In Human Autoimmunity, a Substantial Component of the B Cell Repertoire Consists of Polyclonal, Barely Mutated IgG+ve B Cells

Abstract

B cells are critical for promoting autoimmunity and the success of B cell depletion therapy in rheumatoid arthritis (RA) confirms their importance in driving chronic inflammation. Whilst disease specific autoantibodies are useful diagnostically, our understanding of the pathogenic B cell repertoire remains unclear. Defining it would lead to novel insights and curative treatments. To address this, we have undertaken the largest study to date of over 150 RA patients, utilizing next generation sequencing (NGS) to analyze up to 200,000 BCR sequences per patient. The full-length antigen-binding variable region of the heavy chain (IgGHV) of the IgG B cell receptor (BCR) were sequenced. Surprisingly, RA patients do not express particular clonal expansions of B cells at diagnosis. Rather they express a polyclonal IgG repertoire with a significant increase in BCRs that have barely mutated away from the germline sequence. This pattern remains even after commencing disease modifying therapy. These hypomutated BCRs are expressed by TNF-alpha secreting IgG +ve CD27 −ve B cells, that are expanded in RA peripheral blood and enriched in the rheumatoid synovium. A similar B cell repertoire is expressed by patients with Sjögren's syndrome. A rate limiting step in the initiation of autoimmunity is the activation of B cells and this data reveals that a sizeable component of the human autoimmune B cell repertoire consists of polyclonal, hypomutated IgG +ve B cells, that may play a critical role in driving chronic inflammation.

Effect of IRT5 probiotics on dry eye in the experimental dry eye mouse model

“…Another explanation for the different clinical response to IRT5 treatment between environmental dry eye and Sjögren’s syndrome autoimmune mouse model may be that different immune cells are involved in each disease. While autoimmunity has substantial relation with B cells [ 40 ], the intestinal microbiome greatly influences the diversity of B cell clones controlling B cell related chronic inflammations [ 41 , 42 ]. On the other hand, environmental dry eye disease is an auto-inflammatory disease that is more associated with T cells, such as Th17 or CD4 or CD8 T cells, and so intestinal microbiome influence on B cells may be insufficient to produce significant clinical responses in dry eye diseases [ 2 , 4 ].…”

Adaptive immunity in the joint of rheumatoid arthritis

“…A single-cell RNA sequence analysis also demonstrated expression of IL-6 and TNF-a in synovial B cells [41]. Regarding the phenotype of these cytokine-producing cells, Cowan et al showed that IgG þ CD27-B cells secreted TNF-a and were enriched in the synovium [42], while Floudas et al reported PD-1-positive B cells, which express higher levels of TNF-a and IL-6 than PD-1-negative B cells, accumulated in the joint [43]. The relevance of B cell-derived TNFa and IL-6 in the activation of synovial fibroblast was suggested by an in vitro culture system [44].…”

Comprehensive B-Cell Immune Repertoire Analysis of Anti-NMDAR Encephalitis and Anti-LGI1 Encephalitis

“…The Gini coefficient is commonly used to measure income inequality in economic studies, and it has also been used to measure the equality of distribution in individual immune repertoires (29,30). A Gini coefficient of 0 indicates equal frequencies of all clones, and a Gini coefficient of 1 indicates a monoclonal sample.…”

“…A Gini coefficient of 0 indicates equal frequencies of all clones, and a Gini coefficient of 1 indicates a monoclonal sample. The Gini coefficient of each isotype was calculated using the R package immunarch and was used to compare the degree of clonal expansion in the repertoire of each sample (30).…”