Long-term effect of high cyclophosphamide doses on the repertoire of T-cell receptors of peripheral blood T-lymphocytes in patients with autoimmune vasculitis

Merzlyak EM1, Kasatskaya SA1, Sosnovskaya AV2, Israelson MA, Staroverov DB, Nakonechnaya TO, Novikov PI2, Chudakov DM, Britanova OV
About authors

1 Group of structural Organization of T-cell Immunity, Department of Adaptive Immunity Genomics, Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Moscow

2 I. M. Sechenov First Moscow State Medical University, Moscow, Russia

Correspondence should be addressed: Olga V. Britanova
ul. Miklukho-Maklaya, d. 16/10, Moscow, Russia, 117997; moc.liamg@natirblo

About paper

Funding: this work was supported by the Russian Science Foundation (Grant No. 16-15-00149). Equipment used in the study was provided by the shared facility of the Institute of Bioorganic Chemistry (the facility is supported by the Ministry of Education and Science of the Russian Federation, project ID RFMEFI62117X0018).

All authors' contribution to this work is equal: selection and analysis of literature, research planning, data collection, analysis, and interpretation, drafting of a manuscript, editing.

Received: 2017-10-04 Accepted: 2017-10-25 Published online: 2018-01-14

Although mechanisms underlying development of autoimmune vasculitis and polyangiitis remain understudied, these pathologies are already known to be largely mediated by T-lymphocytes. Cyclophosphamide (CF) is widely used to treat autoimmune diseases. Lymphoid cells in general (T, B, and NK cells) and naive T-lymphocytes in particular are highly sensitive to CF. In this work we analyzed the repertoires of T-cell receptors (TCRs) in the peripheral blood of young (aged 24 to 35 years, n = 4) and elderly (aged 52 to 68 years, n = 5) patients with ANCA-associated vasculitis (Wegener granulomatosis and Churg–Strauss syndrome) treated with high doses of CF > 3 years before the study. The control group included 7 young and 14 elderly healthy individuals. We revealed no TCR variants previously reported as typically found in patients with ANCA-associated vasculitis. Relative frequency of “public" (often found in a population, largely formed during an embryonic period) TCR variants in the repertories of young patients was significantly lower than in the repertories of healthy donors of the same age, and was similar to the elderly healthy donors. We hypothesize that CF-treatment eliminates substantial proportion of naïve T-cells in the young donors, that contains "public" TCR variants of fetal origin. Long-term consequences of such changes in the structure of T-cell immunity require further investigations.

Keywords: high-throughput sequencing, autoimmune disease, autoimmune vasculitis, cyclophosphamide, T-cell receptor, naive T-lymphocyte