Analysis of B cell selection in autoimmune diseases

PhD ceremony: Ms. N. Hamza, 12.45 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Analysis of B cell selection in autoimmune diseases

Promotor(s): prof. N.A. Bos, prof. C.G.M. Kallenberg, prof. F.G.M. Kroese

Faculty: Medical Sciences

In this thesis, we studied patients with the autoimmune disease primary Sjorgen Syndrome (pSS) who were treated with a B cell-targeting therapeutic antibody (rituximab, RTX). Immunoglobulin variable heavy chain gene (IGHV) sequences were used as B cell markers to trace the presence of B cell clonal populations before and after treatment. Significantly increased clonal expansions in salivary glands of pSS patients and a prevalence of acquired N-glycosylation motifs (ac-Nglycs) in their IgG sequences were observed. Also a strong emphasis on conservation of IgG framework regions in pSS patients compared to non-pSS controls was seen. Treatment with RTX failed to reset these core characteristics of immunoglobulin (Ig)-producing cell populations in pSS patients. This suggested that Ig-producing cells which persisted after RTX could contribute to the disease relapse observed after RTX. This study is the first to suggest that a proportion of B-cells in pSS patients could be selected on the basis of ac-Nglycs in their Ig variable regions. Further studies clearly indicated a similar selection of B cells in other autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus. The presence of ac-Nglycs within IGHV sequences from certain autoimmune diseases could indicate an unconventional selection pressure that enables B-cells with glycosylated BCRs to engage, survive and persist within autoimmune lesions through their interaction with lectin-expressing cells such as dendritic cells or macrophages.