Gender and autoimmunity
Introduction
The etiology of autoimmune diseases is multi-factorial where intrinsic (genetic predisposition) and extrinsic (environmental) triggers contribute to disease progression and pathogenesis. The intrinsic abnormalities are complicated, with diverse genetic polymorphisms described in different ethnic groups, strongly suggesting a mosaic of autoimmunity where the immunologic disarray might not be the same for each patient [1].
Experimental and clinical evidence suggest that autoimmunity is influenced by gender. Immune reactivity is more enhanced in females than in males and lymphocytes and monocytes from females show higher antigen presenting activity and mitogenic responses. Females have higher immunoglobulin levels than males, an enhanced antibody production to both primary and secondary antigen stimulation, and a higher homograft rejection rate. Males, on the other hand, are more prone to infections. These data indicate that the gender bias in autoimmunity may be influenced by sex hormones, portrayed by the role of female sex hormones in the induction and flares of lupus, the prototype of systemic autoimmune diseases.
The sexually dimorphic prevalence of autoimmune diseases remains one of the most intriguing clinical observations among this group of diseases. There is a wealth of clinical and laboratory data generated over the past 20 years demonstrating that sex hormones affect the immune system by modulating multiple immune functions including lymphocyte maturation and activation, synthesis of autoantibodies, and cytokines (Table 1).
Section snippets
Systemic lupus erythematosus (SLE)
The role of sex hormones on autoimmunity has been most extensively evaluated in SLE patients and the female gender represents a strong risk factor linked to both the cause and pathology of the disease. The preponderance of SLE in young woman of childbearing age with a female to male ratio of 9:1, and the tendency for lupus flares during pregnancy and remissions after menopause or cyclophosphamide induced ovarian failure, suggest that female sex hormones are crucial regulators of lupus activity
Myasthenia gravis (MG)
MG is an organ-specific autoimmune disease caused by autoantibodies against the nicotinic acetylcholine receptor (AChR). MG affects predominantly women and is specifically pronounced in MG patients who have muscle specific kinase (MuSK) antibodies [22].
A recent study demonstrated an increased expression of the estrogen receptor (ER) α in thymocytes and ERα and ERβ in circulating T cells of patients with MG indicating the importance of estrogen in the pathogenesis of MG and possibly, the effect
Sjogren's syndrome
The NOD mouse is an accepted murine model of Sjogren's syndrome. Although gonadectomy worsens the disease in male NOD mice, treatment with a near-physiological dose of estrogen does not accelerate the disease significantly. These data lead to the speculation that the sexual dichotomy in this model is due to the protective effects of androgens and not caused by estrogens alone [26].
Recent studies elucidated specific genetic factors responsible for the development of Sjogren's-like syndrome in
Rheumatoid arthritis (RA)
Significant gender dimorphism is also observed in patients with RA. Several studies confirm that there are reduced levels of androgens and progesterone in RA patients. Men with RA have low levels of testosterone, DHEA and estrone while estradiol, the most potent naturally occurring estrogen, is increased and correlates with the inflammatory indices [28].
Synovial fluid levels of estrogens relative to androgens are significantly elevated in both male and female patients with RA, which is most
Systemic sclerosis (SSc)
SSc shows gender bias with an overall ratio (women to men) of approximately 3:1.6 and a ratio of 5:17 for limited SSc. Although the difference can reach a ratio of 15:1 in women during childbearing years, the published data on the implications of female sex hormones in the pathogenesis of SSc are rather limited. Some studies have shown that estrogens induce fibroblast dysfunction [33] and thereby contribute to the pathogenesis of SSc. The SERM tamoxifen was reported to have beneficial effect in
Conclusions
Female predominance in autoimmunity is very prominent, and may be related to sex hormones and /or sex related genes. As suggested by animal models and clinical studies, in some autoimmune diseases such as SLE, endogenous estrogen and prolactin, as well as exogenous endocrine disruptors may break tolerance and induce a development of autoimmunity. In other autoimmune diseases, such as MG and RA, the pathogenesis of the disease does not seem to be heavily influenced by the sex hormones, which
Bulletins
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As suggested by animal models and clinical studies, in some autoimmune diseases such as SLE, endogenous estrogen and prolactin, as well as exogenous endocrine disruptors may break tolerance and induce the development of autoimmunity.
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In the B cell compartment, both prolactin and estrogen are immunostimulators that affect maturation and selection of autoreactive B cells, as well as autoantibody secretion, while progesterone is an immunosuppressor.
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Treatment with bromocriptine, an inhibitor of
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Both authors contributed equally to this work.