B Lymphocyte Autoimmunity in Rheumatoid Synovitis Is Independent of Ectopic Lymphoid Neogenesis

Abstract

B lymphocyte autoimmunity plays a crucial role in the pathogenesis of rheumatoid arthritis. The local production of autoantibodies and the presence of ectopic lymphoid neogenesis in the rheumatoid synovium suggest that these dedicated microenvironments resembling canonical lymphoid follicles may regulate the initiation and maturation of B cell autoimmunity. In this study, we assessed experimentally the relevance of ectopic lymphoid neogenesis for B cell autoimmunity by a detailed structural, molecular, and serological analysis of seropositive and seronegative human synovitis. We demonstrate that synovial lymphoid neogenesis is a reversible process associated with inflammation which is neither restricted to nor preferentially associated with autoantibody positive rheumatic conditions. Despite the abundant expression of key chemokines and cytokines required for full differentiation toward germinal center reactions, synovial lymphoid neogenesis in rheumatoid arthritis only occasionally progresses toward fully differentiated follicles. In agreement with that observation, we could not detect Ag-driven clonal expansion and affinity maturation of B lymphocytes. Furthermore, ectopic lymphoid neogenesis is not directly associated with local production of anti-citrullinated protein Abs and rheumatoid factor in the rheumatoid joint. Therefore, we conclude that synovial lymphoid neogenesis is not a major determinant of these rheumatoid arthritis-specific autoantibody responses.

Synovial tissue research: a state-of-the-art review

“…In two large studies in established RA, large lymphocyte aggregates were found in around 30% of patients but did not associate with a clinical phenotype. 126,127 In early arthritis, the presence of lymphocyte aggregates did not predict an aggressive disease course and aggregates were rapidly diminished by several anti-rheumatic treatments. 119,128 Taken together, these studies suggest that lymphocyte aggregates are a pro-inflammatory phenomenon and not a persistent primary driver of synovitis.…”

Alterations of the synovial T cell repertoire in anti–citrullinated protein antibody–positive rheumatoid arthritis

“…Synovial tissue biopsy samples were processed and evaluated for lining layer thickness, vascularity, global inflammatory infiltration, and lymphoid aggregates, as described previously (35)(36)(37). Synovial tissues from the 158 RA patients were divided into 2 groups.…”

“…Analysis of the Ig V H gene was performed as described elsewhere (37,43). Ig V H and VDJ genes were amplified by PCR and ligated into the pGEM-T vector (Promega, Madison, WI) and transfected into Escherichia coli DH5␣.…”

B-Cell Subsets in the Joint Compartments of Seropositive and Seronegative Rheumatoid Arthritis (RA) and No-RA Arthritides Express Memory Markers and ZAP70 and Characterize the Aggregate Pattern Irrespectively of the Autoantibody Status

“…An aggregate pattern was defined as the presence of inflammatory cells with a 20-cell diameter focus at least, if less, the pattern was considered as diffuse (16,17). The definition of aggregates includes both the aggregate and germinal center (GC)-like infiltrates (defined by the presence of follicular dendritic cells), since one of the aims of the study was to assess the degree of differentiation toward GC reactions to evaluate if the aggregate infiltrates have a biological or clinical relevance.…”