Factors underlying higher prevalence of systemic lupus erythematosus in females

Lupus predominantly affects women, with a 9:1 female-to-male ratio. Genetically, females carry XX genotypes, while males carry XY genotypes. To balance gene expression, every cell in a female silences one of the two X chromosomes using a long non-coding RNA (lncRNA) Xist. However, the genetic risk underlying autoimmune diseases from the second X chromosome remains unclear.

Dou et al.¹ published an article in Cell investigating the role of Xist ribonucleoproteins (RNP) in sex-bias autoimmunity. Here, we summarize the key findings.

Methods¹

• To induce Xist expression in male mice, a TetOP-∆RepA-Xist [tgXist] transgenic mouse model was developed. Two genetic backgrounds utilized were autoimmune-resistant C57BL/6J and autoimmune-prone SJL/J.
• Doxycycline was given with drinking water to detect Xist expression.
• Wild type (WT) and tgXist mice were injected with pristane to chemically induce systemic lupus erythematosus (SLE). The experimental cohorts are illustrated in Figure 1.
• To test the immunogenicity of Xist in humans, de-identified sera from patients with SLE were obtained.

Key findings¹

• Female-biased autoimmunity: Bibliomic analysis found 30 proteins in Xist RNP that are targeted by autoantibodies in various human diseases.
• No disease activity in the genetically autoimmune resistant background: Pristane-treated tgXist male mice in nonpermissive C57/BL6 background did not manifest disease even after a year of treatment (contrasting the 16-week severe disease onset in the SJL/J background) and have low propensity to develop autoantibodies.
• Female-like changes in T-cell profiles: ATAC sequencing found elevated toll-like receptor 9 in tgXist-expressing males and Xist-expressing females. CIBERSORT analysis showed tgXist- or Cist-expressing males and WT females had more CD4 memory T cells, while control males had higher levels of naïve T cells.
• Multi-organ autoimmune pathology: Pristane treatment in tgXist males and WT females in autoimmune-prone SJL/J mouse background showed greater incidence and severity of glomerulonephritis, hepatic lipogranulomas, pulmonary hemorrhage and lymphohistiocytic alveolitis, compared with controls (Figure 1)
  • Pristane-treated WT females showed elevated levels of four known autoantibodies (RIBO P0, RIBO P2, CENPA, and CENPB) compared with pristane-treated WT males. Pristane-treated tgXist males showed significant elevation in CENPB (p = 0.02) compared with pristane-treated WT males.

Figure 1. Increased pathophysiology in tgXist- and Xist-expressing mice in the SJL/J strain of the pristane-induced SLE model*

Dox, doxycycline; SLE, systemic lupus erythematosus; tgXist, TetOP-∆RepA-Xist; WT, wild type.
*Data from Dou, et al.¹

• Higher autoimmunity: Compared with WT males, the tgXist-diseased males and WT females exhibited:

• • upregulation of atypical B cell markers (Zeb2, FcrI5), Cd19, Ms4a1, and CD22; and
  • downregulation of Cr2, Cr1I, Cd27, Cxcr5, key T-cell regulation genes (Nr3c1, Cd37, Cd52 Cd74), and self-tolerance genes (Siglec-g).

• Shared autoantibodies with autoimmune patients: Multiple proteins from the Xist RNP are novel autoantigens in patients with SLE, for example, HMGB1.
  • Further, the female pristane-induced WT mice induced multiple autoantibodies to Xist RNP, that significantly overlapped with autoantibodies to Xist RNP in human patients with SLE (p = 0.001).