Sexual dimorphism in autoimmunity

Rubtsova, Kira; Marrack, Philippa; Rubtsov, Anatoly V.

doi:10.1172/jci78082

Cited by 165 publications

(126 citation statements)

References 126 publications

Supporting

Mentioning

121

Contrasting

Order By: Relevance

“…ZBTB10 is thought to regulate specificity proteins Sp1, Sp3 and Sp4 (35,36); in cell culture studies, it is suppressed by ROSmicroRNA27a, thereby enhancing estrogen receptor α expression and mediating estrogen effects (36). Potential immunoregulation could either be through Sp1 (critical for interleukin [IL]-10 and CD40 responses) (37,38) or indirectly via estrogen effects on autoimmunity (39,40).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations

Seldin

Alkhairy

Lee

et al. 2015

Mol Med

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

“…Confirmation of these potential differences might imply stronger genetic and/or hormonal influences on MG susceptibility in younger females and older males. Sexual dimorphism and the potential role of X chromosome genes have been emphasized in other studies of autoimmunity (40,62).…”

mentioning

confidence: 99%

Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations

Seldin

Alkhairy

Lee

et al. 2015

Mol Med

View full text Add to dashboard Cite

“…The reasons for differences between females and males in autoimmune disease susceptibility remain an enigma. Sex hormones, the presence or absence of a second X chromosome, microbiota, and disruption at the bloodspinal cord and blood-brain barriers have been implicated as contributing factors (56)(57)(58). Although progress has been made in identifying the genetic determinants of autoimmunity (59), advances in identifying how sex hormones, microbiota, and their interactions with the immune system influence gender-bias autoimmunity remain limited.…”

Section: Relative Abundance Of Key Bacterial Players In Intestinal Immentioning

confidence: 99%

TNFR2 Deficiency Acts in Concert with Gut Microbiota To Precipitate Spontaneous Sex-Biased Central Nervous System Demyelinating Autoimmune Disease

Miller

Bonn

Franklin

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

TNF-α antagonists provide benefit to patients with inflammatory autoimmune disorders such as Crohn’s disease, rheumatoid arthritis, and ankylosing spondylitis. However, TNF antagonism unexplainably exacerbates CNS autoimmunity, including multiple sclerosis and neuromyelitis optica. The underlying mechanisms remain enigmatic. We demonstrate that TNFR2 deficiency results in female-biased spontaneous autoimmune CNS demyelination in myelin oligodendrocyte glycoprotein–specific 2D2 TCR transgenic mice. Disease in TNFR2−/− 2D2 mice was associated with CNS infiltration of T and B cells as well as increased production of myelin oligodendrocyte glycoprotein–specific IL-17, IFN-γ, and IgG2b. Attenuated disease in TNF−/− 2D2 mice relative to TNFR2−/− 2D2 mice identified distinctive roles for TNFR1 and TNFR2. Oral antibiotic treatment eliminated spontaneous autoimmunity in TNFR2−/− 2D2 mice to suggest role for gut microbiota. Illumina sequencing of fecal 16S rRNA identified a distinct microbiota profile in male TNFR2−/− 2D2 that was associated with disease protection. Akkermansia muciniphila, Sutterella sp., Oscillospira sp., Bacteroides acidifaciens, and Anaeroplasma sp. were selectively more abundant in male TNFR2−/− 2D2 mice. In contrast, Bacteroides sp., Bacteroides uniformis, and Parabacteroides sp. were more abundant in affected female TNFR2−/− 2D2 mice, suggesting a role in disease causation. Overall, TNFR2 blockade appears to disrupt commensal bacteria–host immune symbiosis to reveal autoimmune demyelination in genetically susceptible mice. Under this paradigm, microbes likely contribute to an individual’s response to anti-TNF therapy. This model provides a foundation for host immune–microbiota-directed measures for the prevention and treatment of CNS-demyelinating autoimmune disorders.

show abstract

“…Interestingly, miRNAs are disproportionately represented on the X chromosome (113 miRNAs) as compared with the Y chromosome (2 mi RNAs), and some of those X-linked miRNAs have been associated with autoimmune phenotypes, as discussed by Philippa Marrack and colleagues (6). These authors focus on the fact that the expression and activity of certain genes and/or their products in immune cells can be modulated by sex hormones, and they discuss the mechanisms by which femaleness increases risk (7), including through age-related changes in the immune system that differ between females and males.…”

Section: Discussionmentioning

confidence: 99%

Putting together the autoimmunity puzzle

Cava¹

2015

J. Clin. Invest.

View full text Add to dashboard Cite

R e v i e w S e R i e S : A u t o i m m u n i t y2highlighting the evidence for a key role of these suppressor cells in the prevention and suppression of autoimmunity, these authors review the experimental support for the existence of functionally and phenotypically distinct suppressor cell subsets and their complementary role in regulating immune responses. By including considerations of Treg stability under changing environments and the recent immunotherapeutic approaches for the restoration of peripheral immune tolerance, these authors ponder the current challenges in achieving remission of autoimmunity without continuous immune suppression (i.e., by maintaining uncompromised overall immune responses). The restoration of immune homeostasis might be accomplished by enhancing suppressive immune responses, to limit the damage caused by T cells or B cells (or by the cytokines that they produce). George Tsokos and colleagues analyze the central role of T cells in orchestrating autoimmune responses and the characteristics of these cells in a prototypical systemic autoimmune disease (11), while Betty Diamond and Jolien Suurmond address the importance of the mechanisms that drive autoantibody pathogenicity and the mechanisms by which autoantibody production is initiated (12). Autoantibodies appear long before clinical symptoms of autoimmunity, thus representing a marker for potential disease development (13). Their predictive value is also reflected by the finding that there is an approximately six-to eight-fold increase in the risk of developing an autoimmune disease when only one autoantibody is present compared with three autoantibodies present (14).Autoantibodies develop because of inefficient removal of autoreactive B cells, which in healthy individuals are eliminated both at central and peripheral levels. In untreated patients with active autoimmune disease, both central and peripheral B cell tolerance checkpoints can be defective (15). Fritz Melchers describes three checkpoints of central tolerance for B cells in the bone marrow and discusses the importance of the microenvironment in the effective removal of the vast majority of B cell clones that express polyreactive antibodies (16). He then discusses the mechanisms of peripheral B cell tolerance, namely checkpoint 4, which removes peripheral autoreactive new emigrant B cells before they enter the mature naive B cell pool (17), and checkpoint 5, which eliminates accidental products of hypermutation that are created during antibody affinity maturation (18). ConclusionsIn summary, this Review series surveys the complex mechanisms of autoimmunity and the potential new therapies that might target critical disease pathways, cells, and molecules. Much has been learned about the pathogenesis of autoimmune disease since the original formulation of the concept of horror autotoxicus that was forged by Paul Ehrlich during his study of the development of hemolytic antibodies in animals injected with blood of unrelated species (19)(20)(21)(22)(23)(24). The failure to deve...

show abstract

Sexual dimorphism in autoimmunity

Cited by 165 publications

References 126 publications

Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations

Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations

TNFR2 Deficiency Acts in Concert with Gut Microbiota To Precipitate Spontaneous Sex-Biased Central Nervous System Demyelinating Autoimmune Disease

Putting together the autoimmunity puzzle

Contact Info

Product

Resources

About