The molecular underpinnings of female predominance in lupus

Most people affected by systemic lupus erythematosus (SLE) are women. Although the role of sex hormones has been appreciated, we discuss emerging evidence that links X-linked genes escaping from dosage compensation to female predisposition to lupus. This is exemplified by TLR7 and CXorf21 whose female-biased expression may converge to enhance interferon responses and promote autoantibody-producing B cells, which are hallmarks of SLE. Notably, autosomal transcription factors with female overexpression may regulate molecular programs in the skin that are sufficient to induce lupus. These findings indicate a multifactorial basis for female vulnerability; however, several areas remain elusive, including the epigenetic landscape of X-chromosome inactivation (XCI) in SLE, the interplay with environmental factors, and the role of male-specific factors such as Y-linked genes.