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Immunological Aspects of Multiple Sclerosis with Emphasis on the Potential Use of Autologous Hemopoietic Stem Cell Transplantation
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Paolo A. Muraro, Henry F. McFarland, Roland Martin
Major histocompatibility complex (MHC; or HLA= human leukocyte antigen in humans) class II genes, in particular HLA-DRB1*1501 and—DRB5*0101 (both are expressed in the HLA-DR2 haplotype), and HLA-DQA1 *0102 and—DQB1*0602, have reproducibly shown the strongest association with MS.13,14 It is believed that the surface receptors encoded by these genes contribute via their role as antigen-presenting molecules for CD4+ T lymphocytes. The exact mechanisms by which these genes confer susceptibility to disease, however, remain to be elucidated. A number of other candidate genes has been examined including those encoding for cytokines, chemokines, chemokine receptors, T cell receptors, and complement components.15 Often, positive disease associations that had been reported in one study were not confirmed by others. This disagreement is largely due to disease heterogeneity and the fact that frequently small patient groups have been examined, or the patient cohorts were composed of individuals with different course, MRI presentation, and brain pathology. Recently, whole genome screens in North America anf Europe,16-19 confirmed that the HLA region on chromosome 6 harbors an important susceptibility locus, but that other genes probably contribute to disease as well. It is currently assumed that the genetic susceptibility to MS, as well as to other autoimmune diseases, is based on a quantitative trait to which multiple genes contribute weakly and in an additive fashion.20 Depending on which and how many of the susceptibility loci are carried by an individual in the heterogeneous and out-bred human population, the risk of this particular individual to develop disease will be lower or higher. Furthermore, the individual’s genetic trait will likely contribute to disease heterogeneity, i.e., whether a patient primarily shows prominent inflammation due to the production of excess proinflammatory cytokines, or presents with more vulnerable cells of the target tissue such as oligodendrocytes or neurons, to mention only two possibilities. Unfortunately, the identification of genes associated with different disease phenotypes will require not only defeating the complexities of genetic analysis of susceptibility to MS, but also overcoming the difficulty in measuring disease course and severity.15 Nevertheless, improved genetic techniques such as high density microsatellite mapping of susceptibility alleles and single nucleotide polymorphisms, as well as expression profiling by microarrays and proteomics techniques, will probably advance our understanding of the genotype-phenotype interactions in the near future.
Genetic variants affecting chemical mediated skin immunotoxicity
Published in Journal of Toxicology and Environmental Health, Part B, 2022
Isisdoris Rodrigues de Souza, Patrícia Savio de Araujo-Souza, Daniela Morais Leme
The MHC molecules are cell surface glycoproteins whose function is to present peptide antigens to T cells. T cell activation may elicit different types of immune reactions, playing an essential role in pathogenesis of infectious and allergic diseases (Orentas et al. 1990; Posadas and Pichler 2007). The human genes encoding MHC molecules such as human leukocyte antigen and HLA are located in a region that spans approximately 3.6 Mb on 6p21.3, and includes not only classical HLA class I (HLA-A, HLA-B and HLA-C) and II genes (HLA-DRA1, HLA-DRB1, HLA-DPA1, HLA-DPB1, HLA-DQA1 and HLA-DQB1) but also a large number of highly polymorphic genes, encoding proteins with immune-related functions, such as TNF (Alfirevic and Pirmohamed 2011).