the HLA complex Hanna Mustaniemi, 28.11.2007
The Major Histocompatibility Complex Major histocompatibility complex (MHC) is a gene region found in nearly all vertebrates encodes proteins with important functions in immunity discovered due to its role in transplantation rejection transplantations were accepted within any inbred strain of mice, but rejected between individuals with genetic differences experiments with mice lead to the conclusion that reaction against foreign tissues were controlled by genes existing in several alleles and inherited co-dominantly hence the name histocompatibility complex (Greek histos, tissue)
The human MHC the human MHC is called the HLA complex (HLA genes) located on the short arm of chromosome 6, contains 3.5 4.0 million base pairs one of the most gene dense regions of the human genome estimations on the amount of functional genes vary around 100 200 genes classical and non-classical MHC class I and MHC class II genes MHC class III genes also genes not involved in immunity or involved in immunity less directly
Classical class I and II MHC genes code for integral membrane glycoproteins, known as peptide antigen presenting MHC proteins or molecules classical MHC class I proteins are coded by genes designated HLA-A, A, HLA-B B and HLA-C classical MHC class II proteins are coded by HLA-DP, HLA-DQ and HLA-DR
Function of classical MHC proteins soluble antibodies recognized by B cells are effective only against some extracellular pathogens pathogens rarely leave traces of them on the surface of the cell -> > cells exhibit on their surface a sample of peptides the function of the classical MHC proteins is to bind the peptides es and display them hence the name antigen-presenting proteins in addition, T cells only recognize antigens, that are associated with the same individual s s MHC proteins T cells scan cells all the time to ensure there are no foreign motifs on their surface MHC proteins express both foreign and self peptides immune reaction depends on the T cells antigen recognition
Function of class I MHC proteins class I proteins are expressed on the surfaces of nearly all cells present peptides coming from intracellular proteins these MHC-peptide complexes are recognized by cytotoxic T cells (killer T cells) with the help of the coreceptor CD8 if foreign peptides are encountered, killer T cells deduce the cell is infected and mark it for destruction with the help of additional proteins the cell undergoes apoptosis
Function of class II MHC proteins class II proteins expressed only on B cells, macrophages and dendritic cells peptides presented by them do not come from cytoplasm, but extracellular peptides that have been taken into the cell with the help of endosomes MHC-peptide complexes are recognized by helper T cells with the help of the CD4 coreceptor to avoid the binding of peptides from endogenous proteins, newly synthesized class II MHC proteins are bound by a chaperone polypeptide (the invariant chain)
The segregation is biologically important peptides from cytoplasm cannot reach class II MHC proteins, whereas peptides from endosomal compartments cannot reach class I MHC proteins foreign peptides encountered in association with class I proteins signal the cell has succumbed to a pathogen -> > call for destruction foreign peptides encountered in association with class II proteins signal the cell has encountered a pathogen -> > call for help
Structure of MHC class I molecules consist of two polypeptide chains a large alpha chain encoded by a class I MHC gene a small beta-2 2 microglobulin chain encoded outside the MHC region four domains: peptide-binding, immunoglobulin-like, like, transmembrane and cytoplasmic domains peptide-binding domain the most N-terminalN has a floor and two walls -> > can only bind small peptides ( around 8-118 residues) anchor positions: pockets for specific residues immunoglobulin-like like domain the binding site for T-cell T accessory molecule CD8
Structure of MHC class II molecules consist of two chains alpha and beta chains, both similar to the alpha chain of class I molecules (same domains) a separate gene controls each chain: class II MHC loci consist of 2-32 3 genes peptide-binding site has a a hole in the floor can bind longer peptides than class I molecules (around 13-18 18 residues long) immunoglobulin-like like domain the binding site for coreceptor CD4
Polymorphism of classical MHC genes both class I and II MHC genes highly polymorphic exact amount of alleles is not known, around 150 or even more (up to 500?) for some MHC loci the likelihood of getting the same alleles from both parents is unlikely, and alleles are expressed codominantly -> > an individual normally has 6 different class I and class II genes alleles denoted as HLA-A2, A2, HLA-A28, A28, etc. need to maximize peptide binding diversity variation localized at the peptide-binding domains, immunoglobulin-like like domains highly conserved in the case of epidemic caused by a mutated pathogen,those producing a new protein have a large selective advantage if all members of the species had identical proteins, population would be much more vulnerable to pathogens
Nonclassical MHC genes MHC class I-like I genes HLA-E, HLA-F, HLA-G encode proteins similar to class I molecules in sequence and structure no such polymorphism may be encoded outside the MHC fulfill a variety of roles, often specialized antigen-presenting features some present lipids and bacterial cell wall components some NK-receptors recognize only HLA-E E molecules HLA-G G expressed at high level on maternal/fetal interface, role remains unclear even less known about HLA-F MHC class II-like genes HLA-DM and HLA-DO regulate peptide loading onto classical MHC class II molecules
Allograft rejection allograft = graft from a genetically different donor can be tissue or an organ foreign MHC proteins typically activate more T cells than non- MHC foreign proteins class II MHC proteins play the major role in transplantation rejection especially important are HLA-DR proteins HLA-typing done before transplantation to ensure the best possible match HLA alleles of an individual s s parents are likely to be different -> > fetus is an allograft that is not rejected reason unclear, possible explanation is the placenta not allowing maternal T cells to enter
HLA and diseases (1) HLA complex has been associated with over a 100 diseases, many of them autoimmune diseases includes diseases such as asthma, type I diabetes, rheumatoid arthritis, psoriasis, MS among all genes studied for possible association with autoimmune diseases, the best candidate genes are MHC genes most autoimmune diseases associated with class II MHC genes, for example diabetes mellitus associated with the combination of certain HLA-DR and HLA-DQ alleles ankylosing spondylitis associated with HLA-B27 allele: individuals expressing it have 90-100 times bigger risk of developing AS than those who don t t express HLA-B27
HLA and diseases (2) disease-associated associated HLA alleles found in healthy individuals as well expressing a certain HLA allele seems to be a necessary but not a sufficient condition according to one of the models, both genetic predisposition determined by MHC genes and exposure to certain environmental agents are needed in order to develop an autoimmune diseases certain HLA alleles encode proteins that present autoantigens with greater efficiency than healthy ones?
References Berg, Tymoczko, Stryer. Biochemistry,, 6th Edition. W.H. Freeman and Company. Alberts et al. Molecular biology of the cell,, 4th Edition. 2002. (all( the figures) Pinchuck,, George. Schaum's Outline of Immunology. 2001. McGraw-Hill professional. Levinson, Warren E. Medical Microbiology & Immunology: Examination & Board Review. 2004. McGraw-Hill. Allen, Rachel L. Meeting report: Non-classical immunology. 2001. Genome Biology. http://genomebiology.com/2001/2/2/reports/4004