IL-36 mediates immune activation in Sjögren's disease and may represent a novel biomarker of disease

Sjögren's disease (SjD) is a systemic autoimmune disease. The underlying disease mechanisms remain poorly understood, and there are no curative therapies. MyD88-mediated signaling is essential for SjD, although the pathways that rely on MyD88 are not well characterized. Our objective was to determine if MyD88-dependent IL-1 cytokines mediate inflammation in SjD. Using a SjD mouse model and patient samples, RNA sequencing was performed on salivary tissue and peripheral B cells. Splenocytes from SjD mice were stimulated with IL-36 cytokines and B cell activation was assessed. Finally, ELISAs were employed to measure IL-36 in SjD patient sera. Our data revealed that IL-1 family-associated genes were dysregulated in SjD salivary tissue. Salivary B cells showed upregulation of genes associated with MyD88 and IL-36 activation and peripheral B cells from SjD mice had dysregulated IL-1 signaling networks. Moreover, B cells from SjD mice showed enhanced activation when stimulated with IL-36 cytokines, and splenocytes derived from SjD mice exhibited elevated cytokine secretion. Finally, high levels of IL-36α and IL-36γ were present in SjD patient sera and IL-36α levels discriminated SjD patients from non-SjD control subjects. Therefore, IL-36 contributes to disease, and drugs targeting IL-1 cytokines, particularly IL-36, may represent novel therapeutic targets for SjD.