MHC Class II Polymorphisms, Autoreactive T-Cells, and Autoimmunity

Abstract

Major histocompatibility complex (MHC) genes, also known as human leukocyte antigen genes (HLA) in humans, are the prevailing contributors of genetic susceptibility to autoimmune diseases such as Type 1 Diabetes (T1D), multiple sclerosis, and rheumatoid arthritis, among others (1–3). Although the pathways through which MHC molecules afford autoimmune risk or resistance remain to be fully mapped out, it is generally accepted that they do so by shaping the central and peripheral T-cell repertoires of the host toward autoimmune proclivity or resistance, respectively. Disease-predisposing MHC alleles would both spare autoreactive thymocytes from central tolerance and bias their development toward a pathogenic phenotype. Protective MHC alleles, on the other hand, would promote central deletion of autoreactive thymocytes and skew their development toward non-pathogenic phenotypes. This interpretation of the data is at odds with two other observations: that in MHC-heterozygous individuals, resistance is dominant over susceptibility; and that it is difficult to understand how deletion of one or a few clonal autoreactive T-cell types would suffice to curb autoimmune responses driven by hundreds if not thousands of autoreactive T-cell specificities. This review provides an update on current advances in our understanding of the mechanisms underlying MHC class II-associated autoimmune disease susceptibility and/or resistance and attempts to reconcile these seemingly opposing concepts.

The Genetics of Multiple Sclerosis: From 0 to 200 in 50 Years

“…These include the HLA genes, which have been extensively studied as the principal determinants of allogeneic transplantation outcomes [83]. The polymorphism of many of the HLA genes is extraordinary, with more than 14,000 alleles identified to date; more than 100 infectious, autoimmune and inflammatory disease phenotypes, including MS, as well as drug reactions and cancers are associated with HLA genes variation [84, 85]. The association of the HLA locus with MS risk was first described several decades ago [86] and since then has been observed across all populations studied [87].…”

Genetic determinants of risk and progression in multiple sclerosis

“…Among these, the highly polymorphic classical HLA class I ( HLA-A, -B, -C ) and class II ( HLA-DPB1, -DQB1, -DRB1 ) gene clusters are now well characterized in terms of structure, diversity, and function. An extraordinary amount of data confirms their central role in the allogeneic response to tissue and hematological transplantation and risk for autoimmunity [28, 29]. …”

From Primary Immunodeficiency to Autoimmunity: How Extreme Situations Highlight the Main Genetic Factors Involved in Autoimmune Disease

“…Although environmental factors such as stress factors inducing changes In hormone level, infectious injuries and specially own microbiota are also entailed in variable degrees [1], genetic factors have been broadly defined along decades and have shown to play a clear key role in autoimmunity [2,3]. Beyond polymorphisms of HLA (the main genetic factor identified among autoimmune diseases) [4,5], many other genes (costimulatory molecules, cytokines and their receptors, signaling pathways, transcription factors, etc.) are being involved in autoimmunity by genome-wide association studies (GWAS).…”