Women are More Susceptible than Men to Autoimmune Diseases – What is the Reason for this Gender Bias?

Kaushik Bharati, PhD

Ian Mackay and Sir Frank Macfarlane Burnet in the early sixties, first identified the phenomenon of autoimmunity, which occurs as a result of the disruption of immune tolerance of self-antigens, resulting in the immune system attacking the “self” tissues of the body. The prevalence of autoimmune diseases in India is one of the highest in the world (33.3 million), which is second only to China, which has a prevalence of 40.6 million. In India, although autoimmune diseases like Type 1 Diabetes, Ulcerative Colitis, and Crohn’s Disease affect men and women equally (1:1); other diseases like Sjögren’s Syndrome (3:1) and Multiple Sclerosis (2:1) predominantly affect women, while Primary Biliary Cirrhosis exclusively affects women (Ngo et al., Front Neuroendocrinol, 2014). Therefore, gender differences that exist in autoimmunity, follow a female bias.

It has been long recognized that the prevalence of autoimmune diseases is more in women than in men. The reason for this difference is not very clear. However, recent advances in Immunology are helping to elucidate this difference.

Gender Bias in the Immune Response

However unlikely it may seem, the immune response exhibits a gender bias. Both the humoral and cellular immune responses tend to be more aggressive and vigorous in females. Immune cell activation, post-infection cytokine secretion, mitogenic responses, circulating CD4⁺ T-cells are all higher in women than in men. It has also been observed that women exhibit higher titers of antibodies, both in the primary and secondary immune response. Women also exhibit a higher incidence of graft rejection following transplantation, than men. This comparatively lower immune response means that men are more susceptible to infections than women.

Gender differences in the immune response have been extensively studied in mice, and a large body of literature exists in this area. Female mice are more likely than male mice to mount a Th1 response, and in case of infections where a Th1 response is beneficial, can ward off the infection much more effectively than male mice. Some exemplary examples include infections by the Herpes Simplex Virus (HSV), Theiler’s Murine Encephalomyelitis Virus (TMEV) and Vesicular Stomatitis Virus (VSV), where a Th1 response helps to clear the infection rapidly, which is exhibited in female mice than male mice. In other instances, such as infection with Lymphocytic Choriomeningitis Virus (LCMV), where a Th1 response actually aggravates the disease condition, female mice tend to suffer more and often succumb to the infection.

Sex Hormones

The current consensus on gender bias in autoimmunity is that the sex hormones play a significant role in this phenomenon. It has been particularly observed that Systemic Lupus Erythematosus (SLE) is especially prevalent in women of child-bearing age, and the condition tends to flare-up during pregnancy, when the level of estrogens is high. The condition dampens down following menopause, when the level of estrogens fall. This points to the fact that the sex hormones play a crucial role in autoimmunity, with the estrogens increasing the severity of autoimmunity, while the androgens, suppressing it. This is exemplified by the fact that castrated (no androgens) male mice tend to behave immunologically like females, where they suffer more from autoimmune diseases than their uncastrated counterparts.

Pregnancy

Pregnancy brings about a number of physiological changes in the mother. In pregnancy, the mother plays host to the fetus, which contains foreign antigens. It is thus, important that the mother tolerate the fetus, which is a type of semi-allograft. During pregnancy, the maternal immune system is suppressed, which prevents rejection of the fetus. Importantly, any maternal T-cell mediated damage to the fetus is prevented by regulatory T-cells (Tregs). An immunological shift in the Th1-Th2 balance leads to increased Th2 activity and decreased Th1 activity during pregnancy. This leads to the amelioration of Th1-mediated diseases like Rheumatoid Arthritis (RA) and Multiple Sclerosis (MS), and an exacerbation of Th2-mediated diseases like SLE. Importantly, this change in Th1-Th2 modality is brought about by a corresponding change in the cytokine milieu. Another effect of pregnancy is the entry of fetal cells in the maternal circulation and vice versa – a phenomenon known as microchimerism. Some studies have indicated that this could be a contributing factor in the development of autoimmune diseases in later years.

Conclusion

Differences in reproductive function, and pregnancy in women, are likely to have an impact on gender differences in autoimmunity. The phenomenon of microchimerism during pregnancy in autoimmune disease still remains to be resolved. Other aspects like parental inheritance, mitochondrial inheritance, genomic imprinting and chromosomal inactivation could also play a role. Moreover, extrinsic epigenetic factors could also have an influence on autoimmune diseases. Therefore, since gender differences is a major factor impacting autoimmune diseases, all future epidemiological studies in the area of autoimmune diseases should incorporate gender as part of the study criteria.