Abstract
Testosterone deficiency in men is associated with increased risk for autoimmunity and increased B cell numbers through unknown mechanisms. Here we show that testosterone regulates the cytokine BAFF, an essential survival factor for B cells. Male mice lacking the androgen receptor have increased splenic B cell numbers, serum BAFF levels and splenic Baff mRNA. Testosterone deficiency by castration causes expansion of BAFF-producing fibroblastic reticular cells (FRCs) in spleen, which may be coupled to lower splenic noradrenaline levels in castrated males, as an α-adrenergic agonist decreases splenic FRC number in vitro. Antibody-mediated blockade of the BAFF receptor or treatment with the neurotoxin 6-hydroxydopamine revert the increased splenic B cell numbers induced by castration. Among healthy men, serum BAFF levels are higher in men with low testosterone. Our study uncovers a previously unrecognized regulation of BAFF by testosterone and raises important questions about BAFF in testosterone-mediated protection against autoimmunity.
Highlights
Testosterone deficiency in men is associated with increased risk for autoimmunity and increased B cell numbers through unknown mechanisms
Here we show that testosterone is an endogenous regulator of BAFF and propose that the link between testosterone deficiency and increased splenic B cell numbers in males involves nervous regulation of fibroblastic reticular cells (FRCs) and BAFF
Short-term castration of adult mice resulted in a doubling of the number of splenic B cells, to G-ARKO mice in which the androgen receptor (AR) deletion is present from embryonic stage[24], suggesting that the regulation of splenic B cell number by testosterone/AR occurs independently of developmental effects
Summary
Testosterone deficiency in men is associated with increased risk for autoimmunity and increased B cell numbers through unknown mechanisms. Male mice lacking the androgen receptor have increased splenic B cell numbers, serum BAFF levels and splenic Baff mRNA. 7 Sahlgrenska Cancer Center, Department of Surgery, Institute of Clinical Sciences, University of Gothenburg, Box 100, SE-405 30 Gothenburg, Sweden. Sex steroid hormones have profound effects on the immune system, and insight into these effects may provide important clues to the sexual dimorphism of immune-dependent disorders Many autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus (SLE), are less prevalent in men[1] and data suggest that testosterone, the main androgen, may protect against autoimmune disease[1,2]. BAFF inhibitors are approved as therapy for SLE, their clinical usefulness remains limited[16]
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