Contribution of IL-13 to early exocrinopathy in Id3−/− mice

Abstract

Id3−/− mice represent a model for T cell mediated primary Sjogren's syndrome (PSS). An intriguing feature of this disease model is the early appearance of impaired salivary function or exocrinopathy prior to lymphocytic infiltration of the salivary glands. This phenomenon prompted us to examine the role of cytokines produced by T cells in the systemic regulation of gland function. A comprehensive examination of serum cytokine profiles revealed elevated levels of IL-13 in Id3−/− mice. We found that the increase in serum IL-13 levels in Id3−/− mice was largely dependent on αβ T cells. Removal of αβ T cells in Id3−/− mice also eliminates disease symptoms, including lymphocytic infiltration in the gland tissues, and impaired saliva production. We further show that the number of mast cells in the salivary glands of Id3−/− mice is significantly increased, in a trend inversely related to the saliva production. This increase in the number of mast cells is also dependent on the presence of αβ T cells. Treatment of young Id3−/− mice with anti-IL-13 antibodies over a two-month period resulted in a reduction of both serum IL-13 levels and the number of mast cells in the salivary gland tissues, as well as correspondingly improved saliva production. These findings indicate a potentially important role for IL-13 in gland regulation and disease pathology.

Aberrant production of IL-13 by T cells promotes exocrinopathy in Id3 knockout mice

“…Previous studies regarding the contribution of T cells to SS symptoms have focused primarily on αβ T cells (Li, Dai et al 2004, Mahlios and Zhuang 2011). Given that Id3 knockout mice contain a dramatically expanded pool of Vγ1.1/Vδ6.3 T cells and that IL-13 production by γδ T cells is largely restricted to this population, we attempted to determine the contribution of γδ T cells to SS symptoms.…”

“…This finding is particularly important in light of the reported incidence of elevated IL-13 in human SS patients (Mitsias, Tzioufas et al 2002, Szodoray, Alex et al 2004). Given the previously demonstrated contribution of mast cells to disease, as well as their ability to respond to IL-13, it is possible that T cell-derived IL-13 plays a major role in the initiation of the inflammatory response in Id3 knockout mice (Mahlios and Zhuang 2011). Although our studies in animal models are promising, additional studies are needed to address whether IL-13 can be used as an early diagnostic marker or therapeutic target for SS.…”

“…Additionally, depletion of B cells in aged mice has also been shown to ameliorate SS symptoms, indicating a role for humoral immunity in the disease process (Hayakawa, Tedder et al 2007). Recent work from our lab has further demonstrated that eliminating αβ T cells is insufficient to prevent disease symptoms, although onset and progression are slowed, indicating that multiple cell types, including mast cells, are likely contributing to disease (Mahlios and Zhuang 2011). Additionally, serum analysis has shown that many mice suffering from SS produce an excessive amount of the cytokine Interleukin-13 (IL-13), an intercellular messenger involved in various inflammatory processes, notably allergic reactions (Humbert, Durham et al 1997, Grünig, Warnock et al 1998, Walter, McIntire et al 2001).…”

“…IL-13 is normally produced by mature lymphocytes that have been activated by some antigenic stimulation as well as innate and innate-like lymphocytes (McKenzie, Culpepper et al 1993, Voehringer, Reese et al 2006, Price, Liang et al 2010). Furthermore, neutralization of IL-13 in mice already suffering from gland impairment was sufficient to improve gland function, indicating a critical role for IL-13 in SS (Mahlios and Zhuang 2011). While the pathology of autoimmune disease has been well studied in human patients, little is known about the early, pre-clinical phases of most autoimmune diseases, including SS.…”

B7‐H4 deficiency in salivary gland of patients with primary Sjögren's syndrome impairs the regulatory effect on T cells

“…23 Also, the increase of IL-13 has been reported in human SS patients. 24 Furthermore, it has been reported in mice that neutralization of IL-13 in mice already suffering from gland impairment was sufficient to improve gland function 25 and the subsequent study proved that elevated levels of IL-13 are due to aberrant production of IL-13 by T cells, indicating a critical role for IL-13 in SS. 26 Therefore, the reduced expression of B7-H4 in salivary gland tissues may contribute to autoantibody production by accelerating B cell differentiation with reduction of IL-13 and IL-5, another mechanism related to the pathogenesis of pSS.…”