Skewed T-cell receptor repertoire in genetically identical twins correlates with multiple sclerosis

Abstract

Although the cause of multiple sclerosis (MS) is unknown, it is thought to involve a T cell-mediated autoimmune mechanism. Susceptibility to the disease is influenced by genetic factors such as genes of the HLA and T-cell receptor (TCR) complex. Other evidence for a genetic influence includes the low incidence in certain ethnic groups, the increased risk if there are affected family members and the increased concordance rate for disease in monozygotic twin pairs (26%), compared to dizygotic twins. Epidemiological studies indicate that there may be an additional role for environmental factors. Although the target antigen(s) are not yet identified, several myelin or myelin-associated proteins have been suspected, among them myelin basic protein. A lack of genetically comparable controls has impaired the analysis of the T-cell response in MS patients and caused disagreement on TCR usage in the disease. Here we analyse the role of TCR genes in MS by comparing TCR usage in discordant versus concordant monozygotic twins in response to self and foreign antigens. We find that after stimulation with myelin basic protein or tetanus toxoid, control twin sets as well as concordant twin sets select similar V alpha chains. Only the discordant twin sets select different TCRs after stimulation with antigens. Thus exogenous factors or the disease shape the TCR repertoire in MS patients, as seen by comparison with unaffected genetically identical individuals. This skewing of the TCR repertoire could contribute to the pathogenesis of MS and other T-cell-mediated diseases.

Vβ6+ T Cells Are Obligatory for Vaccine-Induced Immunity to Histoplasma capsulatum

“…Likewise, limited heterogeneity in TCR usage has been demonstrated in humans with some infectious diseases (17,18), multiple sclerosis (19), and obliterative bronchioloitis associated with lung transplantation (20). In a high proportion of studies performed during experimental infection, associations have been established between disease and TCR bias, but little is known about the role of the expanded V␤ family in disease recovery or exacerbation.…”

Myelin-Associated Oligodendrocytic Basic Protein: Identification of an Encephalitogenic Epitope and Association with Multiple Sclerosis

“…Studies of monozygotic twins, of case clusters, and of MHC types document that individuals who develop MS must have an appropriate immunogenetic background influenced by several MHC genes likely involved in presenting a limited number of "self" myelin Ags (39 -44). However, the discordance among monozygotic twins (39,45), the epidemiologic studies of susceptibility or resistance to MS in individuals migrating to areas with high or low incidence of disease before their 15th year of age (46), the association of MS with viral infections (47,48), as well as outbreaks of MS in the Faroe Islands (49) indicate that environmental factors, presumably infections, are also important for disease pathogenesis. Hence, it is important to know about all molecules involved in MS. Our data links MOBP with MS.…”

Distinctive properties of identical twins' TCR repertoires revealed by high-throughput sequencing

“…Several studies of TCR repertoires were performed mainly focusing on diseases concordant and discordant MZ twins and using complementarity determining region 3 (CDR3) spectratyping and/or low depth sequencing (8)(9)(10)(11). Some of these studies reported the common use of particular V genes and common clonotypes.…”