Genetic and hormonal factors in female-biased autoimmunity

Rubtsov, Anatoly V.; Rubtsova, Kira; Kappler, John W.; Marrack, Philippa

doi:10.1016/j.autrev.2010.02.008

Cited by 169 publications

(125 citation statements)

References 53 publications

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“…Similar findings were demonstrated in the equivalent animal models for RA and MS; collagen-induced arthritis and experimental auto immune encephalomyelitis, respectively [12,23]. Some investigators claim that this variation is due to an alteration in the Th1/Th2 response by sex hormones [24]. Pregnancy is known to enhance the Th2 response, which may suppress RA and MS, as they are mainly Th1 driven, unlike SLE, which is Th2 driven.…”

Section: Pregnancy and Autoimmune Diseasessupporting

confidence: 64%

Can we explain the higher prevalence of autoimmune disease in women?

Kivity

Ehrenfeld²

2010

Expert Review of Clinical Immunology

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Section: Pregnancy and Autoimmune Diseasessupporting

confidence: 64%

Can we explain the higher prevalence of autoimmune disease in women?

Kivity

Ehrenfeld²

2010

Expert Review of Clinical Immunology

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“…In fact, γHV68 infection of B6.Sle123 females caused an autoantibody profile similar to those of males, which display lower autoantibody titers than females. This bias may be a result of differences among sexes in the expression of TLRs and cytokines that affect autoantibody production (51,52) and indicate the existence of pathways leading to the production of autoantibodies that are not inhibited by the virus. On the contrary, latent γHV68 infection inhibited autoantibody production even in the genetically unrelated lupus-prone MRL/lpr strain, indicating that this virus impinges on a general mechanism of autoantibody formation.…”

Section: Discussionmentioning

confidence: 99%

Murine gammaherpesvirus 68 infection protects lupus-prone mice from the development of autoimmunity

Larson

Thurman

Rubtsov

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Gammaherpesvirus infections, such as those caused by EBV, have been suggested to promote the development of autoimmunity. To test this idea, we infected healthy WT and lupus-prone B6.Sle123 mice with an EBV-related and rodent-specific gammaherpesvirus, γHV68. Although acute γHV68 infection increased autoantibody levels for 4 to 6 wk, latent infection inhibited these responses for 1 y. The inhibition of autoantibody expression was only observed in B6.Sle123 females and not in males, which already displayed lower autoantibody titers. Contrary to the initial hypothesis, infection of young B6.Sle123 mice, both male and female, resulted in suppression of lymphoid activation and expansion and of glomerular inflammation and sclerosis, preserving kidney function. Moreover, γHV68 infection led to reduced autoantibody titers, lymphoid activation, and glomerular inflammation whether lupus-prone females were infected before or during disease manifestation. Finally, γHV68 infection also inhibited autoantibody production in the genetically distinct MRL/ lpr lupus-prone mice. Our findings indicate that γHV68 infection strongly inhibits the development and progression of lupus-like disease in mice that spontaneously develop this condition mediating its beneficial effects at the humoral, cellular, and organ levels. The mechanisms by which the virus exerts this down-modulatory action are not yet clear, but appear to operate via reduced activation of dendritic cells, T cells, and B cells. Gammaherpesviruses coevolved with the vertebrate immune systems, establishing lifelong infections in humans and other mammals. Our findings that γHV68 infection prevents rather than exacerbates autoimmunity in mice suggest that infection with gammaherpesviruses may be protective rather than pathological in most individuals.

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“…The involvement of estrogens, which influence many physiologic processes, has been shown in the development or progression of several autoimmune disorders (1)(2)(3)(4). There is evidence that 17␤-estradiol directly modulates the development and function of immune cells, although the mechanism by which this might occur is not well understood (5,6).…”

mentioning

confidence: 99%

Autoantibodies to estrogen receptor α interfere with T lymphocyte homeostasis and are associated with disease activity in systemic lupus erythematosus

Colasanti¹,

Maselli²,

Conti³

et al. 2012

Arthritis & Rheumatism

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Objective. Estrogens influence many physiologic processes and are also implicated in the development or progression of numerous diseases, including autoimmune disorders. Aberrations of lymphocyte homeostasis that lead to the production of multiple pathogenic autoantibodies, including autoantibodies specific to estrogen receptor (ER), have been detected in the peripheral blood of patients with systemic lupus erythematosus (SLE). This study was undertaken to assess the presence of both anti-ER␣ and anti-ER␤ antibodies in sera from patients with SLE, to analyze the effect of these antibodies on peripheral blood T lymphocyte homeostasis, and to evaluate their role as determinants of disease pathogenesis and progression.Methods. Anti-ER antibody serum immunoreactivity was analyzed by enzyme-linked immunosorbent assay in samples from 86 patients with SLE and 95 healthy donors. Phenotypic and functional analyses were performed by flow cytometry and Western blotting.Results. Anti-ER␣ antibodies were present in 45% of the patients with SLE, whereas anti-ER␤ antibodies were undetectable. In healthy donors, anti-ER␣ antibodies induced cell activation and consequent apoptotic cell death in resting lymphocytes as well as proliferation of anti-CD3-stimulated T lymphocytes. A significant association between anti-ER␣ antibody values and clinical parameters, i.e., the SLE Disease Activity Index and arthritis, was found.Conclusion. Our data suggest that anti-ER␣ autoantibodies interfere with T lymphocyte homeostasis and are significantly associated with lupus disease activity.The involvement of estrogens, which influence many physiologic processes, has been shown in the development or progression of several autoimmune disorders (1-4). There is evidence that 17␤-estradiol directly modulates the development and function of immune cells, although the mechanism by which this might occur is not well understood (5,6). The primary mechanism of 17␤-estradiol activity is mediated by transcription activity of the intracellular estrogen receptors (ERs), ER␣ and ER␤, to produce genomic effects (7). A variety of cellular responses to physiologic concentrations of 17␤-estradiol occur rapidly, within seconds to a few minutes. These rapid estrogen-mediated effects (referred to as nongenomic) are triggered through the activation of membrane-associated ER and are independent of transcription pathways and protein synthesis.

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Genetic and hormonal factors in female-biased autoimmunity

Cited by 169 publications

References 53 publications

Can we explain the higher prevalence of autoimmune disease in women?

Can we explain the higher prevalence of autoimmune disease in women?

Murine gammaherpesvirus 68 infection protects lupus-prone mice from the development of autoimmunity

Autoantibodies to estrogen receptor α interfere with T lymphocyte homeostasis and are associated with disease activity in systemic lupus erythematosus

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