25 Synovitis is dominated by shared T-cell clones Introduction In recent years, we have seen substantial advances in the treatment of rheumatoid arthritis (RA), including the introduction of several new drugs. However, these new therapies are not curative, are effective in only 60% of the RA patients, and often only induce partial clinical response [1]. Thus, there is a clear need to identify novel, targeted, more effective therapies. Genetic and immunological studies show that cells of the adaptive immune response are involved in the pathogenesis of RA [2–9]. Specificity of this immune response is encoded by rearranged T and B cell receptors expressed by clones of T and B lymphocytes, plasmablasts, and plasma cells. Targeting the adaptive immune response via biologics, such as abatacept (CTLA4-Ig) and rituximab, has been proven to be of clinical benefit in RA patients [7,10]. Recent advances in selective immunomodulation of disease-associated T and B cell clones resulted in novel, more selective, intensive, and effective therapies in the field of oncology [11,12]. Such Ag receptor–directed therapies would also hold promise for more effective treatment in RA provided that a common signature for RA can be found. However, so far, analyses on Ag receptor characteristics in RA synovial tissue (ST) have yielded two seemingly paradoxical findings: 1) several studies observed sharing of T cell clones between different joints, whereas 2) other studies show that different joints show a huge variation in T cell clones, even within a single patient [9,13–25]. As a consequence, it is unclear whether T cell clones in RA are homogeneous and whether they can be used for targeted therapies. In this study, we aim to shed more light on this paradox, taking a high-throughput quantitative approach to TCR repertoire analysis in a unique cohort of 13 RA patients in whom synovial biopsy specimens were taken from multiple locations within the same joint, in another (contralateral) joint, as well as in synovial fluid (SF) and peripheral blood (PB) samples. In doing so, we aimed to answer the following three questions: 1) do various clones dominate the T cell response at different locations within one single inflamed joint? 2) do different T cell clones dominate the TCRβ repertoire in multiple joints? and 3) are TCRβ repertoires in ST and SF dominated by different T cell clones? 2
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