHC class II molecules comprise two non-identical and non-covalently associated polypeptide chains (α and β). These two chains have amino ends on the surface, a short transmembrane stretch and intracytoplasmic carboxyl ends. Like MHC 1 they have hyper variable regions. In case of MHC1 there are two chains. Chain I is encoded by MHC. Chain II (beta 2microglobulin) is encoding by chromosome15. In case of MHC II both chains are encoded by MHC II. Two polypeptide chains have a constant region where the CD4 cell is attached.

Class II MHC was first demonstrated by mixed leukocyte reaction. In this case stimulator antigen is taken from donor who are first killed by irradiation and mixed with responder lymphocytes form recipient who are live. The mixture is incubated to permit DNA synthesis. More the DNA synthesis more is rejection to graft. The best donor is therefore a person whose cells stimulate least amount of incorporation of thymidine in DNA.

Structure of class II molecule:

Class II MHC molecules are composed of two polypeptide chains an α and a β chain of approximately equal length. Both chains have four regions:

  • A cytoplasmic region containing sites for phosphoylation and binding to cytoskeletal elements.
  • A transmembrane region containing hydrophic amino acids by which the molecule is anchored in the cell membrane.
  • A highly conserved α2 domain and a highly conserved β2 domain to which CD4 binds.
  • A highly polymorphic peptide binding region formed from the α1 and β1 domains.

Biological importance of MHC:

  • Ability to find out antigen depends upon either class-I and class-II.
  • MHC class I binds Cytotoxic T- cells.
  • MHC class II binds Helper T-cells.
  • These cells bear responsibility to find out self and non-self cells. This is called as MHC-restriction. B cells do not have this requirement and these can recognize the soluble antigens present in plasma with the surface IgG, IgM acting as a receptor.

Cytotoxic T-cell and Helper T-cell activation by MHC-I and MHC-II respectively

T-cell activation

Transplantation and graft rejection:

An autograft that is transferred on own tissue is always accepted. A synergistic graft that is transfer of tissue between genetically identical individuals i.e. identical twins and is almost always accepted. A Xenograft is transfer of tissue between two species and is always rejected by immunocompitant cells. Allograft is tissue transfer between genetically different members of same species i.e. from one human to another. Allograft is usually rejected unless the patient is given immuno-suppressive drugs. Severity and rapidity of rejection depends upon the difference of donor and recipient MHC loci.

  • Allograft rejection: Unless imunosuppresent drugs are given allograft is rejected by a mechanism of allograft reaction.
  • Acute graft rejection: Initially graft is normal but after 11-14 days marked reduction in circulation and mononuclear infiltration occurs which eventually lead to necrosis this is also called as primary reaction or first set reaction
  • Hyper-acute (white graft) rejection: In this case graft is rejected very rapidly as a result of presence of large amount of preformed antibodies for e.g. anti ABO antibodies. T-cell mediated rejection is the main cause of many types of graft for e.g. skin graft etc. But sometime antibodies contribute to rejection such as a bone marrow transplant.
  • T-cell deficient animals do not reject graft but B cell deficient do.
  • If a second allograft from same donor is applied graft is rejected within 5-6 days. This rejection is done primarily by pre-sensitized T-cells. It is also called as second set reaction.
  • Acceptance of or rejection of a graft mainly depend on in large part by the class I and class II MHC proteins but MHC II play a major role .Proteins encoded by DR are important.
  • Allo-antigens activate both T-cells Helper as well as cytotoxic.
  • Activated T-cells proliferate and react against allograft antigens. Cytotoxic CD-8 T-cells kill most of the allograft cells.
  • Foreign MHC proteins elicit much stronger immune response as compared to other simple foreign proteins. Reason for this is unclear.

Allograft is rejected in two steps:

  1. APC’s (macrophages and dendritic cells in the graft present self proteins of the host and activate the immune response)
  2. Donor proteins (MCH I&II) may be shed and subsequently processed by recipients antigen presenting cells and initiate immune response

Prior to tissue transplantation a test, “TISSUE TYPING” test is done to find closest match between recipient and donor. Class I proteins and certain class II proteins especially DR are detected by using panel of known antibodies. Nucleiotid sequencing is done. Further matching can be done by mixed leucocyte reaction.

Graft versus host reaction (GVH): Transplantation may be normal but in some patients GVH develops. It occurs in those patients who are irradiated and immuno-compromised. This rejection is due to proliferation of immunocompetent cells present in graft of donor. These cells develop antigenainst recipient proteins and subsequently the severe dysfunction develops. Donor cytotoxic T-cells destroy recipient cells.

Requirements for (GVH) to occur :

  •  Graft must contain immuno-competent cells.
  •  Host must be immuno-compromised.
  •  Host must express antigen foreign to donor’s i.e. donor cells recognize recipient cell as foreign.

If donors and recipients MHC complexes are matched even then the (GVH) can occur due to minor antigens. GVH can be reduced by treating the donor graft with anti-thymocyte globulins or monoclonal antibodies before grafting. It eliminates mature T-cell from graft.

Effect of immunosuppression on graft rejection:

To reduce the chances of rejection of transplanted tissue immunosuppressive antigenent such as cyclosporine, tacrolimus, rapamycin, corticosteroids, arothiaprine, OKT3 antibody and radiations are used.

  • Cyclosporin & Tacrolimus: Both have same mode of action. They interrupt signal transduction by inhibiting calcineurin. Tacrolimus is more immunosuppressive and has more side effects. Cyclosporin is widely used.
  • Rapamycin: Inhibits transduction but at some other site than cyclosporine.
  • Corticosteroids: These act primarily by inhibiting Cytokine e.g. IL-1 & TNF.
  • Azothiaprine: Inhibit DNA synthesis and block growth of T cells.
  • OKT3: It is a monoclonal antibody against CD3 protein that can block T cell function as well as lysis of T-cells is carried out by these antibodies.

Immunosuppression increases the risk of development of neoplasm by 100 times and also development of opurtunistic disease and infections take place.

Summary of major histocompatibility complex:

  1. As Each MHC molecule has only one binding site, only one peptide can bind to it at a time.
  2. A peptide must associate with a given MHC of that individual; otherwise no immune response can occur. 
  3. Mature T cells must have a T cell receptor that recognizes the peptide associated with MHC. 
  4. MHC molecules are membrane-bound so recognition of these molecules by T cells requires cell-cell contact. 
  5. MHC gene alleles are co-dominant so their product is expressed on the cell surface of an individual nucleated cell. 
  6. Cytokines (especially interferon-γ) increase level of expression of MHC. 
  7. Class I MHC is recognized by cytotoxic T-cells (CD-8 cells).  Class II MHC is recognized by helper T-cells (CD-4 cells).
  8. Polymorphism in MHC is important for survival of the species.

 

 


References:

  1. Kuby Immunology. Thomas J. Kindt, Richard A. Goldsby, Barbara A. Osborne, Janis Kuby
  2. Immunology at a Glance.  By J. H. L. Playfair, B.M. Chain.
  3. Immunology: Understanding The Immune System. By Klaus D. Elgert
  4. Immunology: A Short Course. By Richard Coico, Geoffrey Sunshine.
  5. Immunology.  By David K. Male.
  6. Immunology: Essential And Fundamental. By Sulabha Pathak, Urmi Palan.

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