Major Histocompatibility Complex (MHC)

Major Histocompatibility Complex (MHC) * The MHC is a closely linked complex of genes that govern production of the major histocompatibility * In humans, MHC resides on the short arm of chromosome 6 * Three genes (HLA-A, HLA-B, HLA-C) code for the class I MHC proteins * Several HLA-D loci determine the class II MHC proteins i.e. DP, DQ and DR * HLA genes are very diverse (polymorphic) i.e. there are many alleles of the class I and II genes

The Human Leukocyte Antigen (HLA) System Essential to immune function: HLA molecules present peptide antigens to the immune system (T-cells) Important for self versus non-self distinction

Major Histocompatibility Complex (MHC) * Between the class I and class II gene loci, there is a third locus (Class III) * This locus contains genes encoding tumor necrosis factor, lymphotoxin and two complement components (C2 and C4) * Class III antigens do not participate in MHC restriction or graft rejection

MHC Class I Antigens * Class I MHC antigens are : HLA-A, HLA-B and HLA-C * These antigens are glycoproteins found on surfaces of all nucleated human cells and on platelets * HLA-A contains 24 different antigenic specificities, HLA-B contains 52 and HLA-C contains 11 * Class I MHC antigens are involved of MHC restriction of cell mediated cytotoxicity

HLA Class I Monitors Inside of the Cell Tapasin CR CN The MHC class I and class II molecules present antigens from different sources. Class I molecules present intracellular antigens that are processed in the cytoplasm and pumped into the endoplasmic reticulum, where new HLA molecules are being assembled. Processing of the antigens is performed by the proteosome, a multimeric enzyme composed of 28 subunits. Two subunits are encoded by the LMP genes found within the HLA region of the chromosome. The subunits may change in response to IFN-. LMP2, LMP7 and a third component, MECL-1, are induced by IFN- and displace the constitutive components and favor the processing of new peptides, thus insuring that newly synthesized viral proteins will be amply represented on the cell surface. The proteosome also favors the cleavage of proteins into 8-10 amino acids with hydrophobic or basic carboxy termini that fit nicely into the peptide binding groove of the HLA molecule. Peptides that are processed in this manner are transported into the endoplasmic reticulum by TAP (transporter associated with antigen), which is comprised of two subunits, TAP-1 and TAP-2. TAP-2 as an ATP binding site, which regulates the active transport of peptides into the lumen of the ER. The TAP transporter has some specificity, preferring peptides of >8 amino acids with hydrophobic or basic amino acids at the carboxy terminus. This is the preferred peptide for binding in the MHC groove. The newly synthesized HLA molecule is maintained in a partially folded conformation by calnexin (not shown). When 2-microglobulin binds to the HLA molecule, the complex dissociates from calnexin and binds a complex of calreticulin and tapasin, which then bind to TAP-1. The proper binding of a peptide to the HLA molecule dissociates the complex, and the HLA molecule is then transported through the Golgi complex to the cell surface. Dr. Brian Freed

MHC Restriction * Endogenously processed cytosolic peptides in virus infected cells or tumor cells are transported to the surface of the cells * They bind to MHC I molecules to be recognized by cytotoxic T-cells which then kill these cells * In other words; T-cells are only activated when they recognize both antigen and class I MHC molecules in association

MHC Class II Antigens Class II antigens are: HLA-DP, HLA-DQ, HLA-DR antigens These antigens are glycoproteins found on the surface of macrophages, B-cells, Dentritic cells, langerhans cells of skin and activated T cells HLA-DP contain 6 different antigenic specificities, HLA-DQ contains 9 and HLA-DR contains 20

HLA Class II Monitors Outside of Cell Peptides Extra-cellular Proteins DM monitors peptide specificity for DR The presentation of peptides on MHC class II molecules is quite different. HLA-DR and related class II molecules are also assembled in the endoplasmic reticulum, but the associate with a third protein known as the invariant chain, which prevents peptide binding. The invariant chain is processed within endosomes to CLIP (class II-associated invariant chain peptide). In the presence of HLA-DM molecules, CLIP dissociates from HLA-DR or DQ molecules and allows binding of new peptides that have been endocytosed from the extracellular environment. Thus, MHC class II molecules differ from MHC class I molecules in that they preferentially present extracellular antigens rather intracellular ones. HLA-DM serves to ‘edit’ peptide binding, promoting association with high affinity peptides over lower affinity peptides. DM Dr. Brian Freed

MHC Class II Antigens * Helper T-cells recognize antigens on antigen-presenting cells only when the antigens are presented on the surface of cells in association with class II MHC * Class II antigens react with the CD4 molecule on the helper T-cells which secrete cytokines

Class I MHC and Class II MHC MHC Class I MHC Class II Nomenclature HLA-A, HLA-B, HLA-C HLA-DP, HLA-DQ, HLA-DR Found on All nucleated somatic cells Macrophages, B-cells, Dendritic cells, langerhans cells of skin and activated T cells Recognized by CD8 TC cells CD4 TH cells Functions Presentation of Ag to TC cells leading to elimination of tumor or infected host cell Presentation of Ag to TH cells which secrete cytokines

Class I (1.1 Mb) Class II (2.2 Mb) Class III (0.7 Mb) Complement & cytokines Class II (2.2 Mb)

HLA Genetic Nomenclature Gene low high resolution typing “subtype”=01 Allele: HLA-DRB1*0401 Haplotype: HLA-DRB1*0401 HLA-DQB1*0302 HLA-DRB1*0301 HLA-DQB1*0201 DRB1*02 Genotype: HLA-DRB1*04 HLA-DQB1*0302 J. Noble

Antigen–presenting cells (APCs): monocytes, macrophages, dendritic cells, B cells Teaching slides: www.barbaradaviscenter.com

Humoral Versus Cellular Immune Response

Transplantation and Graft Rejection

Types of grafts 1) Autografts : 2) Isografts : The transfer of an individual’s own tissues from place to place e.g. Skin grafts (regularly accepted) 2) Isografts : Transfer of tissues between genetically identical persons e.g. Identical twins ( accepted permanently)

Types of grafts 3) Allografts (homograft): members of same species - Transfer of a graft between genetically different members of same species e.g from one human to another - Rejection occur if donor and recipient are not matched 4) Xenograft (heterograft): - Transfer of tissues between different species - Always rejected

Mechanism Of Graft Rejection 1) Both TH and TC are activated - TC cells destroy graft cells by direct contact TH cells secrete cytokines that attract and activate macrophages, NK cells and polymorphs leading to cellular infiltration and destruction of graft (Type IV) - B cells recognize foreign antigens on the graft and produce antibodies which bind to graft cells and . Activate complement causing cell lysis . Enhance phagocytosis, i.e. opsonization (Type II) . Lead to ADCC by macrophages, NK,PML - Immune complex deposition on the vessel walls induce platelets aggregation and microthrombi leading to ischemia and necrosis of graft (Type II)

Types Of Graft Rejection !) Hyperacute rejection: - It occurs hours after transplantation - In individual with preformed antibodies either due to - blood groups incompatibility or previous sensitization by blood transfusion, previous transplantation 2) Acute Rejection: - It occurs 10 to 30 days after transplantation - It is mainly T-cell mediated 3) Chronic or late rejection: - It occurs over a period of months or years - It may be cell mediated, antibody mediated or both

Graft Versus Host (GVH) Reaction * An immunologically competent graft is transplanted into an immunologically suppressed recipient (host) * The grafted cells survive and react against the host cells i.e instead of reaction of host against the graft, the reverse occurs * GVH reaction is characterized by fever, pancytopenia, weight loss, rash , diarrhea, hepatsplenomegaly and death