William Kovacs, MD

Pennsylvania State University College of Medicine

2011 Human Lupus Biology
2012 B Cells

William Kovacs, MDAndrogen Action And Humoral Autoimmunity In Women With Lupus

The Study and What it Means for Patients

“We recently found evidence for a link between inherited variations in sensitivity to male sex hormones (androgens) and some aspects of lupus in men. Our LRI study is exploring for the first time how differences in sensitivity to androgens might promote autoimmunity by allowing B cells to more easily switch to production of disease-causing autoantibodies. Since these same hormones are present in much lower amounts in women, we’re also looking at whether such inherited differences in androgen sensitivity might influence the course of lupus in women.”

Summary:
Sex hormones and their influence on the immune system are thought to be part of the explanation why women are around nine times more likely to develop lupus than men. We recently found that men with lupus are more likely to produce deleterious autoantibodies if they have inherited lower  sensitivity to male sex hormones (androgens).  We will now investigate whether there is a similar relationship between genetic differences in androgen sensitivity and autoimmunity in women with lupus.  We will test our hypothesis that androgens might normally attenuate some features of autoimmun by preventing B cells from switching  to production  of a more potent class of autoantibodies (a process known as class switching).

Whether genetic differences in androgen sensitivity could influence lupus in women has never been investigated before. This grant from the LRI gives us the opportunity to examine whether even the low levels of androgens produced normally by women might be able to influence the progression of lupus and whether this hormonal signaling pathway might, in some instances, be a potential therapeutic target.

Scientific abstract:
We recently observed a relationship between genetic variation in androgen sensitivity and expression of humoral autoimmunity in men with lupus (1). We now propose to test the hypothesis that inherited variation in androgen signaling might be associated with differences in immunologic or phenotypic manifestations of SLE in women. The relation between genetic variation in androgen sensitivity and expression of autoimmune phenomena in women with SLE will be investigated by genotyping these individuals for variation in the Androgen Receptor (AR) exon 1 CAG repeat, and correlating these genotypes with expression of humoral autoimmunity (ANA, ENAs, and a panel of 86 other autoantibody specificities in both IgG and IgM classes) and with quantitative measures of SLE disease activity (lupus criteria, SLEDAI score, SLICC SCOR) Early explorations into the mechanisms by which androgens might influence humoral autoimmunity revealed a hormonal effect on the immunoglobulin class of produced autoantibodies. Very recent evidence supports a role for gonadal steroids in modulation of process of immunoglobulin class switching and in the modulation of key regulatory steps in that process. We propose to explore mechanisms by which androgen signaling might impact the expression of humoral autoimmunity by examining effects of androgens on immunoglobulin class switching in vitro.