Deconvolution of B cell receptor repertoire in multiple sclerosis patients revealed a delay in tBreg maturation

Abstract

BackgroundB 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.MethodsWe performed a prospective study of the transitional Breg (tBreg) subpopulations with the CD19+CD24highCD38high 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.ResultsThe tBregs from HAMS patients carry the heavy chain with a lower amount of hypermutations than tBregs from healthy donors. The percentage of transitional CD24highCD38high 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.ConclusionsImpaired maturation of regulatory B cells is associated with MS progression.

Multiple Sclerosis Is Associated with Immunoglobulin Germline Gene Variation of Transitional B Cells

“…Moreover, in the case of a severe form of the disease, the difference from the normal value becomes larger. We have also previously found more significant differences in the number of peripheral tBregs and their maturation level in HAMS patients compared with BMS patients and healthy donors [ 20 ]. Therefore, this study has shown that a more significant variation in the tBreg CD19+CD38highCD24high subpopulation repertoire is associated with a more aggressive MS course.…”

“…При этом отличия от нормальных значений увеличиваются в случае более тяжелой формы заболевания. Интересно отметить, что ранее мы обнаружили также более существенные отличия в количестве транзиторных Breg и уровне их зрелости у пациентов с ВАРС по сравнению с ДРС и условно здоровыми донорами [20]. Таким образом, нами показано, что более значимые сдвиги в репертуаре субпопуляции транзиторных В-регуляторных клеток с фенотипом CD19 + CD24 high CD38 high ассоциированы с осложненным течением РС.…”

“…It is not known at what stage of development the most significant changes in the Breg pool occur: in naïve, transitional, or mature B cells? Earlier, we found an increased number of transitional Bregs (tBregs) in the peripheral blood of MS patients [ 20 ]. Notably, the tBregs’ immunoglobulin heavy chains in MS patients carry fewer hypermutations compared to healthy donors.…”

“…Неизвестно, на какой стадии развития происходят наиболее значимые изменения в пуле Breg: у наивных, транзиторных или зрелых В-клеток. Ранее мы обнаружили повышенное содержание транзиторных Breg в периферической крови пациентов с РС [20]. При этом тяжелая цепь иммуноглобулинов транзиторных Breg при развитии РС содержит меньшее количество гипермутаций, чем у здоровых доноров.…”

The Level of Anti-Viral Antigen-Specific Antibodies to EBNA-1 in the Serum of MS Patients Does not Depend on the Severity of the Disease

“…The study of the titer of antibodies to viral antigens in patients with MS will help understand how the level of activation of the immune system in response to EBV is associated with the severity of MS. Thus, the purpose of our study was to determine the level of antiviral antibodies to EBNA-1 (386–405 aa) in the blood of patients with aggressive MS (highly active MS (HAMS)) and a less severe form of the disease, benign MS (BMS) [ 8 , 9 ].…”