Category: 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.
Wonder Drake– Vanderbilt University School of Medicine
Ozioma Chioma– Vanderbilt University Medical Center
Natalie Hassell– Vanderbilt University
Kenny Abel– Vanderbilt University Medical Center
Lindsay Celada– Vanderbilt University Medical Center
Dawn Newcomb– Vanderbilt University School of Medicine