Increased circulating levels and salivary gland expression of interleukin-18 in patients with Sjögren's syndrome: relationship with autoantibody production and lymphoid organization of the periductal inflammatory infiltrate

Abstract

IL-18, an immunoregulatory and proinflammatory cytokine, has been shown to play an important pathogenic role in Th1-driven autoimmune disorders. In this study, we evaluated the circulating levels and salivary-gland expression of IL-18 in patients with Sjögren's syndrome (SS), a mainly Th1-mediated disease. IL-18 serum levels were measured by ELISA in 37 patients with primary SS, 42 with rheumatoid arthritis, and 21 normal controls. We demonstrated high IL-18 serum levels in SS, similar to those in rheumatoid arthritis patients and significantly higher than in controls (P < 0.01). In addition, IL-18 serum concentrations were significantly higher in anti-SSA/Ro + and anti-SSB/La + than in anti-SSA/Ro -and anti-SSB/La -SS patients (respectively, P = 0.01, P < 0.01). Serum IL-18 correlated strongly with anti-SSA/Ro (P = 0.004) and anti-SSB/ La (P = 0.01) titers. Salivary gland IL-18 expression was investigated by single/double immunohistochemistry in 13 patients with primary SS and in 10 with chronic sialoadenitis, used as controls. The expression of IL-18 was also examined in periductal inflammatory foci in relation to the acquisition of features of secondary lymphoid organs such as T-B compartmentalization, formation of follicular dendritic cell networks, and presence of germinal-center-like structures. IL-18 expression in SS salivary glands was detected in 28 of 32 periductal foci of mononuclear cells (87.5%), while no IL-18 production by infiltrating cells was detected in patients with chronic sialoadenitis. Within the inflammatory foci, IL-18 immunoreactivity co-localized almost exclusively with CD68 + macrophages. In addition, IL-18 was found in 15 of 19 foci (78.9%) with no evidence of T-B cell compartmentalization (nonsegregated) but in 100% of the segregated aggregates, both in T-and B-cell-rich areas. Strikingly, IL-18 was strongly expressed by CD68 + tingible body macrophages in germinalcentre-like structures both in SS salivary glands and in normal lymph nodes. IL-18 expression was observed in the ducts of all SS biopsies but in only 4 of 10 patients with nonspecific chronic sialoadenitis (P < 0.01). This study provides the first evidence of increased circulating levels and salivary gland expression of IL-18 in SS, suggesting an important contribution of this cytokine to the modulation of immune inflammatory pathways in this condition.

The Role of Epithelial Cells in the Pathogenesis of Sjögren’s Syndrome

“…Ductal epithelial cells of SS patients have been also reported to express in situ high levels of IL-12 [20] and mature-type IL-18 [21], although these findings were not corroborated by another study. In addition, the expression of several T-cell-attracting and germinal-center-forming chemokines has been detected in ductal epithelia, including CCL3/MIP1a, CCL4/MIP-1b, IL-8 and CCL5/RANTES [22], STCP-1/ MDC, CXCL-9/Mig, CXCL-10/IP-10, CXCL12/SDF-1, CCL17/TARC, CXCL13/BCA-1, and CCL19/ELC and CCL21/SLC/TCA [23][24][25][26][27].…”

T Lymphocytes in Sjögren’s Syndrome: Contributors to and Regulators of Pathophysiology

“…IL-12 supplied by APC and/or IL-18 and possibly IL-21 cooperate to promote IFNg production by activated T cells [66]. Increased concentrations of IFNg contribute to the upregulation of HLA class II [65] and costimulatory molecules [19] on epithelial cells and APC.…”

Anti-cyclic citrullinated peptide and rheumatoid factor in patients with chronic hepatitis B and hepatitis B carriers

“…For example, Lienesch et al (17) and Orge et al (18) found no increase in anti-CCP in non-arthritic patients with chronic HCV infection. Similarly Bombardieri et al (19) examined RF and anti-CCP in patients with chronic HCV infection and found RF positivity in 37% of the patients vs. no patients with anti-CCP positivity.…”