Objective.: To address the clinical, serologic, pathologic, and immunogenetic features of sicca syndrome that occurs in systemic lupus erythematosus (SLE), as well as its similarities to, and differences from, sicca syndrome that occurs in primary Sjögren's syndrome (SS).Methods.: A cohort of 283 consecutive unselected SLE patients was evaluated for the presence of associated SS using the American–European classification criteria. Clinical and laboratory parameters in SLE patients with SS (SLE–SS) were compared with those in SLE patients without SS (SLE–no SS) and with a group of 86 unselected patients with primary SS.Results.: SS was identified in 26 SLE patients (9.2%); the SS preceded the development of lupus in 18 of them (69.2%). Compared with the SLE–no SS group, patients with SLE–SS were significantly older, had a higher frequency of Raynaud's phenomenon, anti‐Ro/SSA, anti‐La/SSB, and rheumatoid factor, but had a significantly lower frequency of renal involvement, lymphadenopathy, and thrombocytopenia. Compared with the primary SS group, SLE–SS patients displayed a clinically similar sicca syndrome, but were significantly younger and had an increased frequency of perivascular infiltrates in the salivary glands associated with anticardiolipin antibodies in the serum. SLE–SS patients had a high frequency of the DRB1*0301 allele. This HLA profile distinguished the SLE–SS group from the SLE–no SS group, who had an increased frequency of DRB1*1501 and DQB1*0602 alleles, but was similar to the HLA profile of the primary SS group, who had an increased frequency of DRB1*0301.Conclusion.: SLE–SS appears to constitute a subgroup of patients with distinct clinical, serologic, pathologic, and immunogenetic features, in whom SS is expressed as an overlapping entity and is largely similar to primary SS.

Objective: Exosomes are membrane vesicles of endosomal origin that are distinct from apoptotic bodies and are thought to represent an acellular mechanism for antigen transfer to classic antigen‐presenting cells, as well as for direct antigen presentation with the capacity to induce immune response or tolerance. Nevertheless, it is not known whether exosomes are involved in the induction or regulation of immune responses against intracellular autoantigens that characterize autoimmune diseases. Exosomes have been shown to be secreted by several types of cells, whereas studies of non‐neoplastic epithelial cells are lacking. This study was undertaken to investigate the capacity of non‐neoplastic salivary gland epithelial cells (SGECs) to release exosomes, and to determine whether epithelial exosomes contain RNPs, which are major autoantigens in systemic rheumatic diseases.Methods: Exosomes were isolated by ultracentrifugation from culture supernatants of 26 non‐neoplastic SGEC lines established from patients with various rheumatic disorders. They were analyzed by electron microscopy, immunoblotting, or immunoprecipitation.Results: All SGEC lines were found to release comparable and significant amounts of exosomes. Similar to other cell systems, exosome secretion was constitutive and was unrelated to activation or apoptotic processes. SGEC‐derived exosomes were found to contain the autoantigenic Ro/SSA, La/SSB, and Sm RNPs, as well as epithelial‐specific cytokeratins.Conclusion: SGECs constitutively secrete exosomes that contain the major autoantigens Ro/SSA, La/SSB, and Sm. This mechanism may represent a pathway whereby intracellular autoantigens are presented to the immune system with an immunogenic or tolerogenic outcome.

Objective: To evaluate the expression profile of infiltrating macrophages and dendritic cells (DCs) as well as of interleukin‐18 (IL‐18) and IL‐12 in the minor salivary gland (MSG) lesions of patients with Sjögren's syndrome (SS), and to assess the relationship of these factors with disease parameters.Methods: Macrophages, DCs, T cells, B cells, proIL‐18, mature IL‐18, and IL‐12 were detected by single‐ and double‐labeling immunohistochemistry in MSG specimens from 21 patients with primary SS (13 of 21 tested for IL‐12), 7 patients with secondary SS, and 9 disease control patients. Expression profiles were assessed for correlations with various disease parameters, including adverse predictors of lymphoma development.Results: MSGs from patients with SS (but not from disease controls) manifested increased infiltration by macrophages and DCs, strong expression of IL‐18 by macrophages (particularly in B cell–rich areas and in germinal center–like structures in primary SS), and expression of IL‐12 by mononuclear cell infiltrates. In primary SS, high infiltration by macrophages correlated with SG enlargement (P = 0.01). The DC infiltration rate correlated positively with the macrophage infiltration rate (P = 0.04), occurrence of SG enlargement (P = 0.03), and presence of C4 hypocomplementemia (P = 0.05), and inversely with serum C4 complement levels (P = 0.001). The rate of infiltration by IL‐18–expressing cells correlated positively with biopsy focus scores (P < 0.001), larger infiltrates of macrophages (P = 0.01), DCs (P = 0.01), and B cells (P = 0.02), and SG enlargement (P = 0.02), and negatively with serum C4 complement levels (P = 0.02). The rate of infiltration by IL‐12–expressing cells correlated inversely with that by IL‐18–expressing cells (P = 0.001), biopsy focus scores (P = 0.003), and SG enlargement (P = 0.01), and positively with serum C4 complement levels (P = 0.05).Conclusion: In patients with primary SS, infiltration of the SG by macrophages and DCs and expression of IL‐18 and IL‐12 appear to play active roles in the expansion and organization of infiltrative injuries and have a correlation with certain predictors of lymphoma development.

Toll-like receptors (TLR) play an essential role in the activation of both innate and adaptive immune responses. Salivary gland epithelial cells (SGEC) may participate in the development of glandular inflammatory reactions that characterize primary Sjögren's syndrome (pSS). In this study we sought to assess the expression and function of several TLR molecules in cultured non-neoplastic SGEC obtained from pSS patients and disease controls. Long-term cultured non-neoplastic SGEC derived from pSS patients (SS-SGEC) and disease controls (control-SGEC), as well as the monocytic cell line THP-1 (positive control cell line), were examined by reverse transcription–polymerase chain reaction (RT–PCR) analysis and quantitative real-time PCR for mRNA expression of TLR1, -2, -3 and -4 molecules. TLR function was assessed by the induction of the expression (flow cytometry) of the immunoregulatory molecules CD54/intercellular adhesion molecule-1 (ICAM-1), CD40, CD86/B7·2, major histocompatibility complex (MHC) class I and MHC class II following treatment with the TLR ligands: Staphylococcus aureus peptidoglycan (TLR2), the synthetic dsRNA analogue polyinosinic:cytidylic acid (TLR3) and Escherichia coli lipopolysaccharide (TLR4). SGEC were found to express functional TLR2, -3 and -4 molecules, as attested by dose-dependent up-regulation of surface ICAM-1, CD40 and MHC-I expression (as well as of reciprocal TLR mRNA) following treatment with the respective TLR-ligands. SS-SGEC lines displayed significantly higher constitutive expression of TLR1 (P = 0·0027), TLR2 (P = 0·01) and TLR4 (P = 0·03) mRNA compared to control-SGEC. This study demonstrates that cultured SGEC express functional TLR molecules; the high constitutive TLR expression by SS-SGEC is probably suggestive of the intrinsic activation of epithelial cells in pSS and further supports the role of this type of tissue in pathogenesis of the disorder.