The INDIVIDUALIST

A Wiki about biochemical individuality

Immunology

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History

In 1937 Peter Gorer at The Jackson Laboratory showed in mouse studies that transplant rejection is primarily governed by what he called the 'H2 genetic locus', later described as the major histocompatibility complex, a key component of immunity.

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Description

The Major Histocompatibility Complex (MHC) is a set of molecules displayed on cell surfaces that are responsible for lymphocyte recognition and "antigen presentation". It is the most gene-dense region of the mammalian genome and plays an important role in the immune system, autoimmunity, and reproductive success.

The MHC molecules control the immune response through recognition of "self" and "non-self" and, consequently, serve as targets in transplantation rejection. The Class I and Class II MHC molecules belong to a group of molecules known as the Immunoglobulin Supergene Family, which includes immunoglobulins, T-cell receptors, CD4, CD8, and others.

MHC explanation for lay people

There are said to be nine separate types of MHC in humans, similar to the way humans have various blood types. MHC genes make molecules that enable the immune system to recognise invaders. Generally, the more diverse the MHC genes of the parents, the stronger the immune system of the offspring. Animals and humans react to various MHCs in particular ways. In a 1995 experiment, a group of female college students smelled t-shirts that had been worn by male students for two nights, without deodorant, cologne or scented soaps. Overwhelmingly, the women preferred the odors of men with dissimilar MHCs to their own. However, their preference was reversed if they were taking oral contraceptives. (1) The hypothesis is that MHCs affect mate choice and that oral contraceptives can interfere with this.

Besides the red cells, the blood contains a number of different kinds of white cells, or leucocytes, important in various ways in controlling infective diseases. The lymphocytes are one of these kinds. Their main function is the production of antibodies, but they contain a variety of genetically controlled antigens, detectable by their reactions with specific antibodies naturally present in certain human sera. These antigens were at first regarded as pathological curiosities, until it was found that they were present in other tissues and that compatibility with respect to them was a major requirement for the survival of kidney grafts and other tissue and organ grafts. This discovery stimulated world-wide researches into their genetics, and it is now known that they are the products of a set of alleles at five loci, closely linked on a single chromosome (No. 6).

Introduction

In humans, the 3.6 Mb (3 600 000 base pairs) MHC region on Chromosome 6 contains 140 genes between flanking markers MOG and COL11A2. (2)

The MHC complex is divided into three subgroups called MHC class I, MHC class II, and MHC class III.

The MHC class I encodes heterodimeric peptide binding proteins, as well as antigen processing molecules such as TAP and Tapasin. The MHC class II encodes heterodimeric peptide binding proteins and proteins that modulate peptide loading onto MHC class II proteins in the lysosomal compartment such as MHC II DM, MHC II DQ, and MHC II DP. The MHC class III region encodes for other immune components, such as [Complement system? complement components] (e.g., C2, C4, factor B) and some that encode cytokines (e.g., TNF-α).

The MHC proteins act as "signposts" that display fragmented pieces of an antigen on the host cell's surface. They may be self or nonself. If they are nonself, there are two ways by which the host cell may acquire this antigen. If the host is a macrophage or microphage, such as a monocyte or neutrophil, it may engulf the particle (be it bacterial, viral, or particulate matter), break it apart using lysozymes, and display the fragments on Class II MHC molecules. On other hand, if a host cell is infected by a bacteria or virus, or is cancerous, it may display the antigens on its surface with a Class I MHC molecule. In particular, viruses and cancerous cells have a tendency to display unusual, nonself antigens on their surface. These nonself antigens, regardless of which type of MHC molecule they are displayed on, will initiate the specific immunity of the host's body.

HLA Genes

The best-known genes in the MHC region are the subset that encodes cell-surface antigen-presenting proteins. In humans, these genes are referred to as human leukocyte antigen (HLA) genes, although people often use the abbreviation MHC to refer to HLA gene products. To clarify the usage, some of the biomedical literature uses MHC to refer specifically to the HLA protein molecules and reserves MHC for the region of the genome that encodes for this molecule; however this convention is not consistently adhered to.

The most intensely-studied HLA genes are the nine so-called classical MHC genes: HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, and HLA-DRB1. In humans, the MHC is divided into three regions: Class I, II, and III. The A, B, and C genes belong to MHC class I, whereas the six D genes belong to class II.

Besides being scrutinized by immunologists for its pivotal role in the immune system, the MHC has also attracted the attention of many evolutionary biologists, due to the high levels of allelic diversity found within many of its genes. Indeed, much theory has been devoted to explaining why this particular region of the genome harbors so much diversity, especially in light of its immunological importance.

Because of this close linkage the genes, and the corresponding antigens, are passed from one generation to the next in groups of five. They are however not so closely linked as are the linked genes of the blood group systems MNSs, Rh, and Kell and, unlike the situation with these blood-group systems, the rates of crossing-over between them are known, being of the order of 1 per cent per generation. Crossing-over should in the long run produce a state of linkage equilibrium, such that a particular allele at one locus should be linked to a pair of alleles at another locus in the same ratio as the total frequencies of these alleles. This is however often found not to be the case, and many workers think therefore that certain combinations or haplotypes are selectively favoured. (3)

Molecular biology of MHC proteins

The classical MHC molecules (also referred to as HLA molecules in humans) have a vital role in the complex immunological dialog that must occur between T cells and other cells of the body. At maturity, MHC molecules are anchored in the cell membrane, where they display short polypeptides to T cells, via the T cell receptors (TCRs). The polypeptides may be "self," that is, originating from a protein created by the organism itself, or they may be foreign, originating from bacteria, viruses, pollen, etc. The overarching design of the MHC-TCR interaction is that T cells should ignore self peptides while reacting appropriately to the foreign peptides.

The immune system has another and equally important method for identifying an antigen: B cells with their membrane-bound antibodies, also known as B cell receptors (BCRs). However, whereas the BCRs of B cells can bind to antigens without much outside help, the TCRs of T cells require "presentation" of the antigen: this is the job of MHC. It is important to realize that, during the vast majority of the time, MHC are kept busy presenting self-peptides, which the T cells should appropriately ignore. A full-force immune response usually requires the activation of B cells via BCRs and T cells via the MHC-TCR interaction. This duplicity creates a system of "checks and balances" and underscores the immune system's potential for running amok and causing harm to the body (see autoimmune disorders).

All MHC molecules receive polypeptides from inside the cells they are part of and display them on the cell's exterior surface for recognition by T cells. However, there are major differences between MHC class I and II in the method and outcome of peptide presentation.

MHC class I molecules are found on almost every nucleated cell of the body. MHC class I molecules are heterodimers, consisting of a single transmembrane polypeptide chain (the α-chain) and a β2 microglobulin (which is encoded elsewhere, not in the MHC). The α chain has two polymorphic domains, α1, α2, which binds peptides derived from cytosolic proteins. Because MHC class I molecules present peptides derived from cytosolic proteins, the pathway of MHC class I presentation is often called the cytosolic or endogenous pathway.

The peptides are mainly generated in the cytosol by the proteasome. The proteasome is a macromolecule that consists of 24 subunits, of which half of them contain proteolytic activity. The proteasome degrades intracellular proteins into small peptides that are then released into the cytosol. The peptides have to be translocated from the cytosol into the endoplasmic reticulum (ER) to meet the MHC class I molecule, whose peptide-binding site is in the lumen of the ER.

The peptide translocation from the cytosol into the lumen of the ER is accomplished by the Transporter associated with Antigen Processing (TAP). TAP is a member of the ABC transporter family and is a heterodimeric multimembrane-spanning polypeptide consisting of TAP1 and TAP2. The two subunits form a peptide binding site and two ATP binding sites that face the lumen of the cytosol. TAP binds peptides on the cytoplasmic site and translocates them under ATP consumption into to the lumen of the ER. The MHC class I molecule is then in turn loaded with peptides in the lumen of the ER. The peptide-loading process involves several other molecules that form a large multimeric complex consisting of TAP, tapasin, calreticulin, calnexin, and ER60.

Once the peptide is loaded onto the MHC class I molecule, it leaves the ER through the secretory pathway to reach the cell surface. The transport of the MHC class I molecules through the secretory pathway involves several posttranslational modification of the MHC molecule. Some of the posttranslational modifications occur in the ER and involve change to the N-glycan? regions of the protein, followed by extensive changes to the N-glycans in the Golgi apparatus. The N-glycans mature fully before they reach the cell surface.

Peptides that fail to bind MHC class I molecules in the lumen of the endoplasmic reticulum are removed from the ER via the sec61 channel into the cytosol, where they might undergo further trimming in size, and might be translocated by TAP back into ER for binding to an MHC class I molecule.

MHC class I molecules are loaded with proteins generated in the cytosol. As viruses infect a cell by entering its cytoplasm, this cytosolic, MHC class I-dependent pathway of antigen presentation is the primary way for a virus-infected cell to signal T cells. MHC class I molecules generally interact exclusively with CD8+ ("cytotoxic") T cells (CTLs). The fate of the virus-infected cell is almost always apoptosis initiated by the CTL, effectively reducing the risk of infecting neighboring cells.

MHC Class II molecules are found only on a few specialized cell types, including macrophages, dendritic cells, activated T cells, and B cells, all of which are professional antigen-presenting cells (APCs). Like MHC class I molecules, class II molecules are also heterodimers, but in this case consist of two homologous peptides, an α and β chain, both of which are encoded in the MHC. The peptides presented by class II molecules are derived from extracellular proteins (not cytosolic as in class I); hence, the MHC class II-dependent pathway of antigen presentation is called the endocytic or exogenous pathway. Loading of class II molecules must still occur inside the cell; extracellular proteins are endocytosed, digested in lysosomes, and bound by the class II MHC molecule prior to the molecule's migration to the plasma membrane. Because the peptide-binding groove of MHC class II molecules is open at both ends while the corresponding groove on class I molecules is closed at each end, the peptides presented by MHC class II molecules are longer, generally between 15 and 24 amino acid residues long.

Because class II MHC is loaded with extracellular proteins, it is mainly concerned with presentation of extracellular pathogens (for example, bacteria that might be infecting a wound or the blood). Class II molecules interact exclusively with CD4+ ("helper") T cells (THs). The helper T cells then help to trigger an appropriate immune response which may include localized inflammation and swelling due to recruitment of phagocytes or may lead to a full-force antibody immune response due to activation of B cells.

MHC evolution and allelic diversity

MHC gene families are found in essentially all vertebrates, though the gene composition and genomic arrangement vary widely. Chickens, for instance, have one of the smallest known MHC regions (19 genes), though most mammals have an MHC structure and composition fairly similar to that of humans. Gene duplication is almost certainly responsible for much of the genic diversity. In humans, the MHC is littered with many pseudogenes.

One of the most striking features of the MHC, particularly in humans, is the astounding allelic diversity found therein, and especially among the nine classical genes. In humans, the most conspicuously-diverse loci, HLA-A, HLA-B, and HLA-DRB1, have roughly 250, 500, and 300 known alleles respectively -- diversity truly exceptional in the human genome. The MHC gene is the most polymorphic in the genome. And population surveys of the other classical loci routinely find tens to a hundred alleles -- still highly diverse. And perhaps even more remarkable is that many of these alleles are quite ancient: It is often the case that an allele from a particular HLA gene is more closely related to an allele found in chimpanzees than it is to another human allele from the same gene!

Phylogenetically the marsupial MHC lies between eutherian mammals and the minimal essential MHC of birds, although it is closer in organization to non-mammals. Its Class I genes have amplified within the Class II region, resulting in a unique Class I/II region.(4)

Anthropological considerations

The histocompatibility system

A great deal of work has been done on the frequencies of the HLA alleles and haplotypes in populations and it is clear that there are wide variations in frequency in different populations, so that the system will, when more work has been done, become of great importance anthropologically. Up to the present most of the surveys reported refer to caucasoid populations, because tissue and organ grafting is mainly confined to Caucasoids.

However the main biological importance of the histocompatibility antigens is proving to be not their relation to grafting but the highly significant associations which exist between particular alleles and haplotypes and a large number of diseases, mainly diseases with an immunological basis. Many of these associations are so close as to have an important bearing on the causes of the diseases, which in many cases were formerly obscure.

Links

Attribution

References


1. Wedekind, C., Seebeck, T., Bettens, F. and Paepke, A. J. (1995). "MHC-dependent mate preferences in humans". Proc Biol Sci 260 (1359): 245-249.

2. MHC Sequencing Consortium (1999). "Complete sequence and gene map of a human major histocompatibility complex". Nature 401: 921–923.

3. Mourant, AE. Blood Relations, Blood Groups and Anthropology. Oxford University Press, Oxford, UK 1983.

4. Belov, Katherine, Janine E. Deakin, Anthony T. Papenfuss, Michelle L. Baker, Sandra D. Melman, Hannah V. Siddle, Nicolas Gouin5, David L. Goode, Tobias J. Sargeant, Mark D. Robinson, Matthew J. Wakefield, Shaun Mahony, Joseph G. R. Cross, Panayiotis V. Benos, Paul B. Samollow, Terence P. Speed, Jennifer A. Marshall Graves, Robert D. Miller (March 2006). "Reconstructing an Ancestral Mammalian Immune Supercomplex from a Marsupial Major Histocompatibility Complex". PLoS Biol 4(3) (e46).

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