Sometimes it's hard to be a woman

It is a well-known fact that the incidence of autoimmune diseases is higher in females than in males — systemic lupus erythematosus, for example, occurs at a female-to-male ratio of about 10 to 1. The female sex hormone oestrogen is thought to be important for the pathogenesis of autoimmune diseases, but the molecular basis for this has never been defined. In this study, Betty Diamond's group shows that oestrogen can modulate the survival of immature B cells, leading to a more autoreactive B-cell repertoire.

Earlier work from this group in a mouse model system established that the treatment of non-autoimmune mice that were transgenic for the heavy chain of an anti-DNA antibody with oestradiol (E₂) led to the rescue of autoreactive B cells that would normally have been deleted. The current study looked at changes in gene expression in B cells that were treated with E₂ to determine how this can result in a skewed B-cell repertoire. Several E₂-upregulated genes were identified in B cells, and four of the genes — encoding the CD22 receptor and the intracellular tyrosine phosphatase SHP1 (both of which can regulate the threshold for B-cell activation), the anti-apoptotic molecule Bcl-2 and the adhesion molecule VCAM1 — were chosen for further study.

Flow cytometry showed that receptors for E₂ are expressed on B cells. Furthermore, the ectopic expression of constitutively active E₂ receptors on B cells resulted in the increased expression of CD22, SHP1 and Bcl-2. But, is there a functional consequence of increased expression of these molecules? To assess this, the team overexpressed CD22 or SHP1 in a B-lymphoma cell line to mimic the increased expression of these receptors in E₂-treated B cells. Compared with mock-transfected cells, the CD22- or SHP1-transfected cells had decreased calcium-signalling responses after stimulation with mock antigen. This indicates that moderate changes in the level of expression of these molecules can alter B-cell signalling and, so, might affect the tolerization of autoreactive B cells.

Taken together, these results show that E₂ can enhance the survival and activation of autoreactive B cells, which might contribute to the development of autoimmune disease.