Abstract
Systemic Lupus Erythematosus (SLE), among many other auto-immune diseases, is known to be more prevalent in females than in males. This observation has served as the foundation for studies into how sex hormones may interact with the immune system to either drive or inhibit immune activation. Early studies using castration in lupus mouse models showed the potential protective effect of testosterone against lupus development. These studies were later corroborated by observational studies in lupus patients, who upon treatment with testosterone therapy, displayed decreased disease burden. However, there are numerous limitations to treating (especially female) lupus patients with testosterone. Thus, identification of testosterone-targeted cellular and molecular mechanisms affecting immune activation is an attractive target for lupus treatment in the future. Recent studies have examined the effects of androgens on the activation of anti-inflammatory processes. As such, immunoregulatory cell types including myeloid-derived suppressor cells (MDSCs) and regulatory T and B cells have been shown to be susceptible to manipulation by sex hormones. Here, we review studies of SLE and lupus-like disease in which testosterone or testosterone-derivatives were used to skew an ongoing immune reaction toward an anti-inflammatory state. Via evaluation of both clinical studies and immunologic models we propose new areas for research with the goal of identifying testosterone-driven anti-inflammatory mediators suitable for therapeutic targeting in patients with lupus and other autoimmune diseases.
Highlights
Systemic Lupus Erythematosus (SLE) is an autoimmune disorder which may target multiple organs, including skin, joints, and kidneys
Using the NZB/NZW F1 mouse model of lupus, we found previously that myeloid-derived suppressor cells (MDSCs) are significantly increased in male mice in a testosterone dependent fashion [58]
Given the highly inflammatory milieu of female NWB/NZW F1 mice, including elevated levels of serum GM-CSF, IL6, and IFNα, it is possible that naturally occurring MDSCs in female lupus-prone mice are induced to differentiate into effector cells with an immune-stimulatory phenotype [64, 65]
Summary
SLE is an autoimmune disorder which may target multiple organs, including skin, joints, and kidneys. Current standard disease management involves the use of glucocorticoids initially, with added maintenance immunosuppressive therapy as needed These options, are broadly immunosuppressive, have significant adverse effects, and do not directly target the cause of lupus. Men with lupus have been shown to have a worse course of disease than women, women are much more predisposed to getting lupus than men, with a 9:1 female to male ratio among patients This ratio is the highest during reproductive years, when sex hormone levels are the highest. Protective Effects of Androgen in Lupus reproductive years (30–50 years), while in men there is a later peak at ages 50–80 years [1] This female predisposition is poorly understood in its relation to the pathogenesis of lupus, but suggests that sex hormones play a role in disease initiation or progression. In this review we will focus on clinical and laboratory studies evaluating the role of androgens in SLE and mouse lupus-like disease (lupus); highlighting potential areas of further study to improve SLE therapies, within testosterone’s role as an immune regulator
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