Pathogenic effect of interleukin-17A in induction of Sjögren's syndrome-like disease using adenovirus-mediated gene transfer

Abstract

IntroductionSjögren's syndrome (SS) involves a chronic, progressive inflammation primarily of the salivary and lacrimal glands leading to decreased levels of saliva and tears resulting in dry mouth and dry eye diseases. Seminal findings regarding TH17 cell populations that secrete predominantly interleukin (IL)-17A have been shown to play an important role in an increasing number of autoimmune diseases, including SS. In the present study, we investigated the function of IL-17A on the development and onset of SS.MethodsAdenovirus serotype 5 (Ad5) vectors expressing either IL-17A or LacZ were infused via retrograde cannulation into the salivary glands of C57BL/6J mice between 6 and 8 weeks of age or between 15 and 17 weeks of age. The mice were characterized for SS phenotypes.ResultsDisease profiling indicated that SS-non-susceptible C57BL/6J mice whose salivary glands received the Ad5-IL17A vector developed a SS-like disease profile, including the appearance of lymphocytic foci, increased cytokine levels, changes in antinuclear antibody profiles, and temporal loss of saliva flow.ConclusionsInduction of SS pathology by IL-17A in SS-non-susceptible mice strongly suggests that IL-17A is an important inflammatory cytokine in salivary gland dysfunction. Thus, localized anti-IL17 therapy may be effective in preventing glandular dysfunction.

A Crucial Role of RORγt in the Development of Spontaneous Sialadenitis-like Sjögren’s Syndrome

“…The results provide evidence for the role of RORgt overexpression in CD4 + T cells in the development of spontaneous sialadenitis-like SS through downregulation of CD4 + CD25 + Foxp3 + Treg cells. Experimental evidence suggests that IL-17 produced from CD4 + T cells is directly involved in the onset of SS-like disease (11,22). However, we demonstrated in the present study the development of sialadenitis in IL-17-deficient RORgt Tg mice, indicating that IL-17 is not essential for the development of sialadenitis in RORgt Tg mice.…”

Th17 cells in autoimmune diseases

“…Adoptive transfer of Th17 cells into the inducible IL-17A KO mice could rapidly acquire a SS profile [61]. C57BL/6J mice that receive adenovirus serotype 5 (Ad5) -IL17A vector, an SS model, express high levels of IL-17A, which correlates with recruitment of inflammatory cells [62]. In patients with Sjögren's syndrome, both systematically elevated levels of IL-17 [63,64] and presence of Th17 cells [65][66][67] in inflamed tissue have been observed in multiple studies.…”

Interleukin (IL)-17-producing pathogenic T lymphocytes co-express CD20 and are depleted by rituximab in primary Sjögren's syndrome: a pilot study

“…Although the pathogenesis of pSS is not clarified completely, it is well established that an aberrant autoimmune response with T and B lymphocyte hyperactivity and autoantibody production represents the crucial mechanism for the induction of autoimmune epithelitis and the perpetuation of inflammation. Moreover, several lines of evidence in animal models and pSS patients suggest that the proinflammatory cytokine interleukin (IL)-17 and, therefore, IL-17-producing T helper cells (Th17) play a pivotal role in the induction and perpetuation of chronic inflammation occurring in this disease [5][6][7]. We have previously demonstrated that besides CD3 1 CD4 1 T helper type 17 (Th17) cells, a small CD3 1 T cell subset lacking both CD4 and CD8 on the cell surface (double-negative, DN), is expanded in the peripheral blood (PB), infiltrates minor salivary glands (MSGs) of patients with pSS and produces IL-17 spontaneously [8].…”