Short‐term evolution of autoreactive T cell repertoire in multiple sclerosis

Abstract

T cells reactive to self-antigens are present in the peripheral blood of patients with autoimmune diseases as well as in healthy subjects. Although T cell-response to the self-myelin antigen myelin basic protein (MBP) has been widely investigated in multiple sclerosis (MS) patients, very little is known about the evolution over time of this response and its correlation with the disease activity. In recent years magnetic resonance imaging (MRI) techniques have provided new tools for following the inflammatory activity in the central nervous system (CNS) of MS patients. In the present study the T cell response to MBP was longitudinally investigated in terms of frequency, epitope specificity, and cytokine production profile in four patients with relapsing-remitting MS enrolled in a gadolinium-enhanced MRI serial study. In spite of different profiles of inflammatory activity within the CNS, all the patients examined showed major changes in their reactivity to MBP during the follow-up period in terms of both frequency and epitope specificity. Episodic expansions of MBP-specific T cell populations were observed in each patient, and overall they did not correlate with disease activity. In these patients the expansions: 1) occurred in the context of a steady level of disease activity, 2) correlated with a burst of CNS inflammation, 3) followed the appearance of a new active lesion, and 4) were observed even in the absence of detectable signs of CNS inflammation during the entire follow-up period. These results suggest that the evolution over time of the T cell response to a self-antigen such as MBP is more complex than previously expected. The short-term repertoire dynamics of autoreactive T cells in MS underscore the importance of longitudinal studies for evaluating autoreactivity to myelin antigens and probably to any self-antigen in other autoimmune diseases.

Toward biomarkers in multiple sclerosis: new advances

“…Various B-and T-cell responses to CNS autoantigens have indeed been described in MS patients, but none of the trials reached a verdict on the accusation of their involvement in initiating and perpetuating the disease [15,16]. A number of reports have described more subtle changes in function of the myelinspecific T cells in MS patients [17,18], including interleukin (IL)-2 and costimulation responsiveness, resistance to hypoxanthine-guanine phosphoribosyl-transferase, responses to interleukins and avidity for antigen [16]. Again, none is generally accepted as a CD4 + cell marker of MS, although in the composition of its function there are additional clues to the pathogenesis of MS.…”

Systems biology of complex symptom profiles: Capturing interactivity across behavior, brain and immune regulation

“…Moreover, topological architecture is being compared between networks constructed for a priori defined clinical groups with the aim being one of identifying illness-specific network features such as local changes in connectivity and the appearance of hub transcripts or proteins (Fuite, Vernon and Broderick, 2008a). This is a static analysis and there is little if any direct consideration of the subsequent dynamical modes supporting the emergence and exacerbation of symptoms, be they sustained or episodic in illnesses such as multiple sclerosis (Vergelli et al, 2001) and chronic fatigue syndrome (Aschbacher et al, 2012). Even directed graphs that encode this dynamic information are still compared in terms of their structure, for example motif frequency, rather than the dynamics of information flow that they describe (Frankenstein, Alon and Cohen, 2006).…”

A new approach for evaluating antigen-specific T cell responses to myelin antigens during the course of multiple sclerosis

“…As IFN-γ is still the most commonly measured Th1 cytokine (Hellings et al, 2001;Vergelli et al, 2001;Weissert et al, 2002) and has been shown to be involved in MS pathogenesis (Panitch et al, 1987;Woodroofe and Cuzner, 1993), we limited our results presented here to IFN-γ production by myelin-specific T cells. To avoid bias, analysis of the flow cytometrybased assay was performed without the evaluator knowing the patients' clinical status.…”