Major Histocompatibility Complex

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The Major Histocompatibility Complex (HMC) pertains to the interconnected genes located at the shorter arm of the chromosome. (Twyman, 2003) It is contained in the cell surface and is responsible for lymphocyte recognition and antigen presentation. Individuals with the same MHC bearing can exchange grafts more successfully than those MHC non-identical. One probable cause is that a series of unique MHC molecules is evident in every individual. There are a hundred different types of MHC however a person can only retain four MHC both came from each parent. A spliced skin or organ coming from unlike MHC activates the cell destruction of the immune system. (Twyman, 2003) However, there are cases wherein non-compatible transplantation can be successful. In the study on the inbred strain of mice, the b and the k are haplotypes mate, progeny are b/k, and can accept grafts from either parent, though a parent cannot accept progeny graft. In outbred population (high polymorphism), there is only a 25% chance of identical MHC haplotypes in siblings. Parents are always mismatched with kids. Even with the absence of a well-matched donor, transplantation may be successful. (Goodsell, 2005)Now in order to quantify class II MHC the compatibility between donors and recipients, MLR is being applied. The lymphocytes of the donor are being x-irradiated or treated with mitomycin C as a stimulator cell which would represent the graft cells. Yet if there is incompatibility, the responder cells will be activated by the foreign MHC. Thymidine is used to measure the degree of MHC differences. (Dorak, 2007) Several procedures however can mediate graft rejection. Peter Gorer instituted the discovery of MHC using inbred mice as the subject of the study. He started with the transplantation of antibodies from one strain of mice to another to identify a certain group of proteins associated with the red blood and white blood cells. Furthermore, he discovers that a single tumor from mice can be transplanted effectively to a group having the same allele and cannot do so to a group different from the allele. George Snell followed the same discovery. Preconceived by the idea that some genetic factors strongly affect an individual tissue to reject another tissue, he began studying inbred mice to validate his idea. He then produced a strain of mice so that he can isolate histocompatibility genes. The research came by uncovering the location on the chromosome of that specific gene that played an important role in controlling resistance to tissue grafts and labeled it as a major histocompatibility complex. (Goodsell, 2009) During the succeeding years, French Immunologist Jean Dausset and later Baruj Benacerraf discovered that the body has the ability to respond to a particular antigen and that interaction of the T cells and B cells are dependent on the MHC. Such that to generate an effective immune response, both cells must have to carry the same MHC antigens. MHC is divided into two main classes, Class I and Class II. Those classes are under the Immunoglobulin Supergene Family which is a cluster of molecules that covers the T-cell receptors, immunoglobulins, CD4, and CD8. In the broader sense, both classes of MHC genes preset the so-called human leukocyte antigen (HLA). (Twyman, 2003).

MHC Class I. The molecules belonging to this class are composed of two polypeptide chains. It is found in all cell types and its function is to present the fragments of protein that will be manufactured inside the cell. The former peptide chain is found in the BCA region while the β2-microglobulin is encoded to another region. These polypeptides consist of a heavy chain and are connected to the β2-microglobulin molecule. This polypeptide where MHC is encoded contains a length measuring 350 amino acids from which 75 amino acids are on the carboxylic end. This creates the transmembrane and the cytoplasmic portions of the chain. The MHC-encoded polypeptide is composed of approximately 350 amino acids in length having 75 amino acids on the carboxylic end making up the transmembrane and cytoplasmic portions. The polypeptide chain houses three (3) circular domains, (1) alpha-1, (2) alpha-2, and (3) alpha-3. The alpha-1 is located near the amino terminus; the alpha-3 on the hand is closest to the membrane. In between the alpha-1 and the alpha 2 lies a domain of small peptide bonding comprising of 10 amino acids. This peptide bonding is shown in the T-cell in order for the T-cell to distinguish the epitope defined by the peptide bonding. Primarily, T-cell test out the MHC proteins in order to identify abnormal cells. Abnormal cells are recognized because of their display of peptide antigens such as fragments of viral proteins. These cells are attacked and wiped out. The Class I antigen found in the human cell membranes is composed of two different patterns, the farthest end contains two domains having immunoglobulin-folds while the distal end has eight anti-parallel beta-strands crowns with alpha-helices. In between the alpha-helices is where the binding site for processed foreign antigens. (Twyman, 2003).

MHC Class II. Class II molecules are also composed of two homologous peptide chains. It has 230 and 240 amino acids. These MHC proteins are located in phagocytes which are immune cells that swallow up foreign particles. These cells are exploited to avoid malfunctions in the immune system. One manifestation of this is the immune cells attacking the cells of the body. However, this is only true if the antigen being recognized as foreign by the helper T-cell, the phagocyte will then survived. The Class II molecules are divided into two domains, the alpha-1, and the beta-1 domains. The Class II molecules share the same characteristics with Class I molecules because they have a peptide-binding domain. This is an Ig-like area and a trans-membrane part containing a cytoplasmic tail. In the “HLA-DP, DQ –DR region” of chromosome 6 is where the polypeptide chains are instructed while the lymphocytes that make reactions with class II molecules express CD4 and are helped T cells most of the time. (Delves, 2008).

MHC Class III. The MHC Class III genes encode several molecules which primarily control inflammation. Elements of C2, C4, and factor B are included in this class. The genes that belong to this classification are cytokines TNFa and TNFb, complement proteins, heat shock proteins, enzymes that are used in steroid synthesis, and other unknown proteins.

MHC Major Function. The human cells are uniquely created having diverse characteristics and play the most important role in the human immune system. When foreign objects seep inside the body, there is a special type of cell that deals with these dangerous objects. Viruses before inhibiting the normal immune system must have to deal with the scattered antibodies, lymphocytes, and many other body defenses. However, when viruses mutated into the bodies, the cells will send a powerful signal that shall alert the immune system. It is when the breakage of the proteins by the proteasomes occurs which produces peptides. These peptides are transferred in the cell’s endoplasmic reticulum and are joined into two major histocompatibility complex (MHC) subcomponents forming a constant complex. For several hours does the MHC be displayed on the surface of the cell. Something goes wrong when the peptide bond is unstable. MHC is recognized by the T-cell receptors. There will be a linkage between the lymphocyte and the wrong cell as coreceptors verify the interaction from which the linkage is strengthened. Large secretory granules will then be released including several toxic proteins such as perforin and granzymes. The granzymes will then be cut forming the apoptosis process which will likely destroy the faulty cell using its own. When a virus is severely mutated into the cell, the MHC carries those tiny fragments of proteins in the cell wall which will serve as a warning device to the immune system. This will then trigger the immune system to mobilize an immune response. Tumor cells may seem to display normal proteins but it produces an abnormal amount making it recognizable by the MHC. (Goodsell, 2005).

Recent Studies

The study conducted by Ilmonen et al. shows that MHC effects were not mainly veiled on an outbred genetic background and that MHC heterozygosity provides no immunological benefits when resistance is recessive and it can actually reduce fitness. The study was undertaken to further investigate the established hypothesis that heterozygosity at MHC loci provides enhanced resistance to infectious diseases. To illustrate the study, they infected mice being produced by crossbreeding congenic C57BL/10 with wild ones to different strains of Salmonella. Findings show that MHC is a factor in resistance which is characterized to be more of a recessive gene than being the dominant one. This contradicts the theory that highly polymorphic genes are influenced by the dominant selection. (Ilmonen et al., 2007).

In another study conducted by Barribeau et al, they have examined the role of major histocompatibility in conferring pathogen resistance using the declining populations of amphibians as the objects of the study. Aeromonas hydrophila, a type of bacteria is injected into a specific kind of tadpole (Xenopus laevis) with four MHC haplotype groupings that are unique with each tadpole. In the initial experiment, a dose of A.hydrophilia bacteria yielded a sequence of ff, FG, gj, and JJ tadpoles whose parents are MHC homozygous. The succeeding test where the parents are heterozygous resulted in a different sequence of ff, fi,fr, gg,rg and RR. One of the aims is to discover patterns of MHC resistance similar between families which do not belong to the non-MHC transmissible differences. Findings show that tadpoles with r or g MHC haplotypes are more vulnerable to death as compared to tadpoles with j haplotypes. Also, there are variations in growth rates of MHC types regardless of exposure dose. The heterozygous tadpoles that have haplotypes that are resistant and vulnerable are found in the middle of the homozygous genotype in terms of size and survival. Findings also show that MHC’s effect on growth and survival is constantly based on the tests involving different families. Also, the MHC alleles have dissimilar resistance or tolerance to the bacterial pathogen. This affects the growth and survival of tadpoles. (Barribeau et al., 2007) The study conducted by Barker et. Al. is laryngeal transplantation using an MHC-matched minipig model. Knowing the effects of ischemia-reperfusion injury (IRI) is essential in determining the immunological changes involving incompatible transplants. They measured the changes using “immunologically active mucosal cells” in 3 h of cold ischemia and 8 h of in situ reperfusion of the MHC-matched minipig model (N=4). To achieve quantitative, varied-color immunofluorescence histology, biopsies were used. After the transplantation and reperfusion, the immune active cells’ population was greatly modified on above or the supraglottis (P < 0.05) and below or the subglottis (P < 0.001) the vocal cords. On the other hand, the outcomes of the changes between the two subsites were varied as supraglottis registered lowered cell numbers while subglottis increased cell numbers. The modifications were way below the normal “inter-and intrepid variation” in cell count in spite of the presence of IRI evidence. (Barker, 2006) In another study conducted by Weinzierl et al., they have concluded that the majority of epitopes found from antigens with tumors are absent in mRNA expression studies. It is because the mRNA expressions illustrate a different situation happening on the surface of the cell which is visible in T-cells. (Weinzierl et al., 2007) Since no evidence of a correlation existing among the different levels of mRNA (the “transcriptome”) and the concentration of MHC-peptide complexes (the “MHC ligandome”) on cells, mRNA and MHC in renal cell carcinomas and functioning kidney tissues were put into analysis. From the peptides that were presented mostly on tumor or normal tissues, the majority of the peptides expressed changes from zero to minor mRNA levels. Data from other cases show that peptides and their mRNA are not related in terms of existence simultaneously. Another study was conducted with regard to the relationship between antigenicity and the T cell receptor. Influenza A virus was applied on mice (C57BL/6) and made a variety of TCR repertoires. These are parts of “Nucleo protein-peptide amino acids 366-374 (NP366)” and “acid polymerase peptide amino acids 224-233 (PA224)”. The H-2Db that showed the amino acids has an NP366 type complex structure with inadequate TCR repertoire and public TCR habit. On the other hand, the PA224 complex type of H-2Db chose a varied, private TCR repertoire. Exchanging arginine with alanine in position 7 of PA224 decreased the side chains of the epitope that are nearby. An infection characterized by a mutation on the arginine of PA 224 (position 7) selected TCR repertoire that is the same as the NP366 variety of H-2Db.

As a result, there is a relationship between the decreased TCR usage and the deficiency of well-known characteristics of peptides and MHC Class I. (Turner, 2005) In transplantation and organ testing, several cross-match methods were further analyzed to avoid the noxious effect of incompatibility. In Rebecca and Garovoy, the following methods were deemed necessary to be reviewed before any necessary undertaking:

The sensitivity required in crossmatch testing:

Importance of B-cell crossmatch which is a replacement for incompatibilities in class II;
Significance of the classes of immunoglobin and its subordinates of “donor-reactive antibodies”;
Serum screening analysis techniques;
The proper timing and amount of serum screening.

Despite a number of variables, when the data from reported studies are considered collectively, several observations can be made. The “leukocyte antigen-donor-specific antibodies” can possess a threat to graft function and survival when they are present in the recipient during transplantation. (Lebeck, 2008) Several recurrent mistakes have been found especially in renal transplantation that there is a decrease in long-term graft survival rates with increasing antigen mismatched by the recipient of renal transplant. The policy was being drafted by the United States Network of Organ Sharing (UNOS) regarding the mandatory sharing of HLA-matched kidneys to zeroed the mismatched kidney sharing. In another study by Vignal et. al. with regard to the HLA-DRB1 locus being susceptible to a gene for rheumatoid arthritis, the MHC’s polygenic contribution to RA involves two added “non-DRB1 susceptibility loci”. (Vignal, 2009).

Recent studies demonstrate the Class I of the MHC (peptide complex) expressable as “single-chain trimers” (SCT). This connection is made by linkers in order to establish a single polypeptide chain. The experiment uses a mouse where a human disease was inflicted onto it and observations show that SCTs are the proactive stimulants of “cytotoxic T lymphocytes”. It is because the SCTs consist of a peptide stable, located on the surface of the cell, that is processed and loaded beforehand. HLA Class I SCTs are regarded as stable biochemically or vulnerable to exogenous peptide binding. Another characteristic of SCTs is that they remain undamaged inside the cells and have the ability to generate a trap that isolates exogenous peptide binding. Further studies are needed to validate the study. (Truscott, 2008) Also, the tumor-isolated peptides that belong to MHC class I and II resulted in the discovery of less than a hundred “tumor-specific antigens”. Some of these are mutant gene products, while most are normal proteins that are expressed in varied ways after cell transformation. Dendritic cells containing tumor antigen have the ability to copy the immune response in vitro. Other tumor antigens like B1 cyclin, NY-ESO-1, cancer-testis were discovered using the antibodies of cancer patients only. It implies that vaccination can increase immunity against tumor antigens. Studies also suggest a decrease in the risk of cancer can be attained from vaccinations against measles, mumps, rubella, pertussis, and chickenpox. Experiments involving animals show that cancer can be arbitrated by immunogenicity against multiple self-antigens. (N Engl J Med, 2008) Another study conducted by Barack et. Al., shows that “alpha-beta T cell receptors (αβTCRs)” are MHC proteins. Studies show the linkage of T-cell receptors and MHC in terms of binding, the process beyond this occurrence is still unknown. Recent structures of T-cell receptors imply that amino acids located in CDR1 and CDR2 regions are reactive to MHC in a constant manner. The amino acids may have been acquired to set out the T-cells beforehand in distinguishing MHC ligands. (Marack, 2008).

References

Barker et. al. 2006. Early immunological changes associated with laryngeal transplantation in a major histocompatibility complex-matched pig model. Clin Exp Immunol. 146(3): 503–508.

Barribeau, S. M. et al. 2007. Major Histocompatibility Complex Based Resistance to a Common Bacterial Pathogen of Amphibians. Plos One. Vol 3 No. 7.

Delves, P. J. 2008. Human Leukocyte Antigen (HLA) System. Merck[Online]. 2009. Web.

Dorak, T. M. 2007. Major Histocompatibility Complex. 2009. Web.

Finn OJ. 2008. Cancer Immunology. N Engl J Med. 358(25):2704-2715.

Goodsell, D. S. 2005 The Molecular Perspective: Major Histocompatibility Complex.The Oncologist.

Ilmonen, P. et. al. 2007. Major Histocompatibility Complex Heterozygosity Reduces Fitness in Experimentally Infected Mice. Genetics. 176: 2501-2508.

Lakshmanan et al. 1997. Major Histocompatibility Complex Class II DNA Polymorphisms in Chicken Strains Selected for Marek’s Disease Resistance and Egg Production or for Egg Production Alone. Poultry Science, 76(11): 1517-1523.

Lebeck, L. K. 2008. Histocompatibility Testing and Organ Sharing. Atlas of the Diseases of Kidney. Chapter 8 Pp. 1-12.

Marrack, P. et. al. 2008. T cell receptor specificity for major histocompatibility complex proteins. Current Opinion in Immunology. 20(2) 203-207.

MHC Complex. 2008. Web.

Turner, S.J. et. al. 2005. Lack of prominent peptide−major histocompatibility complex features limits repertoire diversity in virus-specific CD8⁺ T cell populations. Immunology[online]. 2009. Web.

Truscott, S. M. et, al. 2008. Human Major Histocompatibility Complex (MHC) Class I Molecules with Disulfide Traps Secure Disease-related Antigenic Peptides and Exclude Competitor Peptides^.J Biol Chem. 283(12):7480-90.

Twyman, R. 2003. The major histocompatibility complex. A cluster of genes essential to the immune system. Wellcome Trust [Online]. 2009. Web.

Weinzierl et. al. 2007. Distorted relation between mRNA copy number and corresponding major histocompatibility complex ligand density on the cell surface. Mol Cell Proteomics. 6(1):102-13.

Vignal et. al. 2009. Genetic association of the major histocompatibility complex with rheumatoid arthritis implicates two non-DRB1 loci. Arthritis & Rheumatism. 60(1):52-63.

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Major Histocompatibility Complex

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