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Detection of Autoantibodies against Aquaporin-1 in the Sera of Patients with Primary Sjogren's Syndrome.

ABSTRACT: The pathophysiology of glandular dysfunction in Sjögren's syndrome (SS) has not been fully elucidated. Previously, we reported the presence of autoantibodies to AQP-5 in patients with SS, which was associated with a low resting salivary flow. The purpose of this study was to investigate the presence of anti-AQP1 autoantibodies. To detect anti-AQP1 autoantibodies, cell-based indirect immunofluorescence assay was developed using MDCK cells that overexpressed human AQP1. By screening 112 SS and 52 control sera, anti-AQP1 autoantibodies were detected in 27.7% of the SS but in none of the control sera. Interestingly, the sera that were positive for anti-AQP1 autoantibodies also contained anti-AQP5 autoantibodies in the previous study. Different from anti-AQP5 autoantibodies, the presence of anti-AQP1 autoantibodies was not associated with the salivary flow rate. Although anti-AQP1 autoantibodies are not useful as a diagnostic marker, the presence of autoantibodies to AQP1 may be an obstacle to AQP1 gene therapy for SS.

SUBMITTER: Alam J

PROVIDER: S-EPMC5407981 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Detection of autoantibodies against aquaporin-5 in the sera of patients with primary Sjogren's syndrome.

Project description:The pathophysiology of exocrine dysfunction observed in Sjögren's syndrome (SS) is not fully understood. The purpose of this study was to investigate whether autoantibodies against human AQP5 are present in the sera of SS patients. Frozen sections of mouse submandibular salivary glands, CHO cells over-expressing a human AQP5-GFP fusion protein or GFP, and MDCK cells over-expressing AQP5 were used in the indirect immunofluorescence assay to detect anti-AQP5 autoantibodies in the sera from patients with primary SS. The lysates of HEK-293 cells over-expressing the AQP5-GFP fusion protein or GFP were used for immunoprecipitation. Serum IgG from the SS patients but not from the control subjects stained acinar cells in the mouse salivary glands, the signals of which colocalized with those of AQP5-specific antibodies. Serum IgG from the SS patients also selectively stained AQP5-GFP expressed in CHO cells. However, both the control and SS sera immunoprecipitated the AQP5-GFP, suggesting that autoantibodies against AQP5 were also present in the control sera. The screening of 53 control and 112 SS samples by indirect immunofluorescence assay using the AQP5-expressing MDCK cells revealed the presence of significantly higher levels of anti-AQP5 IgG in the SS samples than in the control samples with sensitivity of 0.73 and a specificity of 0.68. Furthermore, the presence of anti-AQP5 autoantibodies was associated with low resting salivary flow in SS patients. In conclusion, anti-AQP5 autoantibodies were detected in the sera from SS patients, which could be a novel biomarker of SS and provide new insight into the pathogenesis of SS.

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2021-01-25 | GSE163395 | GEO

IgG Autoantigen Array using sera from primary Sjogren's syndrome patients and non-Sjogren's syndrome controls

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Autoantibodies in sera from Sjogren's syndrome mice

Project description:Autoantibodies in sera from Sjogren's syndrome mice

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Autoantibodies against muscarinic type 3 receptor in Sjogren's syndrome inhibit aquaporin 5 trafficking.

Project description:Sjögren's syndrome (SjS) is a chronic autoimmune disease that mainly targets the salivary and lacrimal glands. It has been controversial whether anti-muscarinic type 3 receptor (α-M3R) autoantibodies in patients with SjS inhibit intracellular trafficking of aquaporin-5 (AQP5), water transport protein, leading to secretory dysfunction. To address this issue, GFP-tagged human AQP5 was overexpressed in human salivary gland cells (HSG-hAQP5) and monitored AQP5 trafficking to the plasma membrane following carbachol (CCh, M3R agonist) stimulation. AQP5 trafficking was indeed mediated by M3R stimulation, shown in partial blockage of trafficking by M3R-antagonist 4-DAMP. HSG-hAQP5 pre-incubated with SjS plasma for 24 hours significantly reduced AQP5 trafficking with CCh, compared with HSG-hAQP5 pre-incubated with healthy control (HC) plasma. This inhibition was confirmed by monoclonal α-M3R antibody and pre-absorbed plasma. Interestingly, HSG-hAQP5 pre-incubated with SjS plasma showed no change in cell volume, compared to the cells incubated with HC plasma showing shrinkage by twenty percent after CCh-stimulation. Our findings clearly indicate that binding of anti-M3R autoantibodies to the receptor, which was verified by immunoprecipitation, suppresses AQP5 trafficking to the membrane and contribute to impaired fluid secretion in SjS. Our current study urges further investigations of clinical associations between SjS symptoms, such as degree of secretory dysfunction, cognitive impairment, and/or bladder irritation, and different profiles (titers, isotypes, and/or specificity) of anti-M3R autoantibodies in individuals with SjS.

| S-EPMC3559734 | biostudies-literature

Clinical features of Sjogren's syndrome patients with autoantibodies against interferons.

Project description:BACKGROUND:Sjögren's syndrome (SS) is an autoimmune disease characterized by immune attack on the salivary and lacrimal glands. Given the known cytokine activation and type I interferon gene expression signature found in SS, we hypothesized that anticytokine autoantibodies might be detectable by Luciferase immunoprecipitation systems in some SS patients and correlate with clinical symptoms. RESULTS:Luciferase immunoprecipitation systems was used to screen for serum anti-cytokine autoantibodies in 57 primary SS patients and 25 healthy volunteers. Autoantibodies were detected against GMCSF, interferon-?, -? and, -? in one, two, two and six patients with SS, respectively. None of the healthy volunteers showed anticytokine autoantibodies and none of the SS or control subjects showed autoantibodies against interferon-?. One 51-year old female SS subject with the highest anti-interferon-? and -? autoantibody levels had stable autoantibody levels over the course of a year. In vitro functional testing of serum autoantibodies from this subject demonstrated partially neutralizing activity for interferon-? signaling. Clinical information on this individual revealed a low focus score and high levels of unstimulated salivary flow, suggesting the possibility that interferon-? autoantibody neutralizing activity may have contributed to the milder sicca symptoms. CONCLUSION:Overall, these findings demonstrate that a subset of SS patients (16%) harbor autoantibodies against GMCSF, interferon-?, interferon-?, and interferon-?. These data support the observation that high levels of interferon-? autoantibodies may attenuate disease symptoms in SS.

| S-EPMC6314934 | biostudies-other

Associations of Anti-Aquaporin 5 Autoantibodies with Serologic and Histopathological Features of Sjogren's Syndrome.

Project description:Biomarkers to stratify the complex and heterogeneous phenotypes of Sjogren's syndrome (SS) are needed. We aimed to validate the prevalence of anti-aquaporin 5 (AQP5) IgG in a non-Korean cohort and to optimize the method to screen the anti-AQP5 IgG. The study cohort included 111 primary SS and 43 non-SS Sjögren's International Collaborative Clinical Alliance (SICCA) controls that were obtained from the Sjögren's International Collaborative Clinical Alliance registry, in addition to 35 systemic lupus erythematosus (SLE) and 35 rheumatoid arthritis (RA) phenotypes. Anti-AQP5 IgG was screened by cell-based immunofluorescence cytochemistry (CB-IFC) assay in the absence or presence of epitope peptides, as well as by ELISA using the epitope peptides as coated antigens. Anti-AQP5 IgG specific to an E1 epitope was best at discriminating between SS and non-SS, and the two different methods (CB-IFC and ELISA) presented comparable performance in diagnostic accuracy (0.690 vs. 0.707). Notably, the SLE and RA groups had substantially lower levels of anti-AQP5 IgG than the SS group. In addition, the presence of anti-AQP5_E1 IgG was associated with serologic and histopathological features of SS. In conclusion, a similar prevalence of anti-AQP5 IgG was confirmed in a non-Korean cohort. Screening anti-AQP5 autoantibodies may help to form subgroups of SS for targeted therapy.

| S-EPMC6912604 | biostudies-literature

IgG Autoantigen Array using sera from primary Sjogren's syndrome patients and non-Sjogren's syndrome controls

Project description:IgG Autoantigen Array using sera from primary Sjogren's syndrome patients and non-Sjogren's syndrome controls

| PRJNA989578 | ENA

Autoantibodies against the Second Extracellular Loop of M3R Do neither Induce nor Indicate Primary Sjogren's Syndrome.

Project description: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.

| S-EPMC4765836 | biostudies-literature

Clinical usefulness of anti-muscarinic type 3 receptor autoantibodies in patients with primary Sjogren's syndrome.

Project description:ObjectivesTo elucidate the clinical values of anti-M3R in Sjögren's syndrome (SS) in the largest cohort for an anti-M3R study.MethodsThe plasma of 361 subjects (156 primary SS [pSS], 62 non-SS-sicca [SICCA], 40 systemic lupus erythematosus [SLE], 50 rheumatoid arthritis [RA], and 53 healthy controls [HC]) was screened using our modified On-Cell-Western assay. Saliva from pSS (n=37) compared to SICCA (n=26) was also analysed. The sensitivity and specificity of anti-M3R and its association with comprehensive clinical and laboratory features were determined.ResultsPlasma-anti-M3R was higher in pSS compared to other groups, differentiating pSS with good-to-excellent diagnostic power with a specificity of 85% and a sensitivity between 75% and 98%. pSS plasma-anti-M3R was positively correlated with ocular staining scores, anti-Ro/SSA, IgG, β2-microglobulin, ESR, and ESSDAI. It was negatively correlated with WBC, C4, and salivary scintigraphic indices. Saliva-anti-M3R was 3.59 times higher in pSS than in SICCA. Interestingly, the agreement between the 2002 American European Consensus Group criteria and the criteria substituted with plasma-anti-M3R for the lip biopsy reached 92%, with a significant kappa of 0.824.ConclusionsAnti-M3R enhances sensitivity and specificity for SS diagnosis, correlating with ocular dryness and glandular hypofunction, and the haematological/biological domains of the ESSDAI. Our findings also highlight the clinical significance of anti-M3R in SS diagnosis, especially where clinical assessments, such as lip biopsy, sialometry, or ocular evaluation, by multi-disciplinary specialists are limited.

| S-EPMC8021605 | biostudies-literature

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