Abstract
IntroductionSjögren's syndrome (SjS) is a systemic autoimmune disease characterized by decreased salivary and lacrimal gland secretions, resulting in severe dry mouth and dry eyes. Recent studies have suggested that TH17 cells and its signature cytokine IL-17 are involved in the underlying pathogenic mechanisms leading to destructive inflammation and autoimmunity. In the present study, we examined whether IL-27, a natural inhibitor of TH17 activity, could down-regulate or reverse SjS in C57BL/6.NOD-Aec1Aec2 mice, a model of primary-SjS.MethodsRecombinant serotype 2 adeno-associated viral (AAV2) vectors expressing either IL-27 (rAAV2-IL27) or LacZ (rAAV2-LacZ) were injected into 6 or 14 week-old C57BL/6.NOD-Aec1Aec2 mice. Changes in IL-27, IL-17, and IL-10 cytokine levels in peripheral blood were determined by ELISAs, while flow cytometry analyses were used to quantify cytokine-positive splenocytes. Histological assessment of salivary glands, anti-nuclear autoantibody (ANA) staining, and stimulated saliva flow rates were used to profile SjS disease severity.ResultsMice systemically treated with intravenous rAAV2-IL27 injections at either 6 or 14 weeks of age exhibited long-term elevated levels of serum IL-27 with concomitantly reduced levels of IL-17 compared with sera from mice injected with rAAV2-LacZ or saline out to 20 weeks post-inoculation. Most importantly, disease profiles revealed that rAAV2-IL27 treatment had little effect on lymphocytic focus (LF) scores, but resulted in structural changes in LF, lower titers of ANAs with changes in staining patterns, and a less severe clinical disease as determined by saliva flow rates.ConclusionsThese data support the concept that IL-27, when provided exogenously, can induce a suppressive effect on SjS development and thus may be an effective therapeutic agent for regulating TH17 pro-inflammatory activity in autoimmune diseases where the TH17 system has been shown to play an important role in their pathogenesis.
Highlights
Sjögren’s syndrome (SjS) is a systemic autoimmune disease characterized by decreased salivary and lacrimal gland secretions, resulting in severe dry mouth and dry eyes
To fully recapitulate the functionality of mouse Interleukin 27 (IL-27) cytokine, a recombinant AAV2 (rAAV2)-IL27 vector was constructed by inserting the genes encoding the two subunits of IL-27 (Ebi3 and p28) into a pTR-UF14 vector
Analysis of the cell lysates and culture media indicated that Epstein-Barr virus-induced gene 3 (Ebi3) expression was highly increased in rAAV2-IL27 transfected cells
Summary
Sjögren’s syndrome (SjS) is a systemic autoimmune disease characterized by decreased salivary and lacrimal gland secretions, resulting in severe dry mouth and dry eyes. Recent studies have suggested that TH17 cells and its signature cytokine IL-17 are involved in the underlying pathogenic mechanisms leading to destructive inflammation and autoimmunity. Interleukin 27 (IL-27), along with IL-12, IL-23, and IL-35, is a novel cytokine of the IL-6/IL-12 family. It is composed of two subunits: IL-12p40-related Epstein-Barr virus-induced gene 3 (Ebi3) protein and IL-12p35-related p28 protein (p28) [1]. IL-27 activates T helper 1 (TH1) responses in the early phases of immunity, in which studies confirmed that IL-27 has anti-tumor effects [7,9]. More recent reports have described the capacity of IL-27 to suppress TH17 cells by inhibiting TH17 cell differentiation, thereby reducing severity of TH17mediated autoimmune diseases [11,12]
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