General differences in male and female immune reactions have long been recognized in observational studies but the underlying mechanism of these differences is still unclear. On one hand, the sex dimorphic features of immune reactions are reflected by increased susceptibility and complicated course of viral, bacterial, parasitic and fungal infections in males [26
]. On the other hand, autoimmunity seems to be a female feature, although the magnitude of female predominance varies across the spectrum of autoimmune diseases and show important geographical differences [28
].Thus, epidemiological data suggest that male and female immune reactions might differ substantially. However, given important geographical differences in female:male ratio in autoimmune disorders, it is more likely that female sex acts as a modifier rather than an independent trigger that would set out the aberrant autoimmune reaction.
From different factors possibly underlying sex-specific immunity, sex hormones have long been recognized to influence immune reactions. Upon immunization, the antibody production and T cell activation is more pronounced in female mice [29
] and the TH
1 cytokines production after immunization is higher in female mice [31
]. In human, higher absolute numbers of CD4+
lymphocytes are observed in women compared to men [31
]. Cytokine secretion in vitro
is enhanced by estrogens, whilst it decreases upon stimulation with androgens [32
]. In addition, sex hormones, especially estrogens seem to influence the cytokine production by TH
lymphocytes in a dose dependent manner in vitro
] which may explain the immunomodulatory effect pregnancy has on several autoimmune diseases including IBD.
The specific immunomodulatory properties of sex hormones have been implicated in the pathogenesis of some autoimmune conditions such as multiple sclerosis [35
] whilst in others, like primary biliary cirrhosis and autoimmune thyroid disease, X-chromosome abnormalities are more likely to play a role [36
]. In IBD, studies on the role of sex hormones in the mediation of an aberrant immune response are scarce and data available are limited to animal models. It has been shown that estrogen decreases while progesterone increases macrophage migration inhibitor factor production in a female rat with trinitrobenzene sulfonic acid-induced colitis [39
]. In HLA-B27 transgenic rat IBD model, estrogen treatment improved the stool frequency, histological score and reduced the levels of myeloperoxidase activity [40
]. In another study, using two different murine models of colitis, treatment with estrogens had beneficial effect on dinitrobenzene sulfonic acid-induced colitis in contrast to dextran sodium sulfate-induced colitis where estradiol increased the macroscopic and histological scores compared to placebo [41
]. Interestingly, a prospective multi-national case-control study on the course of IBD during pregnancy showed a disease-specific effect with similar course of Crohn`s disease in pregnant and non-pregnant patients but increased rate of flares in pregnant ulcerative colitis patients [42
]. Thus, estrogens may have differential immunomodulatory effect on intestinal mucosal immune response, depending on the type or site of inflammation.
In addition to immunomodulatory effect, sex hormones may differentially influence IBD pathogenesis in males and females through their influence on intestinal permeability. In animal models, estrogens seem to decrease intestinal permeability [43
] and this effect follows the cyclic changes of estrogen-progesterone shift. Interestingly, women with IBD and IBS experience fluctuations in their gastrointestinal symptoms across the menstrual cycle [44
] which may be related to these cyclic changes of the intestinal permeability. Thus, taking these observational human data and studies with different animal IBD models together, sex hormones, especially estrogens, seem to have important modulatory effects on intestinal mucosal immunity and permeability. These effects that are probably interrelated might be dichotomic in Crohn`s disease and ulcerative colitis.
With regards to androgens and their putative role in the disease pathogenesis, the data available are very limited. Overall in autoimmune disease, including IBD, decreased levels of testosterone have been described in both, male and female patients [45
]. It is, however, unclear whether these differences are secondary to underlying disease or whether the androgens-deficiency plays a specific pathogenetic role in IBD.
Another thus far unexplored signal of sexually dimorphic pathogenesis of IBD comes from several genetic studies reporting differential risk of some susceptibility gene variants for men and women, respectively. In CD, the R30Q DLG5 variant confers a male-specific risk in various independent populations [47
]. On the other hand, a variant of IL-23 receptor (L310P) seems to protect women but not men from the development of ulcerative colitis [51
]. In addition, two functional single nucleotide polymorphisms (SNP) in the promotor region of IL-10 were associated with ulcerative colitis in females exclusively [52
]. In addition to these sex-specific SNP, a phenomenon of maternal imprinting in familial IBD has been reported [53
]. In a recent analysis of the 286 families with IBD we also observed maternal imprinting with a specific female-to-female transmission [54
]. Thus, gender seems to have a modulatory effect on the translation of some susceptibility genes but the mechanistic explanation of this phenomenon is currently lacking.
Last mechanism that has been suggested to be involved in female-specific pathogenesis of autoimmune disorders implicates X-chromosome abnormalities. In the past years, increasing understanding of the role of X-chromosome in the sexual dimorphism of immune responses has turned the focus towards the mechanisms that would directly (i.e. not through the effect of sex hormones) involve the X-chromosome anomalies in autoimmunity. Thus far, three mechanisms of X-linked pathogenesis of female autoimmune disorders have been proposed: loss of mosaicism, reactivation of silenced X-chromosome and loss of X-chromosome [55
]. From these three mechanisms, only loss of X-chromosome has been thus far confirmed to be linked to a specific autoimmune disorder. In patients with primary biliary cirrhosis, autoimmune thyroid disease, Reynolds sydrome and systemic sclerosis, significantly higher rates of X-monosomy were found in peripheral T- and B-lymphocytes [37
]. The mechanism by which the loss of X-chromosome would lead to autoimmunity is not clear but it has been proposed that this loss of specific X-linked genes in T- and B-cells might results in an enhanced antibody production [37
]. X-chromosome abnormalities have not been studied in IBD thus far, but some observations of increased incidence of IBD in patients with Turner syndrome [57
] might indicate that this mechanism could be implicated in IBD pathogenesis as well. Interestingly, more than half of the patients with concomittant IBD and Turner syndrom, a female disorder characterized by the abscence of all or part of the second X-chromosome, have the same karyotype [58
]. Thus, hypothetically, loss of specific immunoregulatory genes located on the X-chromosome might be implicated in the pathogenesis of IBD associated with Turner syndrome. On the other hand, it is tempting to speculate that the same mechanisms could play a role in the pathogenesis of female IBD in acquired X-chromosome haploinsufficiency.
Taken together, in the IBD pathogenesis, the basic immunological differences between males and females may underlie sex-specific disease pathogenesis. The data currently available are, however, very limited and the subject has not been studied in depth. Sex hormones influence the systemic and mucosal immunity as well as intestinal permeability which may be reflected in specificities of the IBD course during pregnancy and variable symptoms during menstrual cycle. Some genetic variants carry differential risk for men and women, respectively, but the mechanistic explanation for these differences is lacking. There are indications that X-chromosome abnormalities, more specifically loss of X-chromosome, might hypothetically be implicated in IBD pathogenesis in (some) female patients but this has not been studied thus far.