The Effects of Androgens on T Cells: Clues to Female Predominance in Autoimmune Liver Diseases?

Abstract

The immune system responds differently in women and in men. Generally speaking, adult females show stronger innate and adaptive immune responses than males. This results in lower risk of developing most of the infectious diseases and a better ability to clear viral infection in women (1-5). On the other hand, women are at increased risk of developing autoimmune diseases (AID) such as rheumatoid arthritis, multiple sclerosis (MS), systemic lupus erythematosus (SLE), Sjögren's syndrome, and the autoimmune liver diseases autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) (6). Factors contributing to the female sex bias in autoimmune diseases include environmental exposure, e.g., microbiome, behavior, and genetics including X chromosomal inactivation of genes. Several lines of evidence and clinical observations clearly indicate that sex hormones contribute significantly to disease pathogenesis, and the role of estrogen in autoimmune diseases has been extensively studied. In many of these diseases, including the autoimmune liver diseases, T cells are thought to play an important pathogenetic role. We will use this mini-review to focus on the effects of androgens on T cells and how the two major androgens, testosterone and dihydrotestosterone, potentially contribute to the pathogenesis of autoimmune liver diseases (AILD).

Keywords: T cell; androgen; androgen receptor; autoimmunity; immunity; sex hormones; sex-bias; testosterone.

Figure 1

The influence of androgens on T cell function and differentiation: schematic representation. Many autoimmune diseases, including the autoimmune liver diseases PBC and AIH, show a strong female predominance. Androgens modulate T cell development already in the thymus, mainly by altering thymic epithelial cell function (not shown). Human and mouse T cells express cytosolic (AR) and membrane bound androgen receptors (mAR). Androgens lead to changes in cytokine expression in T cells either directly or indirectly via antigen presenting cells, with a shift to a decreased pro-inflammatory cytokine expression, such as IFNγ and TNF, and an increased secretion of anti-inflammatory cytokines such as IL-10 and IL-4. Androgens were reported to reduce TH1-, TH17-, and to increase Treg-differentiation, while changes in other T cell subpopulations (e.g., TH2 cells) remain less clear. We postulate that these androgen-induced effects may influence the incidence and disease course of the T cell driven autoimmune liver diseases, PBC and AIH.