B cells expressing the transcription factor T-bet drive lupus-like autoimmunity

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Journal of Clinical Investigation said:
Abstract

B cells contribute to multiple aspects of autoimmune disorders and may play a role in triggering disease. Thus, targeting B cells may be a promising strategy for treating autoimmune disorders. Better understanding of the B cell subsets that are responsible for the development of autoimmunity will be critical for developing efficient therapies. Here we have reported that B cells expressing the transcription factor T-bet promote the rapid appearance of autoantibodies and germinal centers in spontaneous murine models of systemic lupus erythematosus (SLE). Conditional deletion of T-bet from B cells impaired the formation of germinal centers and mitigated the development of kidney damage and rapid mortality in SLE mice. B cell–specific deletion of T-bet was also associated with lower activation of both B cells and T cells. Taken together, our results suggest that targeting T-bet–expressing B cells may be a potential target for therapy for autoimmune diseases.

Introduction

Autoimmunity is the third most common type of disease in the United States. Although such diseases can be treated, there is no cure for autoimmunity; therefore, it is extremely important to study the mechanisms that trigger these diseases. Innate and adaptive immunity are involved in the development and progression of autoimmune diseases. B cells are known to be involved in different aspects of autoimmune diseases and may contribute in a number of ways including the secretion of autoantibodies, processing and presentation of autoantigen to T cells, and production of inflammatory cytokines. Therefore, B cells are promising targets for treatment of autoimmune diseases (13).

Indeed, this idea has been put into practice and B cell depletion therapy has been tested for multiple autoimmune diseases. The results of B cell depletion in systemic lupus erythematosus (SLE) are still controversial (4). However, such therapies have been effective in some patients with rheumatoid arthritis (RA) and multiple sclerosis (MS) (5, 6). It is not yet known why B cell depletion is effective for some but not all diseases and for some but not all patients with a particular malady. One possibility is that the depletion therapies might not affect all B cell subsets equally well and different diseases, or different patients, might have involvements of different B cell subsets. Nevertheless, B cells are attractive targets for the treatment of many different autoimmune disorders and more targeted approaches focusing on pathogenic autoreactive B cells (as opposed to depletion of all B cells) may be tremendously beneficial.

A novel subset of B cells named age-associated B cells (ABCs) has recently been identified by others and ourselves (710). Unlike other B cells, ABCs express high levels of CD11c and the transcription factor T-bet. T-bet was subsequently demonstrated to be necessary and sufficient for the appearance of this subset (7, 11), and triggering of the B cell antigen receptor (BCR), IFN-γ receptor (IFN-γR), and TLR7 on B cells induces high levels of T-bet expression (12).

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Full paper: https://www.jci.org/articles/view/91250

I'd be grateful if @Jonathan Edwards and our more knowledgeable users could comment on this.

Based on the current state of knowledge, do the researchers' conclusions that it may be worthwhile to target this subset of B cells make sense - at least in theory, given that this is based on a mouse model?
 
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Full paper: https://www.jci.org/articles/view/91250

I'd be grateful if @Jonathan Edwards and our more knowledgeable users could comment on this.

Based on the current state of knowledge, do the researchers' conclusions that it may be worthwhile to target this subset of B cells make sense - at least in theory, given that this is based on a mouse model?
I don't actually think this is a 'subset' of B cells. We have had various hares raise about special types of B cell which are in fact just B cells in a particular state of maturation or activation. Today they may be in this 'subset'. Tomorrow they will have matured to another subset. So there is nothing to 'target' really. Mouse autoimmunity is unrelated to human autoimmunity in terms of cause - it is caused by lab researchers not by natural defects in regulation. I do not think there is any good reason to think mouse autoimmunity helps us understand what to do for human disease.

The real story is that T-bet may be an important signalling system to look at as a target, but I suspect we knew that anyway!