Why Are Women More Susceptible Than Men to Autoimmunity?

ūüí°Info : Of the nearly 50 million individuals in the United States believed to be living with autoimmune disease, approximately 78% are women.

As shown in the following table, female-biased predisposition to autoimmunity is more apparent in some diseases than others.

Autoimmune disease                                               Ratio (female/male)
Hashimoto’s thyroiditis/hypothyroidism               50:1
Systemic lupus erythematosus                                  9:1
Sj√∂gren‚Äôs syndrome¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬†9:1‚Äď20:1
Graves’ disease/hyperthyroidism                             7:1
Rheumatoid arthritis¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† 3:1‚Äď4:1
Scleroderma¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬†3:1‚Äď4:1
Myasthenia gravis¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬†2:1‚Äď3:1
Multiple sclerosis                                                        2:1
Type 1 diabetes mellitus¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬† ¬†1:1‚Äď2:1
Ulcerative colitis                                                          1:1
Autoimmune myocarditis                                          1:1.2

For example, the female-to-male ratio of individuals who suffer from diseases such as multiple sclerosis (MS) or rheumatoid arthritis (RA) is approximately two or three females to one male. There are nine women for every one man afflicted with systemic lupus erythematosus (SLE). However, these statistics do not tell the entire story. In some diseases, such as MS, the severity can be worse in men than in women. That women are more susceptible to autoimmune disease has been recognized for many years. The reasons are not entirely understood, although recent advances are helping to clarify this difference. Although it may seem unlikely, considerable evidence suggests significant gen- der differences in immune responses. In general, females tend to mount more vigorous humoral and cellular immune responses. Immune cell activation, cytokine secretion after infection, numbers of circulating CD4+ T cells and mitogenic responses are all higher in women than men. Immunization studies conducted in mice and humans show that females pro- duce a higher titer of antibodies than males; this is true during both primary and secondary responses. In transplantation, women also suffer from a higher rate of graft rejection. As one might guess, this enhanced immunity in females means that males, in general, are slightly more prone to infections. The prevailing view is that sex hormone differences between men and women account for at least part of the observed gender difference in the rates of autoimmunity. Some of this evidence comes from observations made in SLE, where young women of child-bearing age are at greatest risk for the disease. Lupus flares during pregnancy (a high estrogen state) and increased rates of remission following menopause (a low estrogen state) also point to sex hormones as potential regulators of this autoimmune disease. The general consensus is that estrogens, the more female-specific hormones, are associated with enhanced immunity whereas androgens, or male- based hormones, are associated with its suppression. In mice, whose gender differences are easier to study, a large body of literature documents gender differences in immune responses. Female mice are much more likely than male mice to develop TH1 responses and, in infections for which pro- inflammatory TH1 responses are beneficial, are more likely to be resistant to the infection. An excellent example is infection by viruses such as vesicular stomatitis virus ( VSV ), herpes simplex virus (HSV ), and Theiler’s murine encephalomyelitis virus (TMEV). Clearance of these viruses is enhanced by TH1 responses. In other cases, however, a pro-inflammatory response can be deleterious. For example, a TH1 response to lymphocytic choriomeningitis virus (LCMV ) correlates with more severe disease and significant pathology. Thus, female mice are more likely to succumb to infection with LCMV. The importance of gender in LCMV infection is underscored by experiments demonstrating that castrated male mice behave immunologically like females and are more likely to experience autoimmune disease than uncastrated males. Why this dichotomy between the sexes? One hypothesis posits that this increased risk of autoimmunity in women

is a by-product of the evolutionary role of women as bearers of children. Pregnancy may give us a clue as to how sex plays a role in regulating immune response. During pregnancy, it is critical that the mother tolerate the fetus, which is a type of foreign semi-allograft. This makes it very likely, maybe even crucial for successful implantation and fetal development, that the female immune system undergoes important modifications during pregnancy. Recall that females normally tend to mount more TH1-like responses than TH2 responses. During pregnancy, however, women mount more TH2-like responses. It is thought that pregnancy-associated levels of sex steroids may promote an anti- inflammatory environment. In this regard, it is notable that diseases enhanced by TH2- like responses, such as SLE, which has a strong antibody-mediated component, can be exacerbated during pregnancy, whereas diseases that involve inflammatory responses, such as RA and MS, some- times are ameliorated in pregnant women. Another effect of pregnancy is the presence of fetal cells in the maternal circulation, creating a state called microchimerism. Fetal cells can persist in the maternal circulation for decades. These long-lived fetal cells may play a role in the development of autoimmune disease. Furthermore, the exchange of cells during pregnancy is bidirectional (cells of the mother may also appear in the fetal circulatory system), so that the presence of the mother’s cells in the male circulation could also be a contributing factor in autoimmune disease.

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