Sex bias in systemic lupus erythematosus: a molecular insight

Abstract

Acknowledging sex differences in immune response is particularly important when we consider the differences between men and women in the incidence of disease. For example, over 80% of autoimmune disease occurs in women, whereas men have a higher incidence of solid tumors compared to women. In general women have stronger innate and adaptive immune responses than men, explaining their ability to clear viral and bacterial infections faster, but also contributing to their increased susceptibility to autoimmune disease. The autoimmune disease systemic lupus erythematosus (SLE) is the archetypical sexually dimorphic disease, with 90% of patients being women. Various mechanisms have been suggested to account for the female prevalence of SLE, including sex hormones, X-linked genes, and epigenetic regulation of gene expression. Here, we will discuss how these mechanisms contribute to pathobiology of SLE and how type I interferons work with them to augment sex specific disease pathogenesis in SLE.

Optimizing Noninvasive Vagus Nerve Stimulation for Systemic Lupus Erythematosus: Protocol for a Multicenter Randomized Controlled Trial

“…There is growing evidence that sex affects the pathophysiology, incidence, prevalence, development, and response to therapy in many diseases. In SLE, 90% of all diagnoses are in women [ 42 ], who are most commonly affected by clinical flares between the ages of 15 years and 44 years, or during childbearing years. Due to this disproportionality between sexes, this study aims to have a women:men ratio of 9:1, in keeping with SLE prevalence between sexes.…”

The greatest contribution to medical science is the transformation from studying symptoms to studying their causes—the unrelenting legacy of Robert Koch and Louis Pasteur—and a causality perspective to approach a definition of SLE

“…SLE is linked to several predisposing factors, like monogenic ( 20 – 23 ) and polygenic ( 24 , 25 , 131 , 132 ) abnormalities or combinations, sex/gender ( 133 ), and environmental factors ( 134 – 136 ). Autoimmunity is in this context not a predisposing factor but a disease-modifying factor.…”

Lupus and recurrent pregnancy loss: the role of female sex hormones and B cells

“…In this regard, it is known that the clinical manifestation of the disease typically appears after puberty, affecting women between the ages of 20 to 50, a period during which levels of estradiol and progesterone significantly rise ( 59 ). The strongest evidence supporting the role of female sex hormones in SLE comes from the observation that patients with SLE experience disease exacerbation during the premenstrual period and in pregnancy ( 35 , 59 ). Interestingly, a case report demonstrated that administering cross-gender hormones to a transgender female resulted in lupus nephritis, and the withdrawal of estradiol supplementation upon admission prevented the worsening of symptoms.…”

“…Animal studies also provide support for the role of estrogen in SLE. Ovariectomized lupus-prone mice showed ameliorated disease, while estrogen supplementation in castrated male mice worsened the symptoms [reviewed in ( 35 )]. Moreover, targeted deletion of ERα specifically in B cells has been shown to reduce the production of pathogenic autoantibodies and the development of nephritis in lupus-prone mice ( 61 ).…”

“…Considering the sex and age predisposition of SLE, female sex hormones are undeniably involved in the pathogenesis of the disease ( 34 ). Studies conducted on SLE-prone mice using gonadectomy/hormone deprivation and hormone supplementation have consistently confirmed this association, revealing that estrogen exacerbates the disease, while its removal ameliorates the disease in female subjects [reviewed in ( 35 )]. In the context of pregnancy, the increase in female sex hormone levels may influence or potentiate the abnormal function of the immune cells in patients with SLE, thereby exacerbating the disease symptoms and leading to pregnancy complications, including RPL ( 36 , 37 ).…”