Systemic sclerosis associated interstitial lung disease (SSc-ILD) is a chronic inflammatory condition characterized by severe fibrosis in multiple organs including lungs. SSc is more common in women than in men;however men experience an accelerated disease with reduced survival. Bleomycin-induced lung fibrosis is also more severe in male mice than in females. Mechanisms underlying such sex differences in susceptibility to or damage from SSc remain poorly understood. This proposal is guided by our animal model observations that mice with XX sex chromosome complement exhibit increased susceptibility to the development of systemic inflammatory disease as compared to mice with XY sex chromosome complement, regardless of the gender. Intriguingly, both male and female mice with XY sex chromosome complement develop a more severe fibrosis than mice with XX sex chromosome complement. The increased fibrosis in XY mice is associated with increased IL-13 and reduced expression of IL-13RA2, a decoy receptor for IL-13. The gene for IL-13RA2 is located on X chromosome. Thus, compared to XX mice, the immunized XY mice have reduced expression of IL-13RA2, leading to increased IL-13 that has been implicated in fibrosis. These data suggest a possible role of X chromosome gene dosage in modulating susceptibility to and damage from inflammatory diseases. Using the above mouse model, we will test the hypothesis that regardless of the gonadal sex, XY sex chromosome complement confers a greater risk for lung fibrosis and SSc-ILD. Specifically, we will test whether bleomycin induced lung fibrosis is more severe in mice with XY sex chromosome genotype than in mice with XX sex chromosome genotype (Aim 1).
In Aim 2 of this proposal, we will begin to translate the finding onto humans. Specifically, we will determine the expression of X chromosome encoded genes and seek their correlation with fibrosis in patients with SSc. Using blood and bronchoalveolar lavage (BAL), we will test the hypothesis that expression levels of an X chromosome-encoded gene, IL13RA2, in these samples will negatively correlate with the severity of SSc-ILD. The underlying rationale is that men have one copy of IL13RA2 and thus, may have lower levels of IL-13RA2 than women. Since IL-13RA2 serves as a decoy receptor for type 2 cytokines, men are likely to have higher levels of type 2 cytokines than women at the site of inflammation. Type 2 cytokines can induce the production of TGFb that can induce fibrosis. Thus, while both type 2 cytokines and TGFb can induce immune regulation and reduce the initial susceptibility for autoimmunity and inflammation, excess of these cytokines can cause dysregulated tissue repair, fibrosis and organ damage in men. The findings obtained will form the basis for further studies to establish biomarkers of accelerated SSc progression in men and to identify new targets of treatment for SSc-ILD and other diseases that are characterized by excessive fibrosis.
Scleroderma lung disease is a chronic autoimmune condition characterized by fibrosis. There are no satisfactory treatments for this disease that is associated with high morbidity and mortality. Identification of gene(s) and mechanisms that cause scleroderma lung disease would open new avenues for the development of new, diagnostic and prognostic markers as well as treatments for this and other diseases that are characterized by increased fibrosis.
|Kafaja, Suzanne; Valera, Isela; Divekar, Anagha A et al. (2018) pDCs in lung and skin fibrosis in a bleomycin-induced model and patients with systemic sclerosis. JCI Insight 3:|