Deconvolution of B cell receptor repertoire in multiple sclerosis patients revealed a delay in tBreg maturation
Yakov A. Lomakin, Ivan V. Zvyagin, Leyla A. Ovchinnikova, Мarsel R. Kabilov, Dmitriy B. Staroverov, Artem Mikelov, Alexey E. Tupikin, Maria Yu. Zakharova, N. A. Bykova, Vera S. Mukhina, Alexander V. Favorov, Ivanova Mv, Т. О. Simaniv, Yury P. Rubtsov, Dmitriy M. Chudakov, Maria Zakharova, С. Н. Иллариошкин, Alexey A. Belogurov, Alexander G. Gabibov
Abstract
Background B lymphocytes play a pivotal regulatory role in the development of the immune response. It was previously shown that deficiency in B regulatory cells (Bregs) or a decrease in their anti-inflammatory activity can lead to immunological dysfunctions. However, the exact mechanisms of Bregs development and functioning are only partially resolved. For instance, only a little is known about the structure of their B cell receptor (BCR) repertoires in autoimmune disorders, including multiple sclerosis (MS), a severe neuroinflammatory disease with a yet unknown etiology. Here, we elucidate specific properties of B regulatory cells in MS. Methods We performed a prospective study of the transitional Breg (tBreg) subpopulations with the CD19 + CD24 high CD38 high phenotype from MS patients and healthy donors by (i) measuring their content during two diverging courses of relapsing-remitting MS: benign multiple sclerosis (BMS) and highly active multiple sclerosis (HAMS); (ii) analyzing BCR repertoires of circulating B cells by high-throughput sequencing; and (iii) measuring the percentage of CD27 + cells in tBregs. Results The tBregs from HAMS patients carry the heavy chain with a lower amount of hypermutations than tBregs from healthy donors. The percentage of transitional CD24 high CD38 high B cells is elevated, whereas the frequency of differentiated CD27 + cells in this transitional B cell subset was decreased in the MS patients as compared with healthy donors. Conclusions Impaired maturation of regulatory B cells is associated with MS progression.