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B900 Biomedical Science

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B900 Biomedical Science

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Course Code: B900
University: University Of Birmingham

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Country: United Kingdom

Question:

Major histocompatibility complex is a group of genes which encodes proteins found on the surface of cells to help in recognising antigens and determining histocompatibility. In human being the MHC molecules is known as Human leukocyte antigen and is found on human chromosome.

Answer:

MHC molecules and immunity
The cell-mediated adaptive immunity system is basically regulated by MHC, which is a Major Histo-compatibility Complex molecule (Giles et al. 2015). The immune system of the body fights the pathogens that succeed in invading the normal tissues. Immune system protects the human body in various ways against bacteria, viruses, parasites, cancerous cell or any other. Pathogens enter into the body in an invasive way. Two types of immune system exist, innate immunity and adaptive immunity. Innate immune defences are mediated by white blood cells or WBC, such as granulocytes, monocytes/macrophages and natural killer cells, and by antibacterial proteins, such as acute phase and complement proteins, circulating in blood.But, in case of adaptive immunity, some specific defences against an invader are developed (Rock, Reits and Neefjes 2016). However, several forms of adaptive immunity are there and they are humoral and cell mediated. In order to destroy the antigens, antibodies appear in the body fluids in case of humoral adaptive immunity system but, in cell mediated immunity system cells can destroy other cells become active. They destroy all the disease infected cells (Rock, Reits and Neefjes 2016).
Function of MFC
Some specific functions of MHC molecules have been found by the researchers. MHC molecules helps to introduce T-cell antigen receptors (and, in parallel, B-cell antigen receptors for B cells) at an early stage. Inside the human body cells, proteins are broken down into short fragments (Giles et al. 2015). Those short fragmented proteins can be displayed as peptide antigens by MHC molecules. The self peptide, derived from the own proteins, as well as the foreign peptides derived from the invading pathogens is displayed by MHC molecules (Rock, Reits and Neefjes 2016). HLA (human leukocyte antigen) present in the MHC of human body also helps in monitoring the amount of MHC-presented antigens that destroys cancerous cells which displays increased amount of self-antigens (Moutsianas et al. 2015). There are a vast number of potential peptide targets but the number of MHC proteins is limited and due to this purpose MHC proteins are highly effective in binding several types of peptides. Moreover, MHC proteins have the capability of binding peptides of different kinds and even of different structures. Due to this unique property, MHC proteins are different from other proteins or molecules. Tissue allorecognition is another function of MHC and it plays a major role in preventing successful transplantation of organ (Moutsianas et al. 2015).
MHC and antigen presentation
MHC is useful in controlling the process in which the immune system of human body detects as well as responds to some specific antigens. The MHC molecules also control the antigen specificity of T-cell recognition (Giles et al. 2015). There are two different classes of MHC molecules, class I as well as class II. Both the classes have similarity in function of involving the delivery of very short peptides into the surface of cell recognition and it basically takes place by CD8+ and CD4+ T cells respectively. It is possible to stimulate some specific T-cells by MHC class I which is basically located on all cells which are nucleated (Cho et al. 2015).
Difference between MHC class I and MHC class II
MHC is known to be highly polymorphic and in the immune function, the role of it significant. In E. jankowskii, low level of MHC polymorphism was revealed and it was similar to that in E.Cioides. There is a difference between the two classes of MHC. The properties are not similar. The class I is the glycoproteins, which are expressed upon the surface of all the nucleated cells. The main role of the class I MHC is the presentations of peptide antigens into the TC (cytotoxic T) cells. The molecules of MHC class I consists of one membrane spanning alpha chain which is encoded by MHC gene and one beta chain, which is encoded by the beta2 microglobulin gene (Cho et al. 2015). It also presents foreign intracellular antigens. But, in case of MHC class II molecules, it consists of two membrane spanning chains, alpha and beta, but their sizes are similar and both are produced by the MHC genes. The glycoproteins of MHC class II is present only on some specialized antigen presenting cells. It also presents 14-18 amino acid peptides which is greater than MHC I. The class II of MHC also presents foreign extracellular antigen that induces antibody production as well. The inflammatory response increases the blood flow to the inflammatory area and it brings immune cells to the site (Van der Meijden et al. 2016). All these properties distinguish MHC class II from the properties of the MHC class I. Again, MHC class II is basically is a class of major histo-compatibility complex molecules. These are generally found only on antigen-presenting cells that includes mononeuclear phagocytes, dendritic cells, etc. All the cells are extremely important in initiating the immune responses. MHC, the group of genes is also useful in encoding the proteins found on the surface of cells, and it helps in the recognition of antigens. At the same time it also determines the histo-compatibility (Giles et al. 2015). MHC molecule is generally found in human chromosome and can be termed as human leukocyte antigen (HLA).
MHC and Autoimmunity
Some molecules of MHC are directly associated with inflammatory diseases as well as with the increased risk of autoimmune. In the year 1967, it was first found that MHC HLA-B antigens increased frequency among the patients having Hodgkin’s lymphoma. Apart from that, multiple sclerosis, rheumatoid arthritis, Crohn’s disease and some other health conditions of human being are also associated with some specific MHC molecules (Hauser et al. 2017). In an analysis, conducted by the association of MHC disease revealed that a susceptibility of shared disease is there to the alleles that arise from HLA-DR4 haplotypes. Simultaneously, the analysis indicates that there is a common as well as disease specific association between autoimmunity and the MHC. The exact and specific mechanism behind the autoimmunity and MHC molecules has not properly been found in the researches but it potentially reflects a breakdown in tolerance to self-antigens in the antigen presentation of normal MHC class II. Therefore, some specific class II alleles work as the determinants of auto-antigen targeting (Cho et al. 2015).  
MHC and tissue allorecognition
Allorecognition is basically the capability of an organism that helps in distinguishing its tissues from those of another organism. This distinguishing is possible within the same species also plays the important role in the implication of transplantation. Various risks are there in organ transplantation and one of them is alloresponse, and in this condition, histoincompatible antigen is identified as well as recognized and it also produces an adaptive immune response by employing allospecific T-cells (Hauser et al. 2017). All these things can lead to the direct rejection of all the tissues that are transplanted. But, the direct involvement of MHC into the mechanism of allorecognition helps in this regard. Here, the T-cell identifies the determinants on the donor. MHC molecules always display a type of antigenic determinant that is termed as epitope. T cells have the ability to identify the epitopes presented by particular allelic variant of MHC molecules. But, if the epitopes are presented by allelic variants of another MHC molecule, then it is not possible for the T-cells to recognize those (Van der Meijden et al. 2016).
Tolerance
The development of the T-cells always depends on the interaction with the MHC molecules. Studies revealed that during the development in the thymus, 98% T cells die due to the process of falling selection. Two stages are there in which the first or initial stage is the positive selection, and in this stage, T cells are found to be interacting with the self MHC in the thymus but the second stage is the negative selection in which T cells, interacting with seld MHC are removed strongly (Giles et al. 2015). Different MHC variants will present different peptides. Someone else’s (allogeneic) MHC variants and the peptides they present will differ from those to which the transplant recipient’s T cells are tolerant. The T cells recognise both types of difference. Autoimmune disease is a phenomenon in the natural world, albeit that it is a disease state rather than part of normal physiology (Moutsianas et al. 2015).
Vitamin D
There are various kinds of vitamins. Human body requires many vitamins and one of them is Vitamin d, which is commonly referred as “sunshine vitamin” because it is generally produced in the skin, in response to the direct sunlight. During the exposure to the sunlight, the ultraviolet ray present in it is mainly responsible for photolyzing 7-dehydrocholesterol (Mokry et al. 2015). There are many functions of vitamin D in improving the health of human being. This vitamin is soluble in fat and it consists of the compound vitamins of Vitamin D1, D2, D3. When body is exposed to sunlight it naturally produces vitamin D and also some food supplements are there in the market to ensure the adequate amount of vitamin D in the blood. Vitamin D, which is mainly obtained from the direct sun exposure, supplement and food, is found to be biologically inert and in order to get activated it has to undergo two different steps of hydroxylation inside the human body. The first stage of the hydroxylation occurs in the liver, and in this stage, the vitamin D is converted into 25-hydroxyvitamin D, and again, the second stage of the hydroxylation occurs primarily inside the kidney and forms the physiologically active 1, known as calcitriol (Mokry et al. 2015). The major function of vitamin D is to maintain the calcium and phosphate level of blood. Even, recent research suggests that proper intake of vitamin D provides protection from osteoporosis, hypertension and several other autoimmune diseases.
Role of Vitamin D
Vitamin is essential in promoting calcium absorption in the gut and also maintains the adequate concentration of serum calcium and phosphate which helps in enabling the normal mineralization of bones and again it prevents hypocalcemic tetany as well. Sufficiency of Vitamin D inside the human body prevents rickets in children and osteomalacia among adults. Vitamin D has various other roles in the human body, as it is associated with the immune system. It has the ability to modulate the innate as well as the adaptive immune responses. Deficiency of vitamin D is responsible for increased susceptibility to infection. It also contributes to the cell growth and reduction of inflammation (Mokry et al. 2015). There is an association between the vitamin D deficiency and multiple sclerosis. It has been found in many studies that the women who take vitamin D as dietary supplements are less likely to be suffered from multiple sclerosis and even, the incidence is less than 33% when compared to the women who are not taking vitamin D as dietary supplement. Many researchers are in the progress of investigating the therapeutic effects of the vitamin D in preventing multiple sclerosis (Kreiter et al. 2015).
Properties of Vitamin D
Vitamin D has the properties of vitamin as well as hormone. It is highly necessary for the mineral homeostasis and the proper and well formation of the bones. Two different forms vitamin D are there which includes ergocalciferol and cholecalciferol. The ergocalciferol is used as food additive and the cholecalciferol is the naturally occuraing Vitamin D, which is directly synthesized in the skin with exposure to sunlight and some specific food supplements. According to studies, it triggers the immune cells of body and produces antibodies (Palacios and Gonzalez 2014). Therefore, vitamin D has a great contribution to the overall immunity system of human body. Evidences from more than 500 studies support the fact that vitamin D plays huge role in the immune system of human being. It assists in the maintenance of muscle comfort and joints. There is adequate amount of vitamin D in the sunlight and exposure to sunlight and some specific dietary food supplements can help in supplying sufficient vitamin D to the human being but studies in the United States National Centres and a report regarding the Health Statistics states that approximately 70% of individuals suffer from vitamin D deficiency (Palacios and Gonzalez 2014). The people of vitamin D deficient include elderly as well as the breastfed infants as they cannot get the sufficient amount of sun exposure. In addition, people who have fat mal-absorption syndrome such as inflammatory bowel disease, cystic fibrosis and others also are at risk of suffering from the vitamin D deficiency. Usage of some specific medications such as carbamazepine and phenytoin can increase the metabolism rate of vitamin D inside the human body. All these agents also help in increasing the hepatic metabolism of vitamin D to the compounds that are inactive and at the same time it reduces calcium absorption. People, especially women mainly suffer from this syndrome due to not having sufficient amount of calcium absorption inside body (Matzaraki et al. 2017).  
In the year 2008, the American Academy of Dermatology provided a new version of position statement on the vitamin D and regarding the role of it in the maintenance of optimal health after reviewing evidences. American Academy of Paediatrics recommends 400 IU per day of vitamin D3 taken with food for children. In some cases, higher doses of vitamin D is necessary for human being and such patients should always be referred for further assistance of physicians and they should never follow the process of self-treatment as the dosage of vitamin D must be determined by an expert physician only (Thompson et al. 2017). US food and Nutrition Board has also set an upper limit for the intake of vitamin D, in order to avoid the toxicity caused by the over intake of it. According to them the upper intake of vitamin D is 2000 IU per day for the individuals older than one year and for the infants the upper limit is 1000 IU. Again, some studies reported that an estimated number of more than 6.3 million children of United States are lacking the adequate amount of vitamin D (Lefevre 2015). According to evidences, 7 out of 10 children in the United States have low level of vitamin D which puts them in the risk of rickets, cardiovascular disease and weak bones (Campos et al. 2015).     
Multiple Sclerosis and vitamin D
 Multiple sclerosis is basically a complex trait in the medical term and in this disease, the allelic variation in the MHC class II is found to be exerting the strongest effect on the genetic risk. The risk of developing an autoimmune disease, such as MS, is determined by a number of genetic and environmental factors (Van der Meijden et al. 2016). Some strong epidemiological information about multiple sclerosis provides evidence that environmental factor has major contribution to the incidence as well as prevalence of the disease and sunlight or vitamin D is the main environmental factor in this regard (Dendrou, Fugger and Friese 2015). Growing evidences indicate that insufficient sun exposure or lack of vitamin D is one of the greatest reasons of Multiple Sclerosis (MS). This is a very complex neurological disease and it is related to the strong genetic component. Studies show that there is a massive involvement of vitamin D in the nervous as well as in the immune system of human being. Some circumstantial evidence show that MS patients are vitamin D deficient and dietary vitamin intake is helpful in reducing all the risks regarding MS (Gorman et al. 2016).
Vitamin D is generally a secosteroid hormone and it is mainly synthesized in the skin and also ingested through proper dietary supplement. According to many study researchers, dietary intake consists of a much smaller amount of vitamin D and thus sunlight is the main and most effective source of vitamin D (Van der Meijden et al. 2016). Again, some epidemiological studies clearly indicated that the existence or prevalence of MS among the human beings vary according to the geographical location because in some latitude and longitudinal locations people cannot have enough sun exposure which in turn causes the lack of vitamin D inside the body and in this way people living in those areas suffer from MS and other vitamin D deficiency related disease (Gherardin et al. 2016). A study presented the report that there is an association between MS susceptibility and the status of vitamin D which is dependent on the genotype and the outcome of vitamin D status and MS is determined by the gene-sex interactions (Lublin et al. 2014). Vitamin D is able to limit the presentation capacity of the antigen and the antigen-presenting cells of human body and it helps in building a strong health of the bones. Some recent studies indicated that the gene which is responsible for the occurrence of MS is primarily expressed by the T cells (Gherardin et al. 2016).
The impacts of Vitamin D on the gene expression of MHC class II is widely appreciated and even some studies revealed that vitamin D has the ability to alter HLA-DR antigen presentation as well as expression and moreover, vitamin D regulates MHC class II protein expression and function. The antibodies are always helpful in improving the immunity systems and the role of vitamin D in increasing the immunity of human being is also highly significant (Van der Meijden et al. 2016). The role of vitamin D is also important in preventing many bone-related diseases and it also helps in preventing multiple sclerosis. However, gene has a great contribution towards the MHC classes which in turn affects the immune system and vitamin D helps in improving the immune system of human body (Van der Meijden et al. 2016).
References
Campos, J.H., Soares, R.P., Ribeiro, K., Cronemberger Andrade, A., Batista, W.L. and Torrecilhas, A.C., 2015. Extracellular vesicles: role in inflammatory responses and potential uses in vaccination in cancer and infectious diseases. Journal of immunology research, 2015.
Cho, K.J., Walseng, E., Ishido, S. and Roche, P.A., 2015. Ubiquitination by March-I prevents MHC class II recycling and promotes MHC class II turnover in antigen-presenting cells. Proceedings of the National Academy of Sciences, 112(33), pp.10449-10454.
Dendrou, C.A., Fugger, L. and Friese, M.A., 2015. Immunopathology of multiple sclerosis. Nature Reviews Immunology, 15(9), p.545.
Gherardin, N.A., Keller, A.N., Woolley, R.E., Le Nours, J., Ritchie, D.S., Neeson, P.J., Birkinshaw, R.W., Eckle, S.B., Waddington, J.N., Liu, L. and Fairlie, D.P., 2016. Diversity of T cells restricted by the MHC class I-related molecule MR1 facilitates differential antigen recognition. Immunity, 44(1), pp.32-45.
Giles, J.R., Kashgarian, M., Koni, P.A. and Shlomchik, M.J., 2015. B cell–specific MHC class II deletion reveals multiple nonredundant roles for B cell antigen presentation in murine lupus. The Journal of Immunology, p.1500792.
Gorman, S., Geldenhuys, S., Judge, M., Weeden, C.E., Waithman, J. and Hart, P.H., 2016. Dietary vitamin D increases percentages and function of regulatory T cells in the skin-draining lymph nodes and suppresses dermal inflammation. Journal of immunology research, 2016.
Hauser, S.L., Bar-Or, A., Comi, G., Giovannoni, G., Hartung, H.P., Hemmer, B., Lublin, F., Montalban, X., Rammohan, K.W., Selmaj, K. and Traboulsee, A., 2017. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. New England Journal of Medicine, 376(3), pp.221-234.
Kreiter, S., Vormehr, M., Van de Roemer, N., Diken, M., Löwer, M., Diekmann, J., Boegel, S., Schrörs, B., Vascotto, F., Castle, J.C. and Tadmor, A.D., 2015. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature, 520(7549), p.692.
Lefevre, M.L., 2015. Screening for vitamin D deficiency in adults: US Preventive Services Task Force recommendation statement. Annals of internal medicine, 162(2), pp.133-140.
Lublin, F.D., Reingold, S.C., Cohen, J.A., Cutter, G.R., Sørensen, P.S., Thompson, A.J., Wolinsky, J.S., Balcer, L.J., Banwell, B., Barkhof, F. and Bebo, B., 2014. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology, 83(3), pp.278-286.
Matzaraki, V., Kumar, V., Wijmenga, C. and Zhernakova, A., 2017. The MHC locus and genetic susceptibility to autoimmune and infectious diseases. Genome biology, 18(1), p.76.
Mokry, L.E., Ross, S., Ahmad, O.S., Forgetta, V., Smith, G.D., Leong, A., Greenwood, C.M., Thanassoulis, G. and Richards, J.B., 2015. Vitamin D and risk of multiple sclerosis: a Mendelian randomization study. PLoS medicine, 12(8), p.e1001866.
Moutsianas, L., Jostins, L., Beecham, A.H., Dilthey, A.T., Xifara, D.K., Ban, M., Shah, T.S., Patsopoulos, N.A., Alfredsson, L., Anderson, C.A. and Attfield, K.E., 2015. Class II HLA interactions modulate genetic risk for multiple sclerosis. Nature genetics, 47(10), p.1107.
Palacios, C. and Gonzalez, L., 2014. Is vitamin D deficiency a major global public health problem?. The Journal of steroid biochemistry and molecular biology, 144, pp.138-145.
Rock, K.L., Reits, E. and Neefjes, J., 2016. Present yourself! By MHC class I and MHC class II molecules. Trends in immunology, 37(11), pp.724-737.
Thompson, A.J., Banwell, B.L., Barkhof, F., Carroll, W.M., Coetzee, T., Comi, G., Correale, J., Fazekas, F., Filippi, M., Freedman, M.S. and Fujihara, K., 2017. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. The Lancet Neurology.
Van der Meijden, K., Buskermolen, J., van Essen, H.W., Schuurman, T., Steegenga, W.T., Brouwer-Brolsma, E.M., Langenbach, G.E.J., van Ruijven, L.J., den Heijer, M., Lips, P. and Bravenboer, N., 2016. Long-term vitamin D deficiency in older adult C57BL/6 mice does not affect bone structure, remodeling and mineralization. The Journal of steroid biochemistry and molecular biology, 164, pp.344-352.

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