Interleukin‐25 Axis Is Involved in the Pathogenesis of Human Primary and Experimental Murine Sjögren's Syndrome

Objective To investigate the role of the interleukin‐25 ( IL ‐25)/ IL ‐17 receptor B ( IL ‐17 RB ) axis in experimental Sjögren's syndrome ( SS ) and in patients with primary SS and primary SS –associated lymphoma. Methods Expression of IL ‐25, IL ‐17 RB , IL ‐17B, and tumor necrosis factor receptor–associated factor 6 ( TRAF 6) was analyzed on minor salivary gland ( SG ) samples from patients with primary SS and on parotid gland samples from patients with primary SS –associated B cell non‐Hodgkin's lymphoma ( NHL ). IL ‐17 RB expression and the frequencies of natural group 2 innate lymphoid cells ( ILC 2s), inflammatory ILC 2s, and M2‐polarized macrophages were assessed by flow cytometry in SG mononuclear cells and peripheral blood mononuclear cells ( PBMC s). Tissue distribution of ILC 2s was studied by confocal microscopy. The role of recombinant IL ‐25 and of rituximab in modulating IL ‐25 expression was investigated in in vitro studies. IL ‐25/ IL ‐17 RB and TRAF 6 expression and the role of IL ‐25 inhibition were also studied in the experimental murine model of SS . Results Activation of the IL ‐25/ IL ‐17 RB / TRAF 6 axis correlated with the focus score and was observed in patients with primary SS and in patients with primary SS –associated NHL . A significant increase in the frequency of inflammatory ILC 2s was observed both in SG mononuclear cells and in PBMC s. IL ‐25 stimulation of isolated SG mononuclear cells and PBMC s from patients and controls resulted both in inflammatory ILC 2 expansion and in increased autoantibody production. Rituximab modulated expression of inflammatory ILC 2s and IL ‐25 in primary SS . SG protein–immunized mice developed overt SS symptoms with increased IL ‐25 expression and increased frequency of CD 4+ IL ‐17 RB + TRAF 6+ cells. IL ‐25 neutralization attenuated disease progression and tissue pathology in mice with experimental SS . Conclusion IL ‐25 may promote the inflammatory state in primary SS and may be a potential target for novel disease‐modifying therapeutic strategies in patients with primary SS .