Hiromitsu Asashima

University of Tsukuba, Tsukuba, Ibaraki, Japan

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Publications (28)65.65 Total impact

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    ABSTRACT: The nuclear receptor retinoic acid-related orphan receptor (ROR)γt is required for the generation of Th17 cells, which are involved in various autoimmune diseases, including Sjögren's syndrome (SS). However, the pathological role of RORγt in SS remains to be elucidated. The present study was designed to clarify the role of RORγt in the pathogenesis of sialadenitis-like SS. Histological analysis of RORγt transgenic (Tg) mice was determined, and then Tg mice developed severe spontaneous sialadenitis-like SS. The analysis of infiltrating cells showed that most infiltrating cells were CD4(+) T cells. RORγt-overexpressing CD4(+) T cells induced sialadenitis as a result of transferred CD4(+) T cells from Tg mice into Rag2(-/-) mice. The examination of IL-17-deficient Tg mice indicated that IL-17 was not essential for the development of sialadenitis. The number of CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells was significantly decreased in Tg mice, and CD25 expression and IL-2 stimulated STAT5 activation were inhibited in Treg cells. The inhibitory function of Treg cells of Tg mice was equal to that of wild-type mice in vitro. The abundant Treg cells of Tg mice could suppress the development of sialadenitis, but the reduced Treg cells of Tg mice could not inhibit the induction of sialadenitis in Rag2(-/-) mice transferred with effector cells from Tg mice. These results suggest that both RORγt-overexpressed CD4(+) T cells and reduced Treg cells might contribute to the development of SS-like sialadenitis. Copyright © 2014 by The American Association of Immunologists, Inc.
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    ABSTRACT: The objective of this paper is to identify predictors for the response to treatment of acute lupus hemophagocytic syndrome (ALHS).
    Lupus 11/2014; DOI:10.1177/0961203314559086 · 2.48 Impact Factor
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    ABSTRACT: Objective. To assess the correlation between MR imaging (MRI) of parotid glands with X-ray sialography, histopathology of the labial salivary glands, and salivary secretion, in patients with secondary Sjögren's syndrome (SS) associated with rheumatoid arthritis (RA). Methods. Non-contrast MRI of the parotid glands was performed in 13 secondary SS patients associated with RA who satisfied the revised Japanese diagnostic criteria for SS (1999), and the ACR/EULAR classification criteria for RA (2010). The MRI findings were classified according to the degree of high-intensity signal on T1-weighted images (T1WI) and short inversion time inversion recovery (STIR) images into five grades (0–4), using the modified Nagasaki University grading method. The results of MRI grading were compared with the Rubin and Holt staging of X-ray sialography (0–4), the Greenspan grading of labial salivary gland histopathology (0–4), and salivary secretion by the gum test (ml/10 min). Results. All 13 patients were females, with a mean age of 50.2 ± 11.3 years. According to the MRI grading, 3 patients were Grade 1, 5 were Grade 2, 5 were Grade 3, and none was Grade 0 or Grade 4. The mean stage by X-ray sialography was 1.7 ± 1.0, the mean grade by histopathology was 2.4 ± 1.2, and the mean volume of salivary secretion was 9.7 ± 3.9 ml. The MRI grading correlated significantly with the Rubin and Holt staging and Greenspan grading (P < 0.01 each, Spearman's rank correlation), and significantly and inversely with the results of the gum test (P < 0.05). Conclusion. The results suggest that MRI of the parotid glands is a useful noninvasive tool for evaluating destruction and inflammation in the salivary glands.
    Modern Rheumatology 10/2014; DOI:10.3109/14397595.2014.958892 · 2.21 Impact Factor
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    ABSTRACT: Rheumatoid arthritis is an autoimmune disease associated with the recognition of self proteins secluded in arthritic joints. We generated transgenic rice seeds expressing three types of altered peptide ligands (APL) and the T cell epitope of type II collagen (CII256-271). When these transgenic rice and non-transgenic rice seeds were orally administrated to DBA/1 J mice once a day for 14 days, followed by immunization with CII, the clinical score of collagen-induced arthritis (CIA) was reduced and inflammation and erosion in the joints were prevented in mice fed APL7 transgenic rice only. IL-10 production against the CII antigen significantly increased in the splenocytes and iLN of CIA mice immunized with the CII antigen, whereas IFN-γ, IL-17, and IL-2 levels were not altered. These results suggest that IL-10-mediated immune suppression is involved in the prophylactic effects caused by transgenic rice expressing APL7.
    Bioscience Biotechnology and Biochemistry 10/2014; 78(10):1662-8. DOI:10.1080/09168451.2014.936349 · 1.21 Impact Factor
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    ABSTRACT: Objective To compare gene expression in labial salivary glands (LSGs) from patients with IgG4-related disease with that in LSGs from patients with Sjogren's syndrome (SS). Methods Gene expression was analyzed by DNA microarray in LSG samples from 5 patients with IgG4-related disease, 5 SS patients, and 3 healthy controls. Genes differentially expressed in IgG4-related disease and SS were identified, and gene annotation enrichment analysis of these differentially expressed genes was performed using Gene Ontology (GO) annotation. Validation of the results was performed by quantitative polymerase chain reaction (PCR) using LSG samples from 9 patients with IgG4-related disease, 10 SS patients, and 4 controls. ResultsGene expression patterns in patients with IgG4-related disease, SS patients, and healthy controls were quite different from each other in hierarchical clustering as well as in principal components analysis. In IgG4-related disease compared with SS, a total of 1,771 probe sets (corresponding to 1,321 genes) were identified as up-regulated, and 1,785 probe sets (corresponding to 1,320 genes) were identified as down-regulated (false discovery rate of <5%). GO term analysis indicated that the up-regulated set of differentially expressed genes in IgG4-related disease encoded proteins that function in cell proliferation, extracellular matrix organization, and organ development. PCR validated significantly higher expression of lactotransferrin in patients with IgG4-related disease than in SS patients (P < 0.05) and significantly higher expression of CCL18 in patients with IgG4-related disease than in SS patients and controls (P < 0.05). Conclusion The results clearly showed that the gene expression pattern in LSGs from patients with IgG4-related disease is different from that in LSGs from SS patients.
    10/2014; 66(10). DOI:10.1002/art.38748
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    ABSTRACT: Objective. To assess the efficacy and safety of abatacept for secondary Sjögren's syndrome (SS) associated with rheumatoid arthritis (RA). Methods. The primary endpoint of this 1-year, open-labeled, prospective, observational multicenter study of RA-associated secondary SS was the rate of SDAI remission at 52 weeks after initiation of abatacept therapy. The secondary endpoints included that of Saxson's test and Schirmer's test. Adverse events during the study period were also analyzed. Results. Thirty-two patients (all females) were enrolled in this study. Interim analysis at 24 weeks included assessment of efficacy (n = 31) and safety (n = 32). The mean SDAI decreased from 19.8 ± 11.0 (± SD) at baseline to 9.9 ± 9.9 at 24 weeks (P < 0.05). Patients with clinical remission, as assessed by SDAI, increased from 0 patient (0 week) to 8 patients (25.8%) at 24 weeks. Saliva volume (assessed by Saxson's test) increased slightly from 2232 ± 1908 (0 week) to 2424 ± 2004 (24 weeks) mg/2 min (n = 29). In 11 patients with Greenspan grading 1/2 of labial salivary glands biopsy, saliva volume increased from 2945 ± 2090 (0 week) to 3419 ± 2121 (24 weeks) mg/2 min (P < 0.05). Schirmer's test for tear volume showed increase from 3.6 ± 4.6 (0 week) to 5.5 ± 7.1 (24 weeks) mm/5 min (n = 25; P < 0.05). Five adverse events occurred in five of 32 patients (15.6%), and three of these events were infections. Conclusion. Abatacept seems to be effective for both RA and RA-related secondary SS.
    Modern Rheumatology 09/2014; DOI:10.3109/14397595.2014.951144 · 2.21 Impact Factor
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    ABSTRACT: Rheumatoid arthritis (RA) is an autoimmune disease associated with the recognition of self proteins secluded in arthritic joints. We previously reported that altered peptide ligands (APLs) of type II collagen (CII256-271) suppress the development of collagen-induced arthritis (CIA). In this study, we generated transgenic rice expressing CII256-271 and APL6 contained in fusion proteins with the rice storage protein glutelin in the seed endosperm. These transgene products successfully and stably accumulated at high levels (7–24 mg/g seeds) in protein storage vacuoles (PB-II) of mature seeds. We examined the efficacy of these transgenic rice seeds by performing oral administration of the seeds to CIA model mice that had been immunized with CII. Treatment with APL6 transgenic rice for 14 days significantly inhibited the development of arthritis (based on clinical score) and delayed disease onset during the early phase of arthritis. These effects were mediated by the induction of IL-10 from CD4+ CD25− T cells against CII antigen in splenocytes and inguinal lymph nodes (iLNs), and treatment of APL had no effect on the production of IFN-γ, IL-17, IL-2 or Foxp3+ Treg cells. These findings suggest that abnormal immune suppressive mechanisms are involved in the therapeutic effect of rice-based oral vaccine expressing high levels of APLs of type II collagen on the autoimmune disease CIA, suggesting that the seed-based mucosal vaccine against CIA functions via a unique mechanism.
    Plant Biotechnology Journal 07/2014; DOI:10.1111/pbi.12223 · 5.68 Impact Factor
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    ABSTRACT: Objective. To define the clinical features of IgG4-related disease (IgG4-RD) complicated with perivascular lesions. Methods. The clinical features of seven patients with IgG4-RD and perivascular lesions diagnosed at the University of Tsukuba Hospital between October 2008 and October 2013, were analyzed, including clinical background, results of imaging studies, satisfaction of the 2011 comprehensive diagnostic criteria (CDC) for IgG4-RD, laboratory data, distribution of perivascular lesions, involvement of other organs, and response to steroid therapy. Results. We studied six men and one woman with a mean age of 66.9 ± 6.7 years (± SD). Six of seven patients were diagnosed as definite IgG4-RD, while the seventh was considered possible IgG4-RD, based on the CDC for IgG4-RD. Serum IgG4 levels at diagnosis were higher than 135 mg/dl in all seven patients (mean, 933 ± 527). Serum C-reactive protein (CRP) levels were elevated in two only (mean, 1.42 ± 3.56 mg/dl). The perivascular lesions were located in the pulmonary artery (n = 1), thoracic aorta (n = 2), abdominal aorta (n = 6), coronary (n = 1), celiac (n = 1), superior mesenteric (n = 1), renal (n = 2), inferior mesenteric (n = 5), and iliac (n = 3) arteries. In addition to perivascular lesions, six patients showed involvement of other organs. All seven patients were treated with prednisolone (0.6 mg/kg/day), which rapidly improved the perivascular and other organ lesions in six patients (the other one patient have not yet been evaluated due to the short follow-up). Conclusion. Perivascular lesions show wide distribution in patients with IgG4-RD. Serum CRP levels are not necessarily elevated in these patients. Steroid therapy is effective in IgG4-RD and results in resolution of lesions.
    Modern Rheumatology 04/2014; DOI:10.3109/14397595.2014.903596 · 2.21 Impact Factor
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    ABSTRACT: AimM3 muscarinic acetylcholine receptor (M3R) is expressed in biliary tracts as well as in exocrine glands. It is reported some patients with primary biliary cirrhosis (PBC) carry auto-antibodies against M3R. The aim of this study is to clarify the presence, potential use as diagnostic marker, and clinical roles of anti-M3R antibodies in PBC.Methods We synthesized peptides encoding the extracellular domains of human-M3R, including the N-terminal region, the first, second, and third extracellular loops. Antibodies against these regions were examined by peptide-based ELISA in sera of 90 patients with PBC and 40 with chronic hepatitis C (CHC), 21 with nonalcoholic steatohepatitis (NASH), 10 with primary sclerosing cholangitis (PSC), 14 with obstructive jaundice, 10 with drug induced liver injury, and 42 healthy controls.ResultsAntibodies to the N-terminal, first, second and third loop were detected in 90.0% (81/90), 73.3% (66/90), 76.7% (69/90), and 66.7% (60/90) of PBC, in 67.5% (27/40), 10.0% (4/40), 67.5% (27/40), and 27.5% (11/40) of CHC, in 85.7% (18/21), 9.5% (2/21), 4.8% (1/21), and 57.1% (12/21) of NASH, in 60.0% (6/10), 20.0% (2/10), 60.0% (6/10), and 60.0% (6/10) of PSC, in 100.0% (14/14), 0% (0/14), 64.3% (9/14), and 78.6% (11/14) of obstructive jaundice, in 100.0% (10/10), 0% (0/10), 30.0% (3/10), and 10.0% (1/10) of drug induced liver injury, and in 4.8% (2/42), 7.1% (3/42), 2.4% (1/42), and 2.4% (1/42) of the controls, respectively.ConclusionsA high frequency of PBC carried anti-M3R antibodies. Anti-M3R antibodies against the first loop of M3R are potentially useful diagnostic maker for PBC.
    Hepatology Research 04/2014; DOI:10.1111/hepr.12346 · 2.22 Impact Factor
  • Modern Rheumatology 03/2014; DOI:10.3109/14397595.2014.884683 · 2.21 Impact Factor
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    ABSTRACT: Reported here are 2 patients with connective tissue disease who developed pulmonary nocardiosis. Case 1 involved a 73-year-old man with malignant rheumatoid arthritis treated with prednisolone 25 mg/day. Chest X-rays revealed a pulmonary cavity and bronchoscopy detected Nocardia species. The patient was successfully treated with trimethoprim/sulfamethoxazole. Case 2 involved a 41-year-old woman with systemic lupus erythematosus. The patient received remission induction therapy with 50 mg/day of prednisolone and tacrolimus. Six weeks later, a chest CT scan revealed a pulmonary cavity; bronchoscopy resulted in a diagnosis of pulmonary nocardiosis. The patient had difficulty tolerating trimethoprim/sulfamethoxazole, so she was switched to and successfully treated with imipenem/cilastatin and amikacin.
    02/2014; 3(1):25-8. DOI:10.5582/irdr.3.25
  • Annals of the Rheumatic Diseases 01/2014; 71(Suppl 3):171-171. DOI:10.1136/annrheumdis-2012-eular.2020 · 9.27 Impact Factor
  • Annals of the Rheumatic Diseases 01/2014; 72(Suppl 3):A466-A466. DOI:10.1136/annrheumdis-2013-eular.1399 · 9.27 Impact Factor
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    ABSTRACT: CD4+ T cells constitute the majority of infiltrating cells in salivary glands and lachrymal glands of patients with Sjögren's syndrome (SS). The pathophysiology of SS involves T cell recognition of antigens through the T cell antigen receptor, which triggers cytokine production and chronic inflammation. The M3 muscarinic acetylcholine receptor (M3R) molecule is expressed in exocrine glands, such as salivary glands and lachrymal glands, and plays an important role in exocrine secretion. Previous studies indicated the presence of M3R reactive T cells in peripheral blood of 40% of patients with SS and autoantibodies against M3R in sera of 9-100% of the same patients. Thus, M3R is considered a candidate receptor for autoantigen recognition by T and B cells. The relationship between B cell epitopes and the function of anti-M3R antibodies has been reported, suggesting the pathogenic role of anti-M3R antibodies in xerostomia commonly seen in SS patients. We generated new experimental mouse model, M3R-induced sialadenitis (MIS), using Rag1(-/-) mice inoculated with splenocytes from M3R(-/-) mice immunized with M3R synthetic peptides. Mice with MIS developed severe SS-like sialadenitis. Cell transfer experiments using M3R(-/-)xIFNγ(-/-) mice and M3R(-/-)xIL-17(-/-) mice showed that IFNγ and IL-17 are key cytokines in the pathogenesis of sialadenitis. These findings indicate the crucial roles of M3R-reactive Th1 and Th17 cells in autoimmune sialadenitis, and suggest that these cells, in addition to anti-M3R antibodies, are potential targets in new treatments for SS.
    Journal of Autoimmunity 01/2014; DOI:10.1016/j.jaut.2013.12.012 · 7.02 Impact Factor
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    ABSTRACT: Objective. To characterize the epidemiology of Sjögren's syndrome (SS), including prevalence, disease type, extra-glandular involvement, satisfaction of diagnostic criteria sets, and treatment used in Japan. Methods. The Research Team for Autoimmune Diseases, the Research Program for Intractable Disease by the Ministry of Health, Labor and Welfare conducted primary and secondary surveys on epidemiology of SS in 2011. The primary survey covered 4,729 out of 14,095 Japan-wide Hospital Departments to investigate the prevalence of SS. The secondary survey encompassed 214 Hospital Departments that agreed to the survey, to characterize disease type, extra-glandular involvement, satisfaction of diagnostic criteria sets, and treatments. Results. The number of patients with SS in Japan estimated by the primary survey was 68,483. The secondary survey involving data collected from 2,195 SS patients from 98 Hospital Departments showed that the mean age of patients was 60.8 ± 15.2 years, male/female ratio was 1/17.4, primary/secondary SS was about 60%/40% and glandular/extra-glandular form in primary SS was about 70%/25%. The satisfaction rate was 53.8% for the 1999 revised Japanese Ministry of Health criteria for the diagnosis of SS, 47.7% for the 2002 American-European Consensus Group classification criteria for SS and 49.6% for 2012 American College of Rheumatology classification criteria for SS. Corticosteroids were used by 752 of 2,195 patients (34%), immunosuppressants by 358 patients (16%), biologics by 68 patients (3%) and secretagogues by 695 patients (32%). Conclusion. The surveys provided valuable information on the epidemiology of SS including prevalence, disease type, extra-glandular involvement, satisfaction of diagnostic criteria sets and treatments used today in Japan.
    Modern Rheumatology 11/2013; DOI:10.3109/14397595.2013.843765 · 2.21 Impact Factor
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    ABSTRACT: Objective. IgG4-related disease (IgG4-RD) is characterized by IgG4-positive plasmacytic infiltration and fibrosis in various organs. Orbital involvement in IgG4-RD includes lacrimal glands, extra-ocular muscles, trigeminal nerve and other parts of the orbit. Immunohistochemical staining is used to diagnose IgG4-RD in patients with orbital inflammation. The purpose of this retrospective study was to clarify the clinicopathological features of IgG4-RD complicated with orbital involvement. Methods. We examined the clinical features, pathological findings and response to treatment in nine patients with IgG4-RD who underwent orbital tissue biopsy between April 2010 and August 2012 at the University of Tsukuba Hospital. Results. Among the nine patients, eight had dacryoadenitis, one had infraorbital nerve swelling, and another one had IgG4-related orbital inflammation. Involvement of other organs was identified in all patients, including involvement of the salivary glands, lymph nodes, lung, kidney and para-aorta. In all patients, biopsy samples from orbital tissues showed lymphoplasmacytic infiltration and fibrosis, and IgG4-positive/IgG-positive plasmacyte ratio of > 40%. All patients were treated with prednisolone (0.6 mg/kg/day) and responded well in early phase, although relapse was noted in two patients following tapering of prednisolone, evident by swelling of lacrimal glands. Conclusion. Patients with IgG4-RD complicated with orbital involvement often present with involvement of other organs. The histopathological findings of orbital tissue match the characteristic features of IgG4-RD. Corticosteroid is effective for orbital and systemic involvement in IgG4-RD.
    Modern Rheumatology 10/2013; DOI:10.3109/14397595.2013.844307 · 2.21 Impact Factor
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    ABSTRACT: For the diagnosis of Sjögren's syndrome (SS), cut-off levels of β2-microglobulin (β2MG) and sodium (Na+) in unstimulated whole saliva have not yet been shown. We aimed to determine the cut-off levels of salivary β2MG and Na+ which differentiate SS patients from non-SS patients and healthy controls. Seventy-one patients of primary SS (pSS, 69 females/2 males, 60.0±16.8 years old), 50 of secondary SS (sSS, 49/1, 55.8±17.4), 54 of connective tissue diseases other than SS (non-SS-CTD, 43/11, 60.0±16.0), and 75 healthy volunteers (HC, 43/32, 50.7±15.6) were included. Unstimulated whole saliva were examined for levels of β2MG, Na+, potassium (K+), and chloride (Cl-). Receiver-operating characteristic curve analysis was carried out. β2MG, Na+, and Cl- levels in the SS group (pSS and sSS) were significantly higher than those in the non-SS group (non-SS-CTD and HC). The salivary β2MG level was 5.3±4.6 mg/L in pSS, 5.1±2.0 in sSS, 2.5±2.1 in non-SS-CTD, and 1.2±0.7 in HC, respectively. The Na+ level was 39.2±25.2 mEq/L, 36.4±26.1, 19.6±16.8, and 16.5±7.3, and the Cl- level was 51.1±25.0, 47.8±24.3, 32.1±16.6, and 27.0±7.9 in the same order. The K+ level in the SS group was significantly higher than that in HC. The optimal cut-off β2 MG and Na+ levels that differentiate the SS group from the non-SS group were 2.3 mg/L and 23 mEq/L. Salivary β2MG and Na+ levels are useful markers for differentiating SS patients from non-SS-CTD patients and HC.
    Clinical and experimental rheumatology 06/2013; · 2.97 Impact Factor
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    ABSTRACT: This study demonstrates whether serum β2-microglobulin (β2-MG) level can be an indicator of the status of systemic lupus erythematosus (SLE) and adult-onset Still's disease (AOSD), and development of hemophagocytic syndrome (HPS) complication. Serum β2-MG level was compared between the active and inactive statuses of SLE and AOSD in hospitalized patients. Active status was defined as a state for which a therapy was introduced. Serum β2-MG level was also compared between patients with and without HPS complication. HPS was diagnosed on the basis of clinical and pathological findings. Laboratory markers of HPS including peripheral blood cell counts and levels of serum lactate dehydrogenase (LDH), serum ferritin, plasma fibrin/fibrinogen degradation product (FDP), and plasma D-dimer were examined to determine their correlations with serum β2-MG level. Sixteen SLE and seven AOSD patients (all females, aged 39.0 ± 16.4) were included. The serum β2-MG level was high in the active status of underlying diseases and decreased significantly after the therapy (3.5 ± 1.4 vs. 2.1 ± 0.8 mg/L, p < 0.001). Among patients with active status, the β2-MG level was higher in patients with HPS (two with SLE and three with AOSD) than in patients without HPS (4.9 ± 1.8 vs. 3.3 ± 1.4 mg/L, p < 0.05). Serum β2-MG level significantly correlated with the levels of serum LDH (r s = 0.42, p < 0.05), plasma FDP (r s = 0.58, p < 0.05), and plasma D-dimer (r s = 0.77, p < 0.01). Serum β2-MG level would be a useful indicator of disease activity and development of HPS complication in patients with SLE and AOSD.
    Clinical Rheumatology 03/2013; 32(7). DOI:10.1007/s10067-013-2220-8 · 1.77 Impact Factor
  • Hiroto Tsuboi, Mana Iizuka, Hiromitsu Asashima, Takayuki Sumida
    Japanese Journal of Clinical Immunology 01/2013; 36(2):77-85. DOI:10.2177/jsci.36.77
  • Hiroto Tsuboi, Mana Iizuka, Hiromitsu Asashima, Takayuki Sumida
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    ABSTRACT: Sjögren's syndrome (SS) is an autoimmune disease that affects exocrine glands including salivary and lacrimal glands. It is characterized by lymphocytic infiltration into exocrine glands, leading to dry mouth and eyes. A number of auto-antibodies are detected in patients with SS. However, no SS-specific pathologic auto-antibodies have yet been found in this condition. M3 muscarinic acetylcholine receptor (M3R) plays a crucial role in the secretion of saliva. It is reported that some patients with SS carried inhibitory auto-antibodies against M3R. To clarify the epitopes and function of anti-M3R antibodies in SS, we examined antibodies to the extracellular domains (N terminal region, the first, second, and third extracellular loop) of M3R by ELISA using synthesized peptide antigens encoding these domains in 42 SS and 42 healthy controls (HC). Titers and positivity of anti-M3R antibodies to every extracellular domain of M3R were significantly higher in SS than in HC. Our results indicated the presence of several B cell epitopes on M3R in SS. Moreover, we analyzed the functions of anti-M3R antibodies by Ca(2+)-influx assays using a human salivary gland (HSG) cell line. The functional analysis indicated that the influence of such anti-M3R antibodies on Ca(2+)-influx in HSG cells might differ based on the epitopes to which they bind. Interestingly, both IgG from anti-M3R antibodies to the second extracellular loop positive SS and anti-M3R monoclonal antibodies against the second extracellular loop of M3R, which we generated, suppressed Ca(2+)-influx in the HSG cells induced by cevimeline stimulation. These observations suggested that auto-antibodies against the second extracellular loop of M3R could be involved in salivary dysfunction in patients with SS. These results indicated the presence of several B cell epitopes on M3R in SS and the influence of anti-M3R antibodies on salivary secretion might differ based on these epitopes. Thus, anti-M3R antibodies could be not only potential pathologic auto-antibodies, but also new diagnostic makers and therapeutic targets for SS.
    Japanese Journal of Clinical Immunology 01/2013; 36(2):77-85.