Is autoimmunity a matter of sex?
Introduction
Autoimmune diseases (AID) include more that 70 different disorders affecting over 10 million patients in the United States. These disorders manifest a wide variability in terms of targeted tissues, age of onset, and response to immunosuppressive treatments. The one feature that is shared by the majority of these conditions, however, is the predominance in the female sex with over 80% of patients with AID being women [1], [2].
Even though the female predisposition to AID has been known for over a century, the precise cause of this bias remains unknown and relatively few hypotheses have been proposed. A susceptible genetic background is considered to be necessary, yet not sufficient, to explain both AID onset and the female predominance, while several environmental factors have been suggested as additional players in tolerance breakdown.
Among sex-related factors that have been proposed, we note that (i) hormones and reproductive history; (ii) fetal microchimerism; (iii) X chromosome inactivation; and (iv) X chromosome abnormalities have collected the most data. However, none of these hypotheses has thus far gathered enough convincing evidence and in most cases data are conflicting. The effects of sex hormones on the immune function was first based on the reported role of estrogens in lymphocyte maturation, activation, and synthesis of antibodies and cytokines [3], [4], [5]. Moreover, studies on the immune responses in normal subjects and AID reported that estrogen receptor (ER) ligands are capable to modulate both the innate and adaptive immunity components, alter antigen presenting cell (APC) numbers or functions in vivo and in vitro, and regulate dendritic cell (DC) differentiation [6]. When these observations were used to compare sex hormonal profiles between patients with AID and controls, data were disappointing and weak. Furthermore, the occurrence of AID in men, the onset at different times of the reproductive history, and the lack of consistent effects on disease course also militate against the role of sex hormones. Sex chromosomes have then been widely studied in the past decade, yet the role of fetal microchimerism and X chromosome inactivation awaits confirmation as a severely skewed X chromosome inactivation pattern was found in women with systemic sclerosis [7]. We then demonstrated that women with PBC, systemic sclerosis, and thyroid autoimmune disorders manifest an enhanced rate of X monosomic cells in peripheral blood compared with healthy age-matched women [8], [9].
This review will illustrate the available evidence and proposed theories on sex differences in AID and discuss their potential implications and limitations. Table 1 illustrates the major mechanisms proposed to influence female predominance in AID.
Section snippets
Sex differences and the immune system
The human immune system manifests some degree of sexual dimorphism with basic immune responses differing between females and males. In general terms, women have an enhanced antibody production and increased cell-mediated responses following immunization [10] while men produce a more intense inflammatory response to infectious organisms [11]. Further, women have higher CD4+ T cell counts than men which contributes to an increased CD4/CD8 ratio [12], higher levels of plasma IgM [13], and greater
Sex ratios in autoimmunity
The most striking sex differences in autoimmune diseases are observed in Sjogren's syndrome, SLE, PBC, autoimmune thyroid disease and scleroderma in which 80% of the patients are women. On the other hand, rheumatoid arthritis (RA), multiple sclerosis (MS) and myasthenia gravis have a lower female prevalence but still 60–75% of the patients are women. A third group, which includes inflammatory bowel diseases and immune-mediated (type 1) diabetes, is characterized by a female:male ratio that is
Sex hormones
Estrogens, androgens, and prolactin, have been the first proposed candidates to have important roles in the sex bias observed in autoimmunity, due to their capacity of modulating the immune response via androgen and estrogen receptors (ER). Indeed, progenitors and mature cells express both receptors and suggest that sex hormones can directly modulate the development of immune cells. Sex hormones may also directly influence the homing of lymphocytes to a target organ and the process of antigen
Fetal microchimerism in autoimmunity
It has been hypothesized that AID pathogenesis and female predominance may be secondary to the presence in affected women of allogenic male fetal cells decades after pregnancy (i.e. fetal microchimerism). Microchimeric cells were first found in peripheral blood mononuclear cells from patients with scleroderma and it was suggested that nonautologous cells may be mediating a graft-versus host disease-like reaction in these patients [24], [25]. Other studies have failed to recapitulate these
The genetics of sex chromosomes
The importance of genetic factors as possibly the major determinants in AID susceptibility is supported by familiar clustering , variable prevalence in different ethnic groups, associations with HLA haplotypes or single nucleotide polymorphisms, and concordance rates in monozygotic and dizygotic twins [14]. Quite surprisingly, however, few studies have investigated the genetics of sex chromosomes in AID despite major clues such as the observation that several genes crucial for the maintenance
Are we overlooking autoimmunity in men?
Is it possible that men are being diagnosed less with AID for other reasons than true differences in prevalence rates with sex? When considering AID with subtle onset and progression, this issue is obviously difficult to address but should not be overlooked. Indeed, we cannot currently rule out the possibility that physician awareness plays a role in determining the probability of a possible AID diagnosis. To support this hypothesis, we should consider the opposite example of male-predominant
Conclusions and future directions
The pathogenesis of all AID recognizes the necessary role of environmental factors and genetical susceptibility to lead to tolerance breakdown and females seem to be more prone to AID development based on both components. We have reviewed herein the proposed mechanisms but it appears clear that none of these has reached a definite consensus and some issues need to be addressed. First, all aspects have witnessed crucial developments, as discussed for the case of X chromosome silencing or well
Take-home messages
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Data from the epidemiology of autoimmune diseases, particularly those ensuing later in life, support a variable female predominance in most conditions;
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The human immune system exhibits sexual dimorphism and basic immune responses differ between females and males in terms of antibody production and cellular responses;
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Sex hormones were first suggested for inducing female susceptibility due to their effects on cytokine production, B cell maturation, homing of lymphocytes, and antigen presentation
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