title: 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 germinal-centre-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.
authors.affiliation: Rheumatology Department, GKT School of Medicine, King's College London, UK. pikler@tin.it <pikler@tin.it>
authors.forename: Michele
authors.initials: M
authors.lastname: Bombardieri
authors.forename: Francesca
authors.initials: F
authors.lastname: Barone
authors.forename: Valerio
authors.initials: V
authors.lastname: Pittoni
authors.forename: Cristiano
authors.initials: C
authors.lastname: Alessandri
authors.forename: Paola
authors.initials: P
authors.lastname: Conigliaro
authors.forename: Mark C
authors.initials: MC
authors.lastname: Blades
authors.forename: Roberta
authors.initials: R
authors.lastname: Priori
authors.forename: Iain B
authors.initials: IB
authors.lastname: McInnes
authors.forename: Guido
authors.initials: G
authors.lastname: Valesini
authors.forename: Costantino
authors.initials: C
authors.lastname: Pitzalis
mesh_terms: D000328:Adult; D000368:Aged; D001323:Autoantibodies / Q000096:biosynthesis*; D045744:Cell Line, Tumor; D002634:Chemotaxis, Leukocyte; D002908:Chronic Disease; D004847:Epithelial Cells / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007249:Inflammation / Q000378:metabolism; D020382:Interleukin-18 / Q000096:biosynthesis* / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism; D008208:Lymphatic System / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009928:Organ Specificity / Q000235:genetics; D012469:Salivary Glands / Q000378:metabolism* / Q000473:pathology; D012793:Sialadenitis / Q000097:blood / Q000473:pathology; D012859:Sjogren's Syndrome / Q000097:blood* / Q000473:pathology; D018417:Th1 Cells / Q000378:metabolism*
chemical_list: D001323:Autoantibodies; D020382:Interleukin-18