Hiromitsu Asashima

University of Tsukuba, Tsukuba, Ibaraki, Japan

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Publications (36)102.12 Total impact

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    Preview · Article · Nov 2015 · Allergology International

  • No preview · Article · Sep 2015 · Scandinavian journal of rheumatology

  • No preview · Article · May 2015 · Rheumatology

  • No preview · Article · May 2015 · Rheumatology (Oxford, England)
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    ABSTRACT: The auto-reactive CD4+ T cells are involved in the pathogenesis of Sjögren's syndrome (SS). The present study was to clarify the dominant T cell epitopes of M3 muscarinic acetylcholine receptor (M3R) and to establish a new antigen specific therapy for experimentally-induced SS. Cytokines production from M3R reactive CD4+ T cells, cultured with various M3R peptides, was analyzed by ELISA. The splenocytes of M3R(-/-) mice immunized with M3R peptides were inoculated into Rag1(-/-) mice and the development of sialadenitis was examined. Altered peptide ligands (APLs) of the T cell epitopes, substituted with amino acid residue at T cell receptor contact sites, were synthesized. The effect of APLs to suppress the sialadenitis was evaluated. The mechanisms underlying such effects were assessed. CD4+ M3R reactive T cells produced IL-17 and IFN-γ against N1 and 1(st) peptides, and Rag1(-/-) mice transferred with M3R N1 and/or 1(st) immunized splenocytes developed sialadenitis. Among designed APLs, N1-APL7 (AA15 N→S) significantly suppressed IFN-γ in vitro, and also suppressed the sialadenitis in vivo. Early growth response 2 in CD4+ T cells from cervical lymph nodes was significantly higher than the control, and cell proliferation was reversed by exogenous IL-2. Anergy-related molecules of Itch, Cbl-b, GRAIL, and Deltex-1, were significantly higher when cultured with N1-APL7. The major T cell epitopes were both M3R N1 and 1(st) regions. Moreover, N1-APL7, selected as the antagonistic APL in vitro, also suppressed sialadenitis through the induction of anergy. This is a potentially useful strategy for regulating pathogenic T cell infiltration occurred in SS. This article is protected by copyright. All rights reserved. © 2015 American College of Rheumatology.
    No preview · Article · Apr 2015 · Arthritis and Rheumatology
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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.
    Preview · Article · Nov 2014 · The Journal of Immunology
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    ABSTRACT: Objective: The objective of this paper is to identify predictors for the response to treatment of acute lupus hemophagocytic syndrome (ALHS). Methods: We reviewed seven cases with ALHS admitted to our hospital and published ALHS cases identified in the 2001-2014 Medline database, and then conducted univariate and multivariate analyses to identify predictors for the response to treatment. Results: Review of our cases showed a significant and negative correlation between serum ferritin and anti-DNA antibody (p = 0.0025). All three patients treated with cyclosporine A (CsA) were considered responders despite high serum ferritin and corticosteroid resistance. We also reviewed 93 patients with ALHS identified in 46 articles. Multiple logistic regression analysis identified C-reactive protein (CRP) (OR 0.83, p = 0.042) and hemoglobin (OR 1.53, p = 0.026) measured at diagnosis of ALHS as significant predictors of the response to corticosteroid monotherapy. Moreover, among 32 patients treated with CsA, serum ferritin was significantly higher in CsA responders (12163 ± 16864 µg/l, n = 22) than in non-responders (3456 ± 6267/µg/l, p = 0.020, n = 10). Leukocyte count was significantly lower in the CsA responders (1940.0 ± 972.3/µl) than in the non-responders (3253 ± 2198/µl, p = 0.034). Conclusion: Low CRP and high hemoglobin can predict a positive response to corticosteroid monotherapy while high serum ferritin and low leukocyte count can predict a positive response to CsA in patients with ALHS and therefore, when corticosteroid monotherapy is not effective in such cases, CsA could be the first choice of an additional immunosuppressive agent.
    No preview · Article · Nov 2014 · Lupus
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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.
    No preview · Article · Oct 2014 · Modern Rheumatology
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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.
    Full-text · Article · Oct 2014 · Bioscience Biotechnology and Biochemistry
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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.
    Full-text · Article · Oct 2014 · Arthritis and Rheumatology
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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.
    Full-text · Article · Sep 2014 · Modern Rheumatology
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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.
    Full-text · Article · Jul 2014 · Plant Biotechnology Journal
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    ABSTRACT: Background M3 muscarinic acetylcholine receptor (M3R) is evaluated to be one of the auto-antigens of Sjögren's syndrome (SS). Our previous studies have shown that Rag1–/– mice transferred with splenocytes of M3R–/– mice immunized with M3R peptides mixture (three N-terminal regions; N1, N2, N3, and three extracellular loops; 1st, 2nd, 3rd) (M3R–/– →Rag1–/–) developed sialoadenitis like SS (M3R induced autoimmune sialoadenitis; MIS) [1]. Besides, altered peptide ligands (APLs), the peptides with substitutions in amino acid residues at T-cell receptor contact sites, are reported to regulate the activation of antigen-specific T cells. Objectives To develop antigen-specific therapy, we tried to clarify the T cell epitopes of M3R reactive T cells and also to evaluate the suppressive ability of APLs in MIS both in vitro and in vivo. Methods 1) The splenocytes of M3R–/– mice immunized with M3R peptides mixture were cultured with each M3R peptide. The cytokines (IFN-g and IL-17) production was measured by ELISA. In a similar manner, the splenocytes of M3R–/– mice immunized with each N1 and 1st peptide, which was the candidate for the T cell epitopes, were cultured and evaluated. 2) The splenocytes of M3R–/– mice, immunized with each N1 and 1st peptide, were transferred into Rag1–/– mice (each M3R–/– →Rag1–/–, M3R–/-<1st>→Rag1–/–). On day 45 after transfer, the salivary glands of Rag1–/– mice were pathologically examined. 3) APLs of each N1 and 1st peptide were designed. 4) CD4+ and CD11c+ cells were isolated from M3R–/– mice immunized with each N1 and 1st peptide. Each APL was loaded to CD11c+ cells pre-cultured with each suboptimal concentration of N1 and 1st peptide (N1: 1.5 μM, 1st: 4.5 μM). Afterward, CD4+ T cells were added and cytokines production was measured by ELISA. 5) 100 μg of antagonistic APLs were administered to MIS (M3R–/– →Rag1–/–) intravenously on day 7 and 10 after the cell transfer. Results 1) Splenocytes immunized with M3R peptide mixture produced IL-17 and IFN-g against N1 and 1st peptide. Splenocytes immunized with N1 and 1st peptide produced IL-17 and IFN-g against each corresponding peptide. 2) Both M3R–/– →Rag1–/– and M3R–/–<1st>→Rag1–/– developed sialoadenitis. The majority of infiltrating cells in salivary glands were CD4+ T cells, with only few CD8+ T cells and B220+ B cells. 3) Seven APLs of N1 peptide (N1-APL1-7) and eight APLs of 1st peptide (1st-APL1-8) were designed. 4) N1-APL5 (AA15 N→T), N1-APL6 (AA15 N→C) and N1-APL7 (AA15 N→S) significantly suppressed the production of IFN-g (Inhibition ratio: N1-APL5 89.3%, N1-APL6 84.9%, N1-APL7 89.5%) (p<0.05). As well, 1st-APL8 (AA140 A→M) significantly suppressed IL-17 (Inhibition ratio: 1st-APL8 86.5%) (p<0.05). 5) All the antagonistic APLs in vitro also suppressed MIS in vivo, especially N1-APL7 (Focus score: N1-APL5: 0.78±0.51, N1-APL6: 0.89±0.77, N1-APL7: 0.11±0.12, 1st-APL7: 0.67±0.58, control: 1.44±0.51) (N1-APL7; p<0.05). Conclusions The major T cell epitopes in MIS might be both N1 terminal region and 1st extracellular loop of M3R. Antagonistic APLs in vitro suppressed the induction of MIS in vivo. References Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.1933
    No preview · Article · Jun 2014 · Annals of the Rheumatic Diseases
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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.
    No preview · Article · Apr 2014 · Modern Rheumatology
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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.
    Preview · Article · Apr 2014 · Hepatology Research

  • No preview · Article · Mar 2014 · Modern Rheumatology
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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.
    No preview · Article · Feb 2014
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    ABSTRACT: Background Previously well-known “rheumatoid-lung” has been assumed as interstitial pneumonitis (IP). It is not so prevalent in female-majority of rheumatoid arthritis (RA) patients, but rather observed much more in male patients. We have had an impression that IP in male RA patients has a unique feature of concurrent emphysema development. Objectives To study how frequently, and which pulmonary diseases develop in male RA patients. The background and associated laboratory features were also focused on. Methods Male RA patients who visited our hospital from Jan., 2006 to Apr., 2011 are included. The similar number of female patients visited us in the same duration was included as the controls. Lung diseases were diagnosed mainly based on the medical records, XP/HRCT findings, and pulmonary function tests results. As the major disease entities, usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), organizing pneumonia (OP), emphysema and pleuritis were intended. Brinkman Index (BI, smoking index), and serum levels of RF, KL-6 and CRP were evaluated. Results Lung diseases were observed in 27/72 (37.5%) in male and 5/70 (7.1%) in female patients. In male patients, UIP/NSIP was in 20, OP in 3, emphysema in 18, and pleuritis in 1; 12 had both IP and emphysema. In female, UIP was in 2, OP in 2, emphysema in 1, and pleuritis in 1; 1 had both IP and emphysema. The male patients with lung diseases were older than those without them (72.2±10.3 vs. 63.7±12.9 yr.), had a higher serum RF level (511±390 vs.140±141 U/mL), a higher KL-6 level (801±735 vs. 277±179 U/mL), and a higher Brinkman index. Among the cases with stable arthritis, patients with UIP/NSIP/emphysema showed a low CRP level, while those with OP/pleuritis did a high level. Conclusions Male RA patients had lung diseases at a high rate of over 30%. UIP/NSIP was observed the most, which was frequently combined with emphysema. The male RA patients having a high RF level and a high smoking index might develop UIP/NSIP and the combined emphysema with a high prevalence rate. Such patients showed a high KL-6 level but a low CRP level. Disclosure of Interest None Declared
    No preview · Article · Jan 2014 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background IgG4-related disease (IgG4-RD) is a new disease entity characterized by high serum IgG4 levels, infiltration of IgG4-positive plasmacytes and fibrosis in various organs such as the pancreas, salivary and lacrimal glands. Although the clinical features have been clarified recently, the pathogenesis of this disease remains unclear [1]. We previously showed that significantly higher expressions of IL-10, TGFb, and AID in labial salivary glands (LSG) of IgG4-RD than Sjögren’s syndrome (SS) and controls. In LSG of IgG4-RD, increased IL-10 and TGFb might play pathogenic roles in IgG4-specific class switch recombination and fibrosis. AID also might contribute to up-regulation of IgG4-specific class switch recombination along with IL-10 in LSG [2]. Objectives The purpose of this study was to clarify the molecules which played pathogenic roles in IgG4-RD exhaustively. Methods 1) Gene expression was analyzed by DNA microarray using GeneChip Human Genome U133 Plus 2.0 Array (Affymetrix) in LSG of IgG4-RD (N=3) and SS (N=3). Differentially expressed genes (DEGs) in IgG4-RD and SS were identified, and gene-annotation enrichment analysis of these DEGs was performed using Gene Ontology (GO) annotation. 2) Validation of the result was performed by quantitative PCR using LSG from IgG4-RD (N=8), SS (N=11), and controls (N=3) other than the patients analyzed by DNA microarray. 3) We also examined the expression of molecules in protein level by immunofluorescence assay using lacrimal glands from patients with IgG4-RD. Results 1) Gene expression patterns in IgG4-RD and SS were quite different in hierarchical clustering. In IgG4-RD, 580 up-regulated and 280 down-regulated genes were identified as DEGs (false discovery rate <0.05). GO analysis indicated the up-regulated set of DEGs in IgG4-RD encoded proteins that function in T cell activation, T cell differentiation, chemotaxis, mitosis, immune responses, and inflammatory response. 2) PCR validated significantly higher expression of CCL18 which related to chemotaxis and fibrosis, in LSG of IgG4-RD than in SS and controls (P<0.05). 3) Immunofluorescence assay showed that CD68 positive macrophages could produce CCL18 in lacrimal glands of IgG4-RD. Conclusions DNA microarray analysis in this study showed that the gene expression pattern in LSG of IgG4-RD was different from that of SS, suggesting different pathogenic mechanisms of IgG4-RD and SS. CCL18 produced by macrophages might relate to the pathogenesis of IgG4-RD via the chemotaxis of T cells and B cells, and the induction of collagen production from fibroblasts. References Disclosure of Interest: None Declared
    No preview · Article · Jan 2014 · Annals of the Rheumatic Diseases
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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.
    No preview · Article · Jan 2014 · Journal of Autoimmunity