Gender bias in lupus: does immune response initiated in the gut mucosa have a role?

Abstract

SummaryThe risk of developing systemic lupus erythematosus (SLE) is approximately nine times higher among women compared to men. However, very little is understood concerning the underlying mechanisms that contribute to this gender bias. Further, whether there is a link between immune response initiated in the gut mucosa, the progression of SLE and the associated gender bias has never been investigated. In this report, we show a potential link between the immune response of the gut mucosa and SLE and the gender bias of lupus for the first time, to our knowledge. Both plasma cell-and gut-imprinted-a4b7 T cell frequencies were significantly higher in the spleen and gut mucosa of female (SWR 3 NZB)F 1 (SNF 1 ) mice compared to that of their male counterparts. Importantly, female SNF 1 mice not only showed profoundly higher CD45 1 immune cell densities, but also carried large numbers of interleukin (IL)-17-, IL-22-and IL-9-producing cells in the lamina propria (LP) compared to their male counterparts. Intestinal mucosa of female SNF 1 mice expressed higher levels of a large array of proinflammatory molecules, including type 1 interferons and Toll-like receptors 7 and 8 (TLR-7 and TLR-8), even before puberty. Our work, therefore, indicates that the gut immune system may play a role in the initiation and progression of disease in SLE and the associated gender bias.

The Role of Sex in Uveitis and Ocular Inflammation

“…138 The gut mucosa of female mice have higher concentrations of plasma cells, gut imprinted α4β7 T cells, and of CD45+ IL-17, IL-22 and IL-9 producing cells than male mice. 7 The microbiome has been linked to the female predominant conditions of RA and MS and is thought to have an effect on IL-17 mediated pathways. 139-141 …”

“…7 Eighty-eight to 90.5% of SLE patients are women. 7, 20, 21 SLE commonly affects Asian and African women in their reproductive years. 22-24 Increased levels of estrogen and progesterone (e.g.…”

“…pregnancy, post-partum status) can cause worsening of SLE. 5, 7 This is likely due to upregulation of a Th2 immune response leading to increased antibody synthesis. Although ocular findings are not one of the components of the classification criteria for SLE, SLE is associated with keratoconjunctivitis sicca and posterior segment pathology.…”

“…4 Moreover, estrogen has recently been shown to play a significant role in the development and function of Th17 cells, as well as the production of IL-17. 6, 7 It has also been noted that men and women may present with the same underlying cause of uveitis but with differing severity or ophthalmic manifestations. 8 In addition, infectious uveitides do show gender differences in prevalence, primarily due to behavioral and/or cultural sources.…”

The role of the gastrointestinal tract in the pathogenesis of rheumatic diseases

“…Remarkably, lupus manifestations were improved with oral retinoid acid treatment concurrently with the Lactobacilli restoration. Analyzing immunologic differences in the gut of female lupus-prone SNF1 mice, which develop a more severe form of nephritis than male mice, Gaudreau et al [51] demonstrated that female SNF1 mice have more plasma cells and a4b7 T cells in the Peyer's patches and much higher pro-inflammatory cytokines as IL-6, IL-9, IL-17, IL-22, IFN-a, and IFN-b in distal ileum than their male counterparts. Although the microbiome composition was not analyzed in this study, it has been hypothesized that the observed mucosal immune differences between the sexes may be the expression of an underlying altered gut bacterial flora.…”