A Dual Role for Interferon‐γ in the Pathogenesis of Sjögren's Syndrome‐Like Autoimmune Exocrinopathy in the Nonobese Diabetic Mouse

Abstract

Sjögren's syndrome-like autoimmune exocrinopathy (AEC) in the nonobese diabetic (NOD) mouse progresses from a preimmune phase to an immune phase, resulting in dry mouth and/or dry eyes. In the present study, the impact of the prototypical T-helper type 1 cytokine, interferon-gamma (IFN-g), on the onset of AEC was investigated using both the IFN-g and the IFN-g receptor gene knockout mice, NOD.IFN-g -/-and NOD.IFN-gR -/-, respectively. Neither the NOD.IFN-g -/-nor the NOD.IFN-gR -/-mice exhibited increased acinar cell apoptosis and abnormal salivary protein expression, typically observed in parental NOD mice prior to disease. Without these preimmune phase abnormalities, NOD.IFN-g -/-and NOD.IFN-gR -/-mice showed no subsequent autoimmune responses against the salivary glands at 20 weeks. Interestingly, real-time polymerase chain reaction and electrophoretic gel mobility shift assays suggested that IFNg and STAT1, as well as the transcriptional activity of STAT1 in NOD glands, were increased at birth. Unlike the neonatal submandibular glands of NOD or NOD-scid mice that show abnormal glandular morphogenesis at birth, the submandibular glands of the newly constructed congenic strain, NOD-scid.IFN-g -/-, were found to be normal. Taken together, IFN-g appears to play a critical role not only during the later immune phase of AEC, but also the early preimmune phase, independent of effector functions of immune cells. How exactly IFN-g functions during this period remains speculative.

Salivary gland tissue expression of interleukin‐23 and interleukin‐17 in Sjögren's syndrome: Findings in humans and mice

“…This observation is consistent with previous studies by our group showing high levels of IFN␥ production at this early age (40). Thus, our data are consistent with the concept that there is an early induction of a CD4ϩ Th1/Th17 pathway leading to systemic release of IL-17.…”

“…These data raise several important questions, including the question of when Th17 cells become involved in the autoimmune response and whether they act directly through secretion of inflammatory IL-17 family cytokines or by activating autoimmune T and B cells. If Th17 cells act in SS as reported in EAE, then IL-17 may not be required for initiation of SS, but it still represents a critical regulator of Th1 cells and their production of IFN␥ (41), again consistent with our group's data from the study of Ifng gene-knockout mice (40). In any event, the IL-23/CD4ϩ Th17/IL-17R system appears to bridge aspects of the innate and adaptive immune responses.…”

“…In previous studies by our group, elimination of IFN␥ in SS-susceptible mice ameliorated all pathologic and clinical signs of disease, while elimination of IL-4 prevented loss of secretory function (40,43). These observations indicate an essential role for both Th1 celland Th2 cell-associated cytokines.…”

Spontaneous Autoimmune Dacryoadenitis in Aged CD25KO Mice

“…27 Both NOD.IFN-␥ Ϫ/Ϫ and NOD.IFN-␥R Ϫ/Ϫ mice failed to undergo lymphocytic infiltration of the salivary gland, and retained normal secretory function. 41 Increased levels of IFN-␥ have also been found to up-regulate epithelial expression of Fas and caspase-8, thus potentiating the apoptotic pathway. 8 Additionally, a recent study characterizing a transgenic mouse model of SS overexpressing IL-12, the chief stimulator of the Th-1 axis and subsequent IFN-␥ production, detected focal lymphocytic infiltration of the salivary glands, LG, and the lungs, mimicking a SS phenotype.…”

“…41 Recent investigations focusing on the Th-17 pathway have detected an upregulation of this family in salivary glands of SS patients and NOD mice. 26,27 To characterize the T-helper phenotype associated with the dacryoadenitis observed in CD25KO mice levels of mRNA transcript encoding MMP-9, Th-1-, Th-2-, and Th-17-associated genes were evaluated using real-time PCR.…”