Type I Interferon Receptor Deficiency Prevents Murine Sjögren’s Syndrome

Abstract

In Sjögren's Syndrome (SS), inherent glandular defects, autoimmunity, and mononuclear cell infiltration within the salivary glands cause reduced salivation leading to xerostomia. Excessive production of type I interferons (IFN), triggered by environmental and genetic factors, is considered pathogenic in this disorder. However, whether type I IFN production is causative or an outcome of the disease process is not known. To address this question, we introduced a deficiency of interferon alpha receptor 1 (Ifnar1) into B6.Aec1Aec2 mice, which are known to have the genetic loci necessary for developing a SS-like disorder. This new mouse strain, B6.Aec1Aec2Ifnar1 -/-, lacking type I IFN-mediated signaling, was characterized for pilocarpine-induced salivation, the presence of serum autoantibodies, sialoadenitis, and dacryoadenitis. Compared with the B6.Aec1Aec2Ifnar1 +/+ (wild-type) mice, the B6.Aec1Aec2Ifnar1 -/-(knockout) mice had significantly lower mononuclear cell infiltration in the salivary and lacrimal glands. The knockout mice were completely protected from salivary gland dysfunction. Surprisingly, they had a robust autoantibody response comparable with that of the wild-type mice. These findings demonstrate that, in the absence of type I IFN-mediated signaling, systemic autoantibody responses can be dissociated from glandular pathology. Our study suggests that, in genetically susceptible individuals, the type I IFN pathway can instigate certain features of SS.

Multiple Roles for B-Lymphocytes in Sjogren’s Syndrome

“…Similarly, elimination of the type 1 interferon receptor, or interferon itself, was shown to eliminate multiple features of SS, supporting the notion promoted in human studies on SS that type 1 interferon is a major driver of disease pathogenesis in SS [50,51,52,53]. …”

Myd88 is required for disease development in a primary Sjögren's syndrome mouse model

“…Historically, adaptive immune dysfunction was thought to be the prime driver of SS, although more recent studies show that the innate immune system is equally crucial in mediating disease [34]. Accordingly, work in many different SS mouse models demonstrates an important role for innate immune activation in disease pathogenesis [35][36][37][38][39][40][41][42][43][44][45][46][47][48]. For example, the IL-14a-transgenic pSS model has increased lymphotoxin a in the salivary tissue, even before the arrival of lymphocytes in the gland [43].…”

“…The importance of Myd88independent pathways in SS disease is illustrated further by studies in Ifnar1-deficient animals. To generate these animals, the well-established pSS model, B6.Aec1Aec2, was bred to Ifnar1 2/2 mice [40,64]. The resultant strain, termed B6.…”

Flagellar filament structural protein induces Sjögren's syndrome‐like sialadenitis in mice

“…IFN-c also has been documented to have a distinct role in the pathogenesis of SS (Ogawa et al, 2002;Nezos et al, 2015). In an experimental model, IFNR1 KO NOD mice did not demonstrate either hyposalivation or lymphocytic foci (Szczerba et al, 2013). Our mouse model showed elevated serum IFN-c levels, suggesting that repeated FliC inoculation evoked systemic inflammation and led to elevation of serum IFN-c levels.…”