Revisiting the T-cell receptor alpha/delta locus and possible associations with multiple sclerosis

Abstract

A role for T cells in the pathogenesis of multiple sclerosis (MS) is well supported, evidenced by myriad immunological studies, as well as the unequivocal genetic influence of the major histocompatibility complex (MHC). Despite many attempts, no convincing genetic associations have been made between T-cell receptor (TCR) gene loci and MS. However, these studies may not be definitive because of small sample sizes and under-representative marker coverage of the chromosomal regions being investigated. To explore potential roles between the TCR alpha locus and MS, we have genotyped a large family-based cohort, including 1360 affected individuals and 1659 of their unaffected first-degree relatives, at 40 single-nucleotide polymorphism (SNP) markers within the TCR alpha/delta locus. This represents the largest TCR alpha-MS study to date. From this screen, we identified three potential loci of interest in TCR alpha variable and constant gene regions using the transmission disequilibrium test. Although SNPs implicating each of these regions of interest will require genotyping in independent replication cohorts, these findings suggest a role for TCR gene polymorphisms in MS susceptibility. In the context of these findings we review the evidence.

High‐throughput sequencing of immune repertoires in multiple sclerosis

“…Previous studies using restriction fragment length polymorphisms (RFLP) as genetic markers have reported conflicting results regarding the influence of TCR gene polymorphisms on MS risk . A more recent study used single‐nucleotide polymorphism markers to revisit this and identified three potential loci of interest in TCR alpha V and constant gene regions …”

The Missing Heritability in T1D and Potential New Targets for Prevention

“…There are, however, linkages to TCR in human autoimmune diseases other than T1D. TCR genotype has been implicated in multiple sclerosis (MS) [25]. There are also well-documented associations of TCR genotype with other forms of autoimmunity including Sjogren's syndrome [26, 27] and narcolepsy [28–30], which has a TCRA bias.…”

Sex-Related Differences in Allelic Frequency of the Human Beta T Cell Receptor SNP rs1800907: A Retrospective Analysis from Milan Metropolitan Area

“…TCR antigen recognition is dependent on the presentation of short antigen peptides by the major histocompatibility complex (MHC) proteins expressed on the surface of other cells. The direct molecular interaction between the peptides, i.e., the MHC complex and the TCR, greatly influences TCR gene usage and has a fundamental part in shaping T cell/expressed TCR repertoires, particularly during T cell maturation and differentiation [8]. TCR genes are located at three regions in the genome, 14q11.2 (TCR α, δ), 7q34 (TCR β) and 7p14 (TCR γ).…”