Elevated cytokine levels in tears and saliva of patients with primary Sjögren’s syndrome correlate with clinical ocular and oral manifestations

Abstract

Investigating cytokines in tear fluid and saliva may offer valuable information for understanding the pathogenesis of primary Sjögren’s syndrome (pSS). Cytokine profiles in both tear fluid and saliva of pSS patients, non-Sjögren’s syndrome (non-SS) subjects with sicca symptoms, and healthy controls without sicca complaints were analysed. Furthermore, relationships associating the severity of clinical ocular and oral manifestations with the upregulated cytokines were assessed. In tear fluid, pSS patients showed elevated levels of IL-1ra, IL-2, IL-4, IL-8, IL-12p70, IL-17A, IFN-γ, IP-10, MIP-1b, and Rantes compared to non-SS subjects and healthy controls. The increased cytokine levels (except IP-10) correlated significantly with reduced tear production, less stable tear film, and greater ocular surface damage. In saliva, pSS patients had a higher IP-10 level, which correlated with higher candida score; and an elevated MIP-1a level, which correlated significantly with lower unstimulated and stimulated whole saliva secretion rates. The upregulated cytokines identified in tear fluid and saliva of pSS patients show a clear interplay between innate and adaptive immune responses that may contribute to disease pathogenesis. The increase of IP-10 and MIP in both tears and saliva further emphasises the essential role of macrophages and innate immunity in pSS.

Inhibition of bone morphogenetic protein 6 receptors ameliorates Sjögren’s syndrome in mice

“…Sjögren's syndrome is often associated with a strong interferon response and IFN-γ producing Th1 cells play an important role in the initiation and development of SS in patients and animal models 4,22,[30][31][32] . A recent study reported that BMP6 upregulated interferon signaling and downregulated inhibitors of interferon signaling, suggesting a direct interacting between the BMP6 and IFN signaling 30 .…”

“…Salivary gland epithelia are reported to be involved in immune regulation as non-professional antigen presenting cells and directly produce pro-inflammatory cytokines such as IFN-γ, IL-17, IL-23 and chemokines (for review, see 31 ). As an important pro-inflammatory T cells, IFN-γ producing Th1 cells play an important role in the initiation and development of the pSS 32 . IFN-γ has been suggested as a key effector point in the inflammation and function in models of pSS 4,22 .…”

T Cells Subsets in the Immunopathology and Treatment of Sjogren’s Syndrome

“…Th1 cells have also been narrowly associated to development and disease severity, owing to their selective infiltration into target tissues, analyzed by the presence of the transcription factor T-bet and IFN-γ [ 28 ]. Alternatively, some studies have found an increased expression of predominantly Th1-cytokines, such as IL-2, IL-12, IFN-γ, and IP-10, in liquids like tears and saliva from pSS patients correlating with clinical manifestations [ 29 , 30 ]. Consistent with the underlying mechanism to shape the setting of the inflammatory and detrimental environment, IFN-γ might disrupt tight junction structure in glandular tissue from SS patients [ 31 ], indicating that the local cytokine production may contribute to the observed glandular dysfunction.…”

“…In addition, it is very well known that IFN-γ regulates the activity of certain innate immune cells, whose overactivation may further contribute to SS pathology [ 32 , 33 , 34 , 35 ]. On the other hand, TNF-α is another Th1 cytokine associated to SS development in murine model, detected at high levels in serum [ 36 ] and exhibiting enhanced expression in saliva fluid and salivary glands from SS patients [ 30 , 37 ]. Although TNF-α can be produced not only by T cells, this cytokine effectively acts on both naïve and effector T cells by regulating their proliferation and survival [ 38 ].…”

“…Furthermore, the increased expression of IL-13 cytokine has been implicated in the pathogenesis of autoimmune disease including SS, regulating several responses of other T cells [ 68 ]. In regard to IL-4, elevated levels are present in tears and salivary fluid from pSS patients, correlating with clinical parameters [ 30 , 64 ]. Nevertheless, it is necessary to elucidate the real source for this cytokine, since additional immune and no immune cells might produce it.…”