Gender and autoimmunity

doi:10.1016/j.autrev.2006.10.001

Autoimmunity Reviews

Volume 6, Issue 6, June 2007, Pages 366-372

https://doi.org/10.1016/j.autrev.2006.10.001 Get rights and content

Abstract

The enhanced immunoreactivity in females is a double-edged sword that provides better protection against infections, but may lead to enhanced autoreactivity and thereby contribute to the induction of autoimmunity. Autoimmune diseases demonstrate a gender bias and represent the fifth leading cause of death by disease among females of reproductive age. Clinical and murine experimental studies indicate that the gender bias in autoimmunity may be influenced by sex hormones, predominantly displayed in the development and exacerbations of the prototypical autoimmune disease lupus. The associations between sex hormones and other autoimmune diseases are less clear. Our review on the impact of gender via sex hormones and sex related genes in the pathogenesis of several autoimmune diseases suggests that a better understanding of the underlying mechanisms behind the sexual dimorphism of the immune system may lead to the development of novel therapeutic approaches to 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

•
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.
•
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.
•
Treatment with bromocriptine, an inhibitor of

References (40)

E. Peeva et al.
Spotlight on the role of hormonal factors in the emergence of autoreactive B-lymphocytes
Immunol Lett
(2005)
S.Z. Yacoub Wasef
Gender differences in systemic lupus erythematosus
Gend Med
(2004)
C.M. Grimaldi et al.
Hormonal modulation of B cell development and repertoire selection
Mol Immunol
(2005)
L.D. Apelgren et al.
The effect of a selective estrogen receptor modulator on the progression of spontaneous autoimmune disease in MRL lpr/lpr mice
Cell Immunol
(1996)
R.L. Wilder
Hormones and autoimmunity: animal models of arthritis
Baillieres Clin Rheumatol
(1996)
V. Kouskoff et al.
Organ-specific disease provoked by systemic autoimmunity
Cell
(1996)
C.M. Brickman et al.
The mosaic of autoimmunity
Scand J Clin Lab Invest Suppl
(2001)
J. Roubinian et al.
Effect of castration and sex hormone treatment on survival, anti-nucleic acid antibodies, and glomerulonephritis in NZB/NZW F1 mice
J Exp Med
(1978)
Z.M. Sthoeger et al.
Beneficial effects of the anti-oestrogen tamoxifen on systemic lupus erythematosus of (NZBxNZW)F1 female mice are associated with specific reduction of IgG3 autoantibodies
Ann Rheum Dis
(2003)
E. Peeva et al.
Tamoxifen blocks estrogen-induced B cell maturation but not survival
J Immunol
(2005)

B.D. Greenstein et al.

Effects of an aromatase inhibitor on thymus and kidney and on oestrogen receptors in female MRL/MP-lpr/lpr mice

Lupus

(1993)

M.A. Gutierrez et al.

Prolactin and systemic lupus erythematosus: prolactin secretion by SLE lymphocytes and proliferative (autocrine) activity

Lupus

(1995)

R. Chan et al.

Inflammatory cytokine gene expression in the urinary sediment of patients with lupus nephritis

Arthritis Rheum

(2003)

E. Peeva et al.

Prolactin modulates the naive B cell repertoire

J Clin Invest

(2003)

E. Peeva et al.

Bromocriptine restores tolerance in estrogen-treated mice

J Clin Invest

(2000)

S.E. Walker

Bromocriptine treatment of systemic lupus erythematosus

Lupus

(2001)

M.A. Petri et al.

Effects of prasterone on disease activity and symptoms in women with active systemic lupus erythematosus

Arthritis Rheum

(2004)

R.G. Lahita et al.

Klinefelter's syndrome: hormone metabolism in hypogonadal males with systemic lupus erythematosus

J Rheumatol Suppl

(1987)

J.P. Buyon et al.

The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: a randomized trial

Ann Intern Med

(2005)

A. Ben-Chetrit et al.

Systemic lupus erythematosus induced by ovulation induction treatment

Arthritis Rheum

(1994)

Cited by (270)

Infection and Autoimmunity – An Introductory Note
2024, Infection and Autoimmunity
Almost every infectious agent was linked in one way or another to various responses from the immune system. The responses range from normal reaction to a vast majority of autoimmune manifestations. Led by molecular mimicry, the mechanisms by which an autoimmune phenomena appears in correlation with infection are numerous including bystander activation and superantigens, among others. The recent pandemic of COVID-19 has strengthened the importance of autoimmunity in the context of infection. Nevertheless, historical examples such as acute rheumatic fever is critical for this understanding as well.
Autoimmunity on the Rise: COVID-19 as a Trigger of Autoimmunity
2024, Infection and Autoimmunity
Stimulation of the immune system may act as a double-edged sword; while stimulation of the immune system is carousal for defense against infectious and endogenous compounds, hyper-stimulation of the immune system could lead to autoimmunity. The concept referred to as “the mosaic of autoimmunity” demonstrates the multifactorial origin and diversity of numerous factors contributing to the new onset of diverse autoimmune diseases (AIDs). These tangled factors are categorized into three primary groups: genetic predisposition, hormonal factors, and environmental factors. The varying combinations of these factors could determine which AID is more likely to erupt. Environmental factors are extremely diverse; any unrecognized element could elicit an immune response against it, including both exogenous and endogenous components. This chapter will discuss these concepts and describe how SARS-CoV-2 can function as an environmental factor contributing to autoimmunity. Additionally, we examine the contribution of genetic predisposition toward the nature of the immune response and its part in autoimmunity. Due to genetic and hormonal factors, women possess a more aggressive immune response than men, providing sustainability from various infections while increasing the likelihood of developing an AID. These concepts are necessary to understand why autoimmunity could be on the rise.
The potential role of molecular mimicry by the anaerobic microbiota in the aetiology of autoimmune disease
2023, Anaerobe
Autoimmune diseases are thought to develop as a consequence of various environmental and genetic factors, each of which contributes to dysfunctional immune responses and/or a breakdown in immunological tolerance towards native structures. Molecular mimicry by microbial components is among the environmental factors thought to promote a breakdown in immune tolerance, particularly through the presence of cross-reactive epitopes shared with the human host. While resident members of the microbiota are essential promoters of human health through immunomodulation, defence against pathogenic colonisation and conversion of dietary fibre into nutritional resources for host tissues, there may be an underappreciated role of these microbes in the aetiology and/or progression of autoimmune disease. An increasing number of molecular mimics are being identified amongst the anaerobic microbiota which structurally resemble endogenous components and, in some cases, for example the human ubiquitin mimic of Bacteroides fragilis and DNA methyltransferase of Roseburia intestinalis, have been associated with promoting antibody profiles characteristic of autoimmune diseases. The persistent exposure of molecular mimics from the microbiota to the human immune system is likely to be involved in autoantibody production that contributes to the pathologies associated with immune-mediated inflammatory disorders. Here-in, examples of molecular mimics that have been identified among resident members of the human microbiota and their ability to induce autoimmune disease through cross-reactive autoantibody production are discussed. Improved awareness of the molecular mimics that exist among human colonisers will help elucidate the mechanisms involved in the breakdown of immune tolerance that ultimately lead to chronic inflammation and downstream disease.
Transferrin receptor 2 deficiency promotes macrophage polarization and inflammatory arthritis
2023, Redox Biology
Rheumatoid arthritis is an inflammatory joint disease in which synovial iron deposition has been described. Transferrin receptor 2 (Tfr2) represents a critical regulator of systemic iron levels. Loss of Tfr2 function in humans and mice results in iron overload. As iron contributes to inflammatory processes, we investigated whether Tfr2-deletion affects the pathogenesis of inflammatory arthritis in an iron-dependent manner.
Using a global and conditional genetic disruption of Tfr2, we assessed the relevance of Tfr2 in K/BxN serum-transfer arthritis (STA) and macrophage polarization.
Male Tfr2^−/− mice subjected to STA developed pronounced joint swelling, and bone erosion as compared to Tfr2^+/+ littermate-controls (P < 0.01). Furthermore, an increase of neutrophils and macrophages/monocytes was observed in the inflammatory infiltrate within the paws of Tfr2^−/− mice. To elucidate whether Tfr2 in myeloid cells has a direct role in the pathogenesis of arthritis or whether the effects were mediated via the systemic iron overload, we induced STA in Tfr2^fl/fl-LysMCre + mice, which showed normal iron-loading. Cre + female mice displayed increased disease development compared to Cre-controls. As macrophages regulate iron availability and innate immunity, we hypothesized that Tfr2-deficiency would polarize macrophages toward a pro-inflammatory state (M1) that contributes to arthritis progression. In response to IFN-γ stimulation, Tfr2^−/− macrophages showed increased expression of M1-like cytokines, IFN-γ-target genes, nitric-oxide production, and prolonged STAT1 activation compared to Tfr2^+/+ macrophages (P < 0.01), while pre-treatment with ruxolitinib abolished Tfr2-driven M1-like polarization.
Taken together, these findings suggest a protective role of Tfr2 in macrophages on the progression of arthritis via suppression of M1-like polarization.
Lymphocyte alterations in patients with Common Variable Immunodeficiency (CVID) and autoimmune manifestations
2022, Clinical Immunology
Autoimmunity is a common feature in CVID patients. To date the mechanisms leading to the development of such complications are not fully elucidated.
Data from 122 CVID patients subdivided in three groups based on the absence of autoimmunity (n-AI) or the presence of hematologic autoimmune phenomena (Cy-AI) or non-hematologic autoimmune phenomena (n-Cy-AI) were evaluated.
We identified a total of 128 autoimmune manifestations in 55/122 patients (45.1%). 30/122 (24.6%) patients presented hematologic autoimmune phenomena while 29/122 (23.8%) presented gastrointestinal autoimmune involvement. Immune thrombocytopenia was the most common manifestation (27/122; 22.1%), followed by autoimmune hemolytic anemia (18/122; 14.8%) and autoimmune enteropathy (17/122; 13.9%). Cy-AI patients displayed higher CD4⁺ effector memory and terminally differentiated CD8⁺ cells with lower percentages of naïve and recent thymic emigrants (RTEs) CD4⁺ cells and a significant expansion of the CD19^hiCD21^low population.
CVID patients developing autoimmune cytopenias display characteristic immune phenotypic features.
Leptin antagonism attenuates hypertension and renal injury in an experimental model of autoimmune disease
2024, Clinical Science

View all citing articles on Scopus

¹: Both authors contributed equally to this work.

View full text

Gender and autoimmunity

Abstract

Introduction

Section snippets

Systemic lupus erythematosus (SLE)

Myasthenia gravis (MG)

Sjogren's syndrome

Rheumatoid arthritis (RA)

Systemic sclerosis (SSc)

Conclusions

Bulletins

Immunol Lett

Gend Med

Mol Immunol

Cell Immunol

Baillieres Clin Rheumatol

Cell

The mosaic of autoimmunity

Scand J Clin Lab Invest Suppl

Effect of castration and sex hormone treatment on survival, anti-nucleic acid antibodies, and glomerulonephritis in NZB/NZW F1 mice

J Exp Med

Beneficial effects of the anti-oestrogen tamoxifen on systemic lupus erythematosus of (NZBxNZW)F1 female mice are associated with specific reduction of IgG3 autoantibodies

Ann Rheum Dis

Tamoxifen blocks estrogen-induced B cell maturation but not survival

J Immunol

Effects of an aromatase inhibitor on thymus and kidney and on oestrogen receptors in female MRL/MP-lpr/lpr mice

Lupus

Prolactin and systemic lupus erythematosus: prolactin secretion by SLE lymphocytes and proliferative (autocrine) activity

Lupus

Inflammatory cytokine gene expression in the urinary sediment of patients with lupus nephritis

Arthritis Rheum

Prolactin modulates the naive B cell repertoire

J Clin Invest

Bromocriptine restores tolerance in estrogen-treated mice

J Clin Invest

Bromocriptine treatment of systemic lupus erythematosus

Lupus

Effects of prasterone on disease activity and symptoms in women with active systemic lupus erythematosus

Arthritis Rheum

Klinefelter's syndrome: hormone metabolism in hypogonadal males with systemic lupus erythematosus

J Rheumatol Suppl

The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: a randomized trial

Ann Intern Med

Systemic lupus erythematosus induced by ovulation induction treatment

Arthritis Rheum