madman
Super Moderator
Abstract |
In autoimmune rheumatic diseases, oestrogens can stimulate certain immune responses (including effects on B cells and innate immunity), but can also have dose-related anti-inflammatory effects on T cells, macrophages and other immune cells. By contrast, androgens and progesterone have predominantly immunosuppressive and anti-inflammatory effects. Hormone replacement therapies and oral contraception (and also pregnancy) enhance or decrease the severity of autoimmune rheumatic diseases at a genetic or epigenetic level. Serum androgen concentrations are often low in men and in women with autoimmune rheumatic diseases, suggesting that androgen-like compounds might be a promising therapeutic approach. However, androgen-to-oestrogen conversion (known as intracrinology) is enhanced in inflamed tissues, such as those present in patients with autoimmune rheumatic diseases. In addition, it is becoming evident that the gut microbiota differs between the sexes (known as the microgenderome) and leads to sex-dependent genetic and epigenetic changes in gastrointestinal inflammation, systemic immunity and, potentially, susceptibility to autoimmune or inflammatory rheumatic diseases. Future clinical research needs to focus on the therapeutic use of androgens and progestins or their downstream signalling cascades and on new oestrogenic compounds such as tissue-selective oestrogen complex to modulate altered immune responses.
Key points
• Oestrogens have both pro-inflammatory and anti-inflammatory effects, acting as stimulators of B cell-mediated immune responses but inhibitors of pro-inflammatory macrophages and some T cells.
• In contrast to oestrogens, androgens and progesterone have immunosuppressive and anti-inflammatory effects.
• In men and postmenopausal women with rheumatic diseases, increased androgen to-oestrogen conversion in inflamed tissues and local oestrogen metabolite synthesis support disease.
• Pregnancy, sex hormone replacement therapies and oral contraceptives can negatively or positively affect the severity of autoimmune rheumatic diseases, depending on the respective predominance of oestrogens or androgens (and progesterone).
• Sex-dependent differences in gut microbiota may lead to genetic or epigenetic changes in local gastrointestinal inflammation, systemic immunity and susceptibility to a range of rheumatic diseases.
• Therapies with androgens and progestins, selective oestrogen receptor modulators and tissue-selective oestrogen complex need to be tested more rigorously in autoimmune rheumatic diseases.
Known effects of oestrogens on immune responses
Oestrogens have a dichotomous effect in vivo and in vitro: physiological or low concentrations are pro-inflammatory but high concentrations (for example, in the periovulatory or pregnancy range) are anti-inflammatory 8. At high concentrations, oestrogens inhibit T helper 1 (TH1) cells, TH17 cells (via oestrogen receptor-α (ERα), but have the opposite effect via ERβ70), M1 macrophages, dendritic cells, neutrophils, microglia, vascular smooth muscle cells and fibroblasts vitro via inhibition of-κB (reviewed elsewhere 7,8,11,12,18). Oestrogens at high concentrations also support the function of regulatory T cells and the secretion of IL-4, IL-10 and transforming growth factor-β, which stimulates TH2 cell cytokine pathways (reviewed elsewhere 7,8,11,12,18). However, these effects can aggravate asthma and can worsen disease in patients with active systemic lupus erythematosus or antiphospholipid syndrome and in pregnant women with these conditions 218,219. Oestrogens also demonstrate beneficial anti-inflammatory effects in many animal models of rheumatic diseases, although their effects can be favourable or unfavourable (sometimes in the same model) depending on the prevailing immune reaction; when B cells dominate, oestrogens stimulate the disease, and when T cells dominate, they can inhibit disease 8,220. Oestrogens at high concentrations (such as in the periovulatory to pregnancy range) inhibit some of the later steps of T cell and B cell lymphopoiesis in vivo 8,131,136,221. They upregulate CD22 and the pro-survival molecule Bcl-2 in B cells and increase the amount of B cell-activating factor (reviewed elsewhere7,8,11,12,18), which is expected to worsen disease in patients with active systemic lupus erythematosus or antiphospholipid syndrome. Oestrogens also stimulate many B cell-mediated immune processes at a wide range of hormone concentrations vivo and in vitro, mainly (auto) antibody generation in rheumatic diseases; B cell-dependent autoimmune diseases are supported by the presence of any amount of oestrogen (reviewed elsewhere 8,11,12,18).
Known effects of androgens on immune responses
In contrast to oestrogens (Box 1), androgens such as testosterone are mainly anti-inflammatory in vivo and in vitro, with the exception of their role in a neutrophil generation. Androgens reduce-κB and Toll-like receptor 4 expression and decrease the secretion of cytokines such as TNF, IL-1β and IL-6 by monocytes and macrophages and IL-33 by mast cells in vivo and in vitro (reviewed elsewhere 10,13,16,17,19,20). Androgen therapy in men with hypogonadism reduces serum concentrations of IL-1β and TNF increases concentrations of IL-10 and decreases thymic T cell output. Androgens also inhibit B cell lymphopoiesis and (auto) antibody production in vivo, as well as T helper 1 cell differentiation, by reducing IL-12 and IFNγ in vivo and in vitro (reviewed elsewhere 10,13,16,17,19,20).
Androgens are often reduced in the serum of patients with autoimmune or inflammatory rheumatic diseases 7,16 owing to the conversion of anti-inflammatory androgens to pro-inflammatory oestrogens in inflamed tissue (intracrinology in local cells) 22,222–225. In inflammatory diseases, cytokines such as TNF, IL-1 and IL-6 stimulate the aromatase enzyme (which is necessary for the biosynthesis of oestrogens) in immune cells and fibroblasts, a phenomenon first observed in breast cells 161. Biopharmaceutical medical products can also interfere with sex steroid regulation or generation. The neutralization of TNF and IL-6 with biologic therapies can improve altered hormone axes 162,226,227. In addition, TNF inhibitor therapy protects both a mother with rheumatoid arthritis (RA) and her fetus during pregnancy, which, among other aspects, can be interpreted as a sign of hormonal normalization 228. Men with RA profit more from biologic therapies than women 229, mostly because blockade of androgen-to-oestrogen conversion with TNF inhibitors maintains the physiologically high serum concentrations of androgens in men. Interaction with sex steroids is also an important aspect of leflunomide therapy in RA because this drug inhibits cytokine production by macrophages more strongly when androgens are given in parallel 230.
Conclusions
Overall, oestrogens can be thought of as stimulators of the immune response (mostly (auto) antibody generation in rheumatic diseases via B cells and some non-B cell innate pathways) that might also have anti-inflammatory functions (such as those related to M1 macrophages and T cells) (Fig. 1). Clinical studies of oestrogen receptor agonists failed in patients with RA, but were efficient in mouse models of arthritis, suggesting that the translation of oestrogen studies in animals into humans is not straightforward. We think that oestrogens might still be useful as part of the treatment of certain autoimmune rheumatic diseases, but only for those diseases that are not B cell-mediated (so would not be suitable for SLE, for example). The stratification of patients with rheumatic diseases according to the prevailing mediator of disease and subsequent treatment with oestrogen has yet to be trialled, but the results could prove interesting. TSEC, which combines SERMs with oestrogens, might be another promising pathway.
By contrast, androgens and progesterone mainly exert immunosuppressive and anti-inflammatory activities in autoimmune rheumatic diseases, which suggests that they might be favourable therapeutics (Fig. 1). Indeed, serum androgen concentrations are often low in patients with rheumatic diseases (except for AS, which is currently unexplained). HRT with androgens could have beneficial effects for many general problems related to hypogonadism, such as cachexia and obesity, as well as having anti-inflammatory effects by targeting PTPN1 and JAK–STAT signalling pathways. The use of androgens as HRT might be promising for men with RA, SSc or PsA, but their role in women has yet to be clarified. To this end, collaboration with endocrinologists will help rheumatologists to understand how to best use androgen therapy in women and men. Similarly evident is the anti-inflammatory role of progestins, which are beneficial in women with SLE who use progestin-only therapy as oral or device contraceptives. Rheumatologists have so far been reluctant to actively test androgens as substitution therapy for patients with hypogonadism or progestins as an anti-inflammatory treatment approach. The discovery of the modulation of PTPN1 by androgens suggests that similar intracellular targets might also be discovered for progesterone. Thus, the development of targeted therapies could help to prevent the possible broad therapeutic effects of pure androgen or progestin drugs.
Finally, it is becoming evident that microbiota has sex-related differences, both in animal models and in humans (the microgenderome). These sex-related differences often lead to sex-dependent changes in local gastrointestinal inflammation, systemic immunity and, possibly, in susceptibility to rheumatic diseases. Whether manipulation of the microbiota sex hormone-mediated epigenetic modulation can be favourably used remains an open question. We feel that there is a great potential for new research in this area, but that the technologies required to unravel such interactions will need careful development.
In autoimmune rheumatic diseases, oestrogens can stimulate certain immune responses (including effects on B cells and innate immunity), but can also have dose-related anti-inflammatory effects on T cells, macrophages and other immune cells. By contrast, androgens and progesterone have predominantly immunosuppressive and anti-inflammatory effects. Hormone replacement therapies and oral contraception (and also pregnancy) enhance or decrease the severity of autoimmune rheumatic diseases at a genetic or epigenetic level. Serum androgen concentrations are often low in men and in women with autoimmune rheumatic diseases, suggesting that androgen-like compounds might be a promising therapeutic approach. However, androgen-to-oestrogen conversion (known as intracrinology) is enhanced in inflamed tissues, such as those present in patients with autoimmune rheumatic diseases. In addition, it is becoming evident that the gut microbiota differs between the sexes (known as the microgenderome) and leads to sex-dependent genetic and epigenetic changes in gastrointestinal inflammation, systemic immunity and, potentially, susceptibility to autoimmune or inflammatory rheumatic diseases. Future clinical research needs to focus on the therapeutic use of androgens and progestins or their downstream signalling cascades and on new oestrogenic compounds such as tissue-selective oestrogen complex to modulate altered immune responses.
Key points
• Oestrogens have both pro-inflammatory and anti-inflammatory effects, acting as stimulators of B cell-mediated immune responses but inhibitors of pro-inflammatory macrophages and some T cells.
• In contrast to oestrogens, androgens and progesterone have immunosuppressive and anti-inflammatory effects.
• In men and postmenopausal women with rheumatic diseases, increased androgen to-oestrogen conversion in inflamed tissues and local oestrogen metabolite synthesis support disease.
• Pregnancy, sex hormone replacement therapies and oral contraceptives can negatively or positively affect the severity of autoimmune rheumatic diseases, depending on the respective predominance of oestrogens or androgens (and progesterone).
• Sex-dependent differences in gut microbiota may lead to genetic or epigenetic changes in local gastrointestinal inflammation, systemic immunity and susceptibility to a range of rheumatic diseases.
• Therapies with androgens and progestins, selective oestrogen receptor modulators and tissue-selective oestrogen complex need to be tested more rigorously in autoimmune rheumatic diseases.
Known effects of oestrogens on immune responses
Oestrogens have a dichotomous effect in vivo and in vitro: physiological or low concentrations are pro-inflammatory but high concentrations (for example, in the periovulatory or pregnancy range) are anti-inflammatory 8. At high concentrations, oestrogens inhibit T helper 1 (TH1) cells, TH17 cells (via oestrogen receptor-α (ERα), but have the opposite effect via ERβ70), M1 macrophages, dendritic cells, neutrophils, microglia, vascular smooth muscle cells and fibroblasts vitro via inhibition of-κB (reviewed elsewhere 7,8,11,12,18). Oestrogens at high concentrations also support the function of regulatory T cells and the secretion of IL-4, IL-10 and transforming growth factor-β, which stimulates TH2 cell cytokine pathways (reviewed elsewhere 7,8,11,12,18). However, these effects can aggravate asthma and can worsen disease in patients with active systemic lupus erythematosus or antiphospholipid syndrome and in pregnant women with these conditions 218,219. Oestrogens also demonstrate beneficial anti-inflammatory effects in many animal models of rheumatic diseases, although their effects can be favourable or unfavourable (sometimes in the same model) depending on the prevailing immune reaction; when B cells dominate, oestrogens stimulate the disease, and when T cells dominate, they can inhibit disease 8,220. Oestrogens at high concentrations (such as in the periovulatory to pregnancy range) inhibit some of the later steps of T cell and B cell lymphopoiesis in vivo 8,131,136,221. They upregulate CD22 and the pro-survival molecule Bcl-2 in B cells and increase the amount of B cell-activating factor (reviewed elsewhere7,8,11,12,18), which is expected to worsen disease in patients with active systemic lupus erythematosus or antiphospholipid syndrome. Oestrogens also stimulate many B cell-mediated immune processes at a wide range of hormone concentrations vivo and in vitro, mainly (auto) antibody generation in rheumatic diseases; B cell-dependent autoimmune diseases are supported by the presence of any amount of oestrogen (reviewed elsewhere 8,11,12,18).
Known effects of androgens on immune responses
In contrast to oestrogens (Box 1), androgens such as testosterone are mainly anti-inflammatory in vivo and in vitro, with the exception of their role in a neutrophil generation. Androgens reduce-κB and Toll-like receptor 4 expression and decrease the secretion of cytokines such as TNF, IL-1β and IL-6 by monocytes and macrophages and IL-33 by mast cells in vivo and in vitro (reviewed elsewhere 10,13,16,17,19,20). Androgen therapy in men with hypogonadism reduces serum concentrations of IL-1β and TNF increases concentrations of IL-10 and decreases thymic T cell output. Androgens also inhibit B cell lymphopoiesis and (auto) antibody production in vivo, as well as T helper 1 cell differentiation, by reducing IL-12 and IFNγ in vivo and in vitro (reviewed elsewhere 10,13,16,17,19,20).
Androgens are often reduced in the serum of patients with autoimmune or inflammatory rheumatic diseases 7,16 owing to the conversion of anti-inflammatory androgens to pro-inflammatory oestrogens in inflamed tissue (intracrinology in local cells) 22,222–225. In inflammatory diseases, cytokines such as TNF, IL-1 and IL-6 stimulate the aromatase enzyme (which is necessary for the biosynthesis of oestrogens) in immune cells and fibroblasts, a phenomenon first observed in breast cells 161. Biopharmaceutical medical products can also interfere with sex steroid regulation or generation. The neutralization of TNF and IL-6 with biologic therapies can improve altered hormone axes 162,226,227. In addition, TNF inhibitor therapy protects both a mother with rheumatoid arthritis (RA) and her fetus during pregnancy, which, among other aspects, can be interpreted as a sign of hormonal normalization 228. Men with RA profit more from biologic therapies than women 229, mostly because blockade of androgen-to-oestrogen conversion with TNF inhibitors maintains the physiologically high serum concentrations of androgens in men. Interaction with sex steroids is also an important aspect of leflunomide therapy in RA because this drug inhibits cytokine production by macrophages more strongly when androgens are given in parallel 230.
Conclusions
Overall, oestrogens can be thought of as stimulators of the immune response (mostly (auto) antibody generation in rheumatic diseases via B cells and some non-B cell innate pathways) that might also have anti-inflammatory functions (such as those related to M1 macrophages and T cells) (Fig. 1). Clinical studies of oestrogen receptor agonists failed in patients with RA, but were efficient in mouse models of arthritis, suggesting that the translation of oestrogen studies in animals into humans is not straightforward. We think that oestrogens might still be useful as part of the treatment of certain autoimmune rheumatic diseases, but only for those diseases that are not B cell-mediated (so would not be suitable for SLE, for example). The stratification of patients with rheumatic diseases according to the prevailing mediator of disease and subsequent treatment with oestrogen has yet to be trialled, but the results could prove interesting. TSEC, which combines SERMs with oestrogens, might be another promising pathway.
By contrast, androgens and progesterone mainly exert immunosuppressive and anti-inflammatory activities in autoimmune rheumatic diseases, which suggests that they might be favourable therapeutics (Fig. 1). Indeed, serum androgen concentrations are often low in patients with rheumatic diseases (except for AS, which is currently unexplained). HRT with androgens could have beneficial effects for many general problems related to hypogonadism, such as cachexia and obesity, as well as having anti-inflammatory effects by targeting PTPN1 and JAK–STAT signalling pathways. The use of androgens as HRT might be promising for men with RA, SSc or PsA, but their role in women has yet to be clarified. To this end, collaboration with endocrinologists will help rheumatologists to understand how to best use androgen therapy in women and men. Similarly evident is the anti-inflammatory role of progestins, which are beneficial in women with SLE who use progestin-only therapy as oral or device contraceptives. Rheumatologists have so far been reluctant to actively test androgens as substitution therapy for patients with hypogonadism or progestins as an anti-inflammatory treatment approach. The discovery of the modulation of PTPN1 by androgens suggests that similar intracellular targets might also be discovered for progesterone. Thus, the development of targeted therapies could help to prevent the possible broad therapeutic effects of pure androgen or progestin drugs.
Finally, it is becoming evident that microbiota has sex-related differences, both in animal models and in humans (the microgenderome). These sex-related differences often lead to sex-dependent changes in local gastrointestinal inflammation, systemic immunity and, possibly, in susceptibility to rheumatic diseases. Whether manipulation of the microbiota sex hormone-mediated epigenetic modulation can be favourably used remains an open question. We feel that there is a great potential for new research in this area, but that the technologies required to unravel such interactions will need careful development.
