Sex differences in autoimmune disease from a pathological perspective

Abstract

Autoimmune diseases affect approximately 8% of the population, 78% of whom are women. The reason for the high prevalence in women is unclear. Women are known to respond to infection, vaccination, and trauma with increased antibody production and a more T helper (Th)2-predominant immune response, whereas a Th1 response and inflammation are usually more severe in men. This review discusses the distribution of autoimmune diseases based on sex and age, showing that autoimmune diseases progress from an acute pathology associated with an inflammatory immune response to a chronic pathology associated with fibrosis in both sexes. Autoimmune diseases that are more prevalent in males usually manifest clinically before age 50 and are characterized by acute inflammation, the appearance of autoantibodies, and a proinflammatory Th1 immune response. In contrast, female-predominant autoimmune diseases that manifest during the acute phase, such as Graves' disease and systemic lupus erythematosus, are diseases with a known antibody-mediated pathology. Autoimmune diseases with an increased incidence in females that appear clinically past age 50 are associated with a chronic, fibrotic Th2-mediated pathology. Th17 responses increase neutrophil inflammation and chronic fibrosis. This distinction between acute and chronic pathology has primarily been overlooked, but greatly impacts our understanding of sex differences in autoimmune disease.

Figure 1

Incidence of autoimmune diseases in men and women categorized by age, sex, and immunopathology. Most male-predominant autoimmune diseases manifest clinically (ie, show signs and symptoms of clinical disease) before 50 years of age and are characterized by acute cell-mediated pathology. Acute autoimmune diseases with an increased incidence in women have a clear antibody (Ab)-mediated pathology, whereas those appearing later in life are associated with chronic inflammation, fibrosis, increased numbers of autoantibodies, and a Th2-type immune response. Th17 responses increase acute neutrophil inflammation and chronic fibrosis. Autoimmune diseases in bold represent the age when the autoimmune disease manifests clinically. Ratios represent the incidence of a particular autoimmune disease in females (F) compared to males (M). Blue shading depicts a Th1 response and pink shading a Th2 response and fibrosis. Incidence data were obtained from References and .

Figure 2

Males produce more IFN-γ (Th1 response) and females more IL-4 (Th2 response) during acute myocarditis. There is no significant difference in IL-17 (Th17 response) between males and females in three of four experiments, but IL-17 was significantly increased in males in one of four experiments. Female and male BALB/c mice were infected with CVB3 on day 0, and cytokine levels in the heart were assessed during acute myocarditis at days 10 or 12 after infection. Data show the SEM of 7 to 10 mice per group at day 12. Similar results were obtained in at least three separate experiments. *P < 0.05, **P < 0.01.

Figure 3

Role of sex hormones in regulating inflammation after infection. Testosterone (Te) increases MC and macrophage numbers, TLR4 expression, and NF-κB signaling in males resulting in increased levels of IL-1β, IL-18, and IFN-γ, increased inflammation, and a Th1-type immune response. Estrogen (E2) inhibits NF-κB signaling, reduces Th1 responses, and increases IL-4 transcription resulting in increased Th2 response, B-cell proliferation, autoantibody production, and Tim-3 expression in females. Tim-3 signaling increases Treg cell populations that dampen the TLR4-induced Th1 inflammatory response to infection.