Study Identifies Reasons Why Women are More Susceptible to Autoimmune Disease

Howard Y Chang, MD, PhD

Credit: Stanford University

The Xist ribonucleoprotein (RNP) complex is an important factor of sex-biased autoimmunity, with the XX sex chromosome complement strongly linked to susceptibility to autoimmunity, according to a study published in Cell.¹ Results demonstrated the expression of Xist RNPs in male mice was enough to increase disease severity and change both the expression and epigenomic profiles of B call and T cell effectors of the systemic lupus erythematosus (SLE) pathogenesis.

According to current estimations, 4 out of 5 patients with autoimmune diseases are female. This disparity is especially clear in conditions like SLE, in which the ratio of patient sex is 9:1 females to males, and Sjogren’s disease, which has a 19:1 female to male patient ratio.² Xist long non-coding RNA (IncRNA) is only expressed in females to inactivate 1 of the 2 X chromosomes to obtain gene dosage compensation.

“Although hormones have been extensively studied, the dosage of X chromosome appears to be a major driver of autoimmune risk irrespective of sex or hormonal status in humans and mice,” wrote investigator Howard Y Chang, MD, PhD, associated with the Center for Personal Dynamic Regulomes, Program in Epithellal Biology, Department of Rheumatology at Stanford University School of Medicine, and colleagues. “Specific X-linked genes, such as TLR7, that can escape X inactivation have been nominated as contributors to specific autoimmune diseases. The genetic risk underlying autoimmune diseases from the second X chromosome in aggregate remains unsolved.”

To assess the impact of Xist RNP in autoimmune predilection independent of sex chromosome or hormones, investigators used a non-silencing allele of Xist, which was introduced into an autosome in the autoimmune-resistant C57BL/6J and autoimmune-prone SJL/J strain backgrounds. Male animals were included to assess female-specific IncRNA in male mouse models. An antigen array was created to determine autoimmune patient seroactivity to Xist-associated proteins.

Bibliomic analysis demonstrated 30 proteins of Xist RNP constituents have been identified as the targets of autoantibodies in ≥1 human diseases, thus adding to the theory Xist RNP may promote female-biased autoimmunity. The pristane SLE model showed female bias in disease penetrance and severity in SJL/J mice; however, the C57BL/6J mice were autoimmune resistant. In autoimmune-resistant subjects, a low level of Xist lead to changes in T cell subsets and chromatin states. In subjects with a permissive genetic background and repeated tissue injury, Xist RNP intensifies full-blown end organ pathology and activation of multiple immune cell types.

Investigators noted the small number of animals and patient samples, with sometimes large variation between subjects, as a limitation of the study. They encourage future studies to recruit a larger number of patients and focus on which Xist-related antigens may contribute to female-biased immunity.

“Understanding the risk factors and drivers of autoimmunity has become even more critical in the race to develop effective therapies and sensitive diagnositcs specific to each autoimmune disease,” investigators concluded. “However, the high heterogeneity within autoimmune diseases and overlapping traits across diseases have limited our ability to tailor effective therapies and sensitive diagnostics specific to each autoimmune disease. Our discovery of seropositivity toward multiple Xist-associating proteins in autoimmune patients introduces a novel antigen set with clinical potential for enhancing disease detection and monitoring, as autoantibodies are often detected prior to or early in disease onset.”

References

1. ^{Dou et al., Xist ribonucleoproteins promote female sex-biased autoimmunity, Cell (2024), https://doi.org/10.1016/j.cell.2023.12.037}
2. ^{Fairweather, D, Frisancho-Kiss S, and Rose, NR. (2008). Sex differences in autoimmune disease from a pathological perspective. AM. J. Pathol. 1732, 600-609.}