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).

Acetaminophen-Induced Liver Injury Exposes Murine IL-22 as Sex-Related Gene Product

“…Modulatory properties of the major male sex hormone testosterone are well established and likely contribute to sex dependent immunoregulation [ 28 , 29 , 40 , 41 ]. Androgens are supposed to act on T cells via membranous and nuclear androgen receptors [ 41 , 42 ].…”

Recent Update on the Molecular Mechanisms of Gonadal Steroids Action in Adipose Tissue

“…There are some sex-related differences in human immunity, which partially stem from the influences of different gonadal steroids on leukocyte biology but also are inclined by genes on sex chromosomes [ 156 ]. The levels of gonadal corticoids may deeply influence the adipose tissue immune cell populations via regulation of their proliferation, differentiation and apoptosis [ 157 , 158 , 159 , 160 ]. Further, estrogens and androgens regulate the secretion of bioactive molecules by immune cells, which are related to inflammation, endothelial functionality and insulin sensitivity in adipocytes [ 26 , 27 , 79 , 158 , 160 , 161 ].…”

“…Further, estrogens and androgens regulate the secretion of bioactive molecules by immune cells, which are related to inflammation, endothelial functionality and insulin sensitivity in adipocytes [ 26 , 27 , 79 , 158 , 160 , 161 ]. The effects of estrogens and progestogens on cytokine and immunoglobulin production in different immune cell types (e.g., T lymphocytes, monocytes, B lymphocytes, granulocytes, natural killer cells and dendritic cells) were summarized by Oertelt-Prigione [ 160 ], and an analogous detailed analysis of the androgen effects on immune cells is provided in [ 157 , 159 , 161 ].…”

Gender Differences in Urothelial Bladder Cancer. Effects of Natural Killer Lymphocyte Immunity

“…Hormone binding changes AR conformation, which allows hormone-AR complexes to enter the nucleus and either enhance or depress transcription of multiple genes [7]. In addition, AR interacts with important cytoplasmic signaling molecules, including PI3K, Src, and Ras to initiate MAP kinase signaling [8]. In one non-classical mechanism, ZIP9 (SLC29A9) was identified as a non-AR cell surface androgen receptor.…”

“…Mature T cells appear to express both classic cytoplasmic AR and a plasma membrane androgen receptor [11-13, 165, 173-175]. Exogenous DHT treatment skews mouse T cell activation, proliferation, and differentiation [8]. These effects are likely due to a combination of intrinsic T cell effects [173] and to depression of antigen presenting cell MHC and costimulatory molecule expression or cytokine production [117,119,120,122,139,142].…”