Autoimmune rheumatologic diseases
Background: Prior reports noted the profibrotic properties of the PD-1 pathway signaling in patients with autoimmune interstitial lung disease, such as pulmonary sarcoidosis and rheumatic lung disease. Both are notable for female predominance of disease, invoking the notion of estrogen- mediated pulmonary fibrosis.
Methods: We assessed for baseline distinctions in sarcoidosis patients with pulmonary progression by gender. Concurrently with these analyses, we used the bleomycin-induced pulmonary fibrosis in C57BL/6 mice and assessed for distinctions in pulmonary fibrosis and pSTAT3 signaling, according to gender.
Results: We noted significantly higher percentages of systemic PD-1+CD4+ T cells in the sarcoidosis females, compared to males. This gender distinction was absent in healthy control subjects. Pulmonary-derived PD-1+CD4+ T cells were also distinct by gender in C57BL/6 mice following bleomycin administration. Bleomycin administration to PD-1 null mice revealed significantly less pulmonary fibrosis among female mice, compared to males. Administration of anti-PD-L1 antibody following bleomycin administration also revealed significantly less weight loss and pulmonary fibrosis among the females, compared to males. Investigation for relevant mechanisms demonstrated distinctions in phospho-STAT3 expression in females compared to males. In addition, isolated naïve CD4+ T cells from wild-type and estrogen receptor-α deficient (ESR1-/-) mice revealed significant reductions in IL-17A production and IL-23 receptor expression following anti-CD3/anti-CD28 stimulation. Disparate IL-23R expression by gender was noted in PD-1 null mice following bleomycin administration.
Conclusion: Estrogen induction of profibrotic IL-17A production involves mechanisms dependent and independent of PD-1 pathway signaling.