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Background: Networks formed of numerous autoantibodies (aabs) directed against G-protein coupled receptors (GPCR) have been suggested to play important role in autoimmune disorders. In present study, we aimed to evaluate the association between anti-GPCR antibodies and primary Sjogren's syndrome (pSS) to determine the potential pathogenic factors., Methods: By applying a cell membrane-based ELISA technique, which is capable of detecting aabs against conformational epitopes within GPCR, serum levels of fourteen GPCR were determined in well-characterized patients with pSS (n = 52) and gender-matched healthy controls (n = 54). Comparisons between groups were analyzed by two-tailed Mann-Whitney U test, Bonferroni correction was applied for multiple comparisons. Spearman`s rank correlation coefficients were calculated between variables and visualized by heat map., Results: Compared to healthy subjects, sera of patients with pSS showed significantly higher binding to β2AR and ETAR, but lower binding to C5aR1, C3aR1, CXCR3, and CXCR4. Autoantibodies against C5aR1, C3aR1, CXCR3, and CXCR4 were also decreased in patients with rheumatoid arthritis. In pSS patients, levels of anti-CXCR3 and anti-CXCR4 antibodies were negatively correlated with circulating lymphocyte counts. Furthermore, correlation signatures of anti-GPCR antibodies changed dramatically in the patients with pulmonary involvement., Conclusions: This study demonstrates an association between pSS and autoantibodies recognizing GPCR, especially those functionally involved in immune cell migration and exocrine glandular secretion., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The lacrimal gland is critical for maintaining the homeostasis of the ocular surface microenvironment through secreting aqueous tears in mammals. Many systemic diseases such as Sjögren syndrome, rheumatoid arthritis, and diabetes can alter the lacrimal gland function, eventually resulting in aqueous tear-deficient dry eye. Here, a high-fat diet (HFD) experimental mouse model was used to clarify how hyperlipidemia affects lacrimal gland function. Aqueous tear secretion fell about 50% after 1 month on a HFD. Lipid droplets accumulated in the matrix and acinar cells of the lacrimal gland after this period, along with changes in the lipid metabolism, changes in gene expression levels, and disruption of fatty acid oxidative activity. Immune cell infiltration and rises in the gene expression levels of the inflammation-related cytokines Il1β, Tnfα, Tsg6, Il10, Mmp2, and Mmp9 were found. HFD also induced mitochondrial hypermegasoma, increased apoptosis, and decreased lacrimal gland acinar cell proliferation. Replacement of the HFD with the standard diet partially reversed pathologic changes in the lacrimal gland. Similarly, supplementing the HFD with fenofibrate also partially reversed the inhibited tear secretion and reduced lipid accumulation, inflammation, and oxidative stress levels. The authors conclude that a HFD induces pathophysiological changes and functional decompensation of the lacrimal gland. Therefore, ingestion of a HFD may be a causative factor of dry eye disease., (Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the expression pattern of nucleotide-binding oligomerization domain (Nod)-like receptors that detects "danger" intracellular signaling and its correlation with clinical dry eye (DE) markers., Design: Cross-sectional study., Methods: A total of 50 participants with 50 eyes were included: 23 eyes with Sjögren syndrome (SS)-DE, 14 eyes with non-SS-DE, and 13 healthy controls with non-DE. Ocular Surface Disease Index (OSDI) was self-answered and clinical tests including the tear film breakup time (TBUT), Schirmer test, and corneal fluorescein staining (CFS) were performed. Specimens for expression pattern analysis were obtained by conjunctival impression cytology and biopsy. Nod-1, inhibitor kappa B kinase-alpha (IκKα), and nuclear factor kappa B (NF-κB) expression was determined by reverse transcription quantitative real-time polymerase chain reaction and Western blot. Correlations between Nod-1 and ocular surface parameters were determined., Results: Patients with SS-DE had significantly higher OSDI and CFS scores and lower TBUT and Schirmer test scores than those with non-SS-DE patients (all P < .05). Compared with the control group, both the SS-DE and non-SS-DE groups showed significant upregulation in mRNA expression levels of Nod-1 (relative 3.48-fold and 1.72-fold upregulation, respectively, P < .01), IκKα (relative 1.83-fold and 1.24-fold upregulation, respectively, P < .01), and NF-κB (relative 1.84-fold and 1.32-fold upregulation, respectively, P < .01). Western blot analysis showed that Nod-1 protein expression increased in both the SS-DE and non-SS-DE groups (relative 2.71-fold and 1.64-fold upregulation, respectively, P < .05) compared with that in the control group. Similar findings were observed for IκKα and NF-κB. In DE participants, the expression of Nod-1 significantly correlated with the OSDI (R 2  = 0.61, r = 0.78, P < .01), Schirmer test score (R 2  = 0.44, r = -0.66, P < .01), and CFS (R 2  = 0.46, r = 0.68, P < .01) but did not significantly correlate with TBUT (R 2 < 0.01, r = 0.08, P = .66)., Conclusions: Nod-1 expression was increased in the conjunctiva of DE, especially SS-DE, and was associated with disease severity. Expression of Nod-like receptors might play an important role in initiating the inflammatory response in DE., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Aim: Primary Sjögren's syndrome (pSS) is an autoimmune disease affecting exocrine glands. Both autoreactive T cells and B cells are involved in the development of pSS, but their exact contribution to the pathogenesis is not clear. Here, we aimed to investigate the association of B-cell activating factor (BAFF) and interleukin (IL)-17A with subphenotypes of pSS., Methods: Peripheral blood samples were collected from 31 pSS patients and 28 healthy controls. The serum levels of BAFF and IL-17A were quantified by sandwich ELISA., Results: The increased circulating BAFF levels are associated with higher immunoglobulin G (IgG) levels (P = 0.0167) and anti-Ro/SS antigen A autoantibody (P = 0.032), while the elevated circulating levels of IL-17A are associated with lower C3 levels (P = 0.0213) and higher focus score of salivary gland tissue (P = 0.002)., Conclusion: Our results show that BAFF and IL-17A are associated with different subphenotypes of pSS, suggesting both humoral and cellular immune response are involved in the pathogenesis of pSS., (© 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.)

Objectives: Anti-muscarinic acetylcholine type-3 receptor (anti-M3R) autoantibodies have been suggested to be pathogenic for primary Sjögren's syndrome (pSS), and the second extracellular loop of M3R is suspected to carry a disease-promoting epitope. In this study, we aimed to evaluate the pathogenicity of autoantibodies against peptides derived from the second extracellular loop of M3R in mice and to determine whether those autoantibodies could be used as biomarker for pSS., Methods: BALB/c mice were immunized with modified linear or cyclic peptides of the second extracellular loop of M3R. The function of exocrine glands was evaluated by measuring the secretion of saliva and tears. The histological evaluations were performed by using H&E staining or direct immunofluorescence staining. Autoantibodies against linear or cyclic peptides of the second extracellular loop of M3R in human and mice were determined using ELISA., Results: Immunization induced mice to produce autoantibodies against the linear or cyclic peptides of the second extracellular loop of M3R, and those autoantibodies could bind onto salivary glands. However, those mice showed neither impairment in the secretion of tears or saliva nor histological abnormality in the exocrine glands. Furthermore, passive transfer of the IgG isolated from the immunized mice into healthy mice did not induced the dysfunction of the exocrine glands. The prevalence of autoantibodies against the peptides of the second extracellular loop of M3R was low in pSS patients, and it did not differ significantly from that in healthy controls., Conclusions: Our results suggest that the autoantibodies against peptides of the second extracellular loop of M3R are not pathogenic in vivo and they are not suitable as biomarkers for pSS diagnosis.

Primary Sjögren's syndrome (pSS) is associated with HLA-DRB1 loci, but the association of amino acid variations in the hypervariable region of the HLA-DR β1 chain with pSS is largely unknown. In this study, we aimed to identify the amino acid variations within the hypervariable region of HLA-DRB1 molecule which are associated with the susceptibility to pSS. We sequenced the 2nd exon of the HLA-DRB1 locus in 52 pSS patients and 179 controls. The HLA-DRB1*0803 is the allele that shows the strongest association with pSS in Chinese population (OR = 3.0, P = 2.4 × 10(-4)). Furthermore, amino acid variations within the binding pocket P7 and P9 are associated with the susceptibility to pSS. An interaction between two residues within P7, β47 and β67, is associated with pSS. Structural modeling studies demonstrated that the electrostatics of peptide binding pocket 9 are opposite in pSS-susceptible and -protective HLA-DRB1 alleles. In conclusion, our results suggest that structural heterogeneity of the HLA-DRB1 peptide binding pocket P7 and P9 might play a role in the pathogenesis of pSS., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: To report 2 patients with Sjögren syndrome (SS) who had no or mild dry eye symptoms preoperatively but developed severe and refractory dry eye after laser in situ keratomileusis (LASIK)., Methods: Two women with well-controlled early-stage SS developed severe dry eye, punctate epithelial keratopathy, and refractive regression 15 and 2 months after LASIK. Both patients were treated with punctal occlusions, artificial tears, fluorometholone 0.02% eyedrops, autologous serum, and systemic immunosuppressants., Results: Ten months after treatment, both patients exhibited only minor improvements in dry eye symptoms on the basis of changes in Schirmer test results, corneal fluorescein staining, and refractive errors, whereas their tear breakup time and corneal sensation remained unchanged., Conclusions: Severe and refractory dry eye can develop after LASIK in patients with preexisting well-controlled early-stage SS.

Purpose: To define the alterations of corneal nerves in aqueous tear deficiency dry eye patients with or without Sjögren syndrome and to identify the relationship between the morphologic changes of corneal nerves and the extent of dry eye., Methods: Confocal microscopy was used to examine 38 consecutive aqueous tear deficiency patients (8 Sjögren syndrome and 30 non-Sjögren syndrome) and 30 age- and gender-matched normal controls. Images taken by Confocal2 slit-scanning microscope at subbasal epithelial cell layer of central cornea were analyzed. The number and density of corneal nerves and their size, beads, tortuosity, and branching pattern were compared. These data were correlated with age and the degree of dry eye., Results: Sjögren syndrome patients showed a significant increase in average nerve number and tortuosity as compared with normal controls (P = 0.031 and 0.021, respectively). Severe nerve tortuosity (grade 4) and nerve branching appeared more frequently in aqueous tear deficiency than in normal subjects (P = 0.024 and 0.042, respectively). A decreased nerve number was observed with age in the normal controls (P = 0.002). However, such a correlation did not exist in aqueous tear deficiency. In aqueous tear deficiency, rose bengal staining score correlated positively with nerve density (P = 0.048) and nerve number (P = 0.001). Corneal fluorescein staining score was also positively correlated with nerve number (P = 0.027)., Conclusions: Abnormal morphologic changes are observed in aqueous tear deficiency that are more severe in Sjögren syndrome. The distinct changes of corneal nerves include increased nerve number, tortuosity, and chances of branching, suggesting an attempted nerve regeneration. A strong correlation exists between the changes of nerve morphology and the degree of dry eye. These results provide some possible evidence for the abnormal corneal sensation in dry eye.