Rheumatoid Arthritis: Kawanami T

Umehara H, Sawaki T, Kawanami T, Masaki Y, Fukushima T. · Division of Hematology and Immunology, Kanazawa Medical University. · Nippon Rinsho. · Pubmed #19280925 No free full text.

Abstract: Sjögren's syndrome (SS) is chronic autoimmune disease characterized by destructive lymphocyte infiltration of salivary and lacrimal glands, which results in dry eyes and dry mouth. Despite extensive study of the underlying cause of SS, the pathogenesis remains obscure. The Sjögren's International Collaborative Clinical Alliance (SICCA) by five Research Groups located in Argentina, China, Denmark, the United States and Japan, is the first registry and clinical data-specimen repository to establish the International Standard Criteria for diagnosing SS. Patients with SS have a relative increased risk for development of B cell lymphoma compared with other autoimmune rheumatic diseases. We discuss the possible mechanisms for lymphoma development. The topics concerning SS is IgG4-related lymphoproliferative diseases, such as Mikulicz's disease and autoimmune pancreatitis. Based on the analysis of patients registered from all over Japan, we propose a new clinical entity IgG4-positive multi-organ lymphoproliferative syndrome (IgG4+ MOLPS).

Dong L, Masaki Y, Takegami T, Jin ZX, Huang CR, Fukushima T, Sawaki T, Kawanami T, Saeki T, Kitagawa K, Sugai S, Okazaki T, Hirose Y, Umehara H. · Department of Hematology and Immunology, Kanazawa Medical University, Ishikawa, Japan. · Clin Exp Immunol. · Pubmed #17937678 links to  free full text

Abstract: The aim of this study was to clarify the nature of the clonal lymphocyte infiltration in Sjögren's syndrome (SS) patients associated with lymphoproliferative disorders. We examined B cell clonality in lymphoproliferative tissues from six primary SS patients associated with lymphoproliferative disorders or lymphoma by cloning and sequencing of the gene rearrangement of the immunoglobulin heavy chain complementarity determining region 3 (IgVH-CDR3). Three patients with sequential observation showed progressional clonal expansion with the presence of the same subclone in different tissues during the course of disease. Among them, one patient developed mucosa-associated lymphoid tissue (MALT) lymphoma in glandular parotid. The other three SS patients concomitant with malignant B cells lymphomas showed different clonal expansion of B cells between nodal sites and salivary glands. The cloanality analysis indicated that monoclonal B cell population could spread from one glandular site to another site during the course of SS, suggesting that the malignant clone may arise from the general abnormal microenvironment, not restricted to the glandular tissue, in some SS patients.

Umehara H, Tanaka M, Sawaki T, Jin ZX, Huang CR, Dong L, Kawanami T, Karasawa H, Masaki Y, Fukushima T, Hirose Y, Okazaki T. · Division of Hematology and Immunology, Department of Internal Medicine, Kanazawa Medical University, Daigaku, Uchinada-machi, Kahoku-gun, Ishikawa, 920-0293, Japan. · Mod Rheumatol. · Pubmed #16767549 No free full text.

Abstract: Leukocyte adhesion and trafficking at the endothelium requires both adhesion molecules and chemotactic factors. Fractalkine (CX3C) is a unique chemokine, and is expressed on tumor necrosis factor-alpha- and interleukin-1-activated endothelial cells (ECs). Fractalkine receptor, CX3CR1, is expressed on NK cells, monocytes, and some portion of CD4- and CD8-positive T cells. Interactions between fractalkine and CX3CR1 can mediate not only chemotaxis, but also cell adhesion in the absence of substrates for other adhesion molecules. Furthermore, fractalkine activates NK cells, leading to increased cytotoxicity and interferon-gamma production. Recently, accumulating evidence has shown that fractalkine is involved in the pathogenesis of rheumatoid arthritis and allied conditions. This review examines new concepts underlying fractalkine-mediated leukocyte migration and tissue damage, focusing primarily on the pathophysiological roles of fractalkine in rheumatic diseases.

Ogawa N, Shimoyama K, Kawanami T. · Department of Hematology and Immunology, Kanazawa Medical University, Japan. · Nihon Rinsho Meneki Gakkai Kaishi. · Pubmed #15744117 links to  free full text

Abstract: IFNgamma plays an important role to induce several functional molecules on salivary epithelial cells, including class II MHC, Fas and CD40 in salivary glands from patients with Sjogren's syndrome (SS). IFNgamma also contributes to the development of lymphocytic infiltrates by inducing T cell attracting chemokines in SS salivary epithelial cells, such as IP-10 (CXCL10), Mig (CXCL9), and I-TAC (CXCL11). IFNgamma dysregulation in SS salivary gland may attribute to the decreased production of TGFbeta from salivary epithelial cells in some patients. Expression of Fas and CD40 was significantly higher in SS salivary epithelial cells than in normal cells after IFNgamma stimulation. Although neither anti-Fas (CH11) nor anti-CD40 mAb alone could induce typical apoptosis, the two together and preincubation with IFNgamma efficiently induced apoptosis in SS salivary epithelial cells. This apoptosis was almost completely blocked by neutralizing anti-Fas mAb (ZB4). c-FLIP, an important inhibitory molecule in the Fas death pathway, was strongly expressed in SS salivary epithelial cells, but its expression was downregulated, at the protein level, by anti-CD40 mAb. CD40 signals promote Fas-dependent death of SS salivary epithelial cells by downregulating c-FLIP expression. The presence of c-FLIP in these cells may explain their resistance to undergo apoptosis in response to either anti-Fas or anti-CD40 mAb, despite their surface expression of both proteins. These findings suggest that SS salivary epithelial cell death requires the cooperation of Fas and CD40.

Nishida C, Yatera K, Kunimoto M, Yamasaki K, Yoda F, Kawanami T, Sakurai Y, Nakamura T, Yoshii C, Kido M. · No affiliation provided · Nihon Kokyuki Gakkai Zasshi. · Pubmed #19068769 No free full text.

Abstract: Pneumothorax secondary to nodular rheumatoid lung disease is a rare complication of rheumatoid arthritis. Here we report a case of rheumatoid arthritis with pneumothorax due to subpleural pulmonary rheumatoid nodule. A 74-year-old woman with a 14-year history of rheumatoid arthritis has admitted to our hospital due to dyspnea and right chest discomfort, and her chest X-ray film and computed tomography revealed right pneumothorax. Her chest X-ray and computed tomography findings before the onset of pneumothorax had demonstrated multiple subpleural cavitary nodules in both lungs. She had taken antifungal agents under a diagnosis of pulmonary fungal infection for a year without any change of her chest radiological findings. After incomplete reexpansion with sustained air leakage by right chest tube drainage, video-assisted thoracic surgery was performed. The pulmonary cavitary nodules of her right middle and lower lobes were with successfully excised. The histopathology of excised subpleural lung nodules showed typical features of rheumatoid nodules, and the cavitation of the rheumatoid nodule in right S5 had fistula formation to the pleural space, and thus was thought to have caused the pneumothorax.

Shimoyama K, Ogawa N, Sakai T, Sawaki T, Kawanami T, Karasawa H, Masaki Y, Tanaka M, Fukushima T, Hirose Y, Umehara H. · The third Department of Internal Medicine, Hamamatsu University School of Medicine. · Nihon Rinsho Meneki Gakkai Kaishi. · Pubmed #17984582 links to  free full text

Abstract: OBJECTIVE: To examine clinical significance of anti-cyclic citrullinated peptide antibody (anti-CCP antibody) in RA. METHODS: Hundred fifteen patients with polyarthralgia (89 females, 26 males) were recruited, and subjected for the study. We studied anti-CCP antibody, ESR, CRP, IgM-RF, IgG-RF, RAPA, MMP-3, CARF, C1q-IC, Stage, Class, Joint score, Sharp score, KL-6, SP-D, chest CT. RESULTS: Anti-CCP antibody test had high specificity (93.5%). In RA with positive anti-CCP antibody, Sharp score (10.9+/-22.4) was higher than those with negative anti-CCP (1.7+/-1.8), and may serve as a prognostic marker of joint destruction (P<0.05). Anti-CCP antibody in RA with interstitial pneumonia is higher (84.5+/-36.4 U/mL) than those without interstitial pneumonia (52.6+/-44.7 U/mL) (P<0.05). CONCLUSION: Anti-CCP antibody is useful for diagnosis of RA, and could be a specific marker of joint destruction. Further investigation is necessary to clarify the relation of anti-CCP antibody with organ involvement and activity of RA.

Dong L, Masaki Y, Takegami T, Kawanami T, Itoh K, Jin ZX, Huang CR, Tong XP, Fukushima T, Tanaka M, Sawaki T, Sakai T, Sugai S, Okazaki T, Hirose Y, Umehara H. · Department of Hematology and Immunology, Kanazawa Medical University, Uchinada, Ishikawa 920-0293, Japan. · Int Immunol. · Pubmed #17272286 links to  free full text

Abstract: Serum titers of antibody to Epstein-Barr virus (EBV) viral capsid antigen (VCA) have been positively correlated with malignancies of lymphoid proliferation, such as Burkitt's lymphoma and Hodgkin's lymphoma. We have constructed a phage display combinatorial antibody Fab library from a patient with marginal zone B cell lymphoma associated with Sjögren's syndrome and carrying high serum anti-EBV-VCA IgG titer. Fab fragments were selected by panning against EBV-VCA protein coated onto ELISA plates, and selected Fab clones were characterized by ELISA, western blotting (WB), indirect immunofluorescence assay and immunohistochemistry. We have established two Fab clones, Fab-aVCA1 and Fab-aVCA21, which specifically recognize EBV-VCA by ELISA and WB. Inhibition ELISA competition showed that both clones could significantly reduce the binding of specific anti-EBV-VCA mAb to its relevant proteins. Furthermore, these two Fab clones could localize VCA protein in the EBV-positive P3HR1 and Daudi cell lines, as well as in tissue samples from patients with EBV-infected lymphoid malignancies. These results indicate that our two Fab clones are novel human mAbs specific for EBV-VCA protein and may have potential benefits for development of novel diagnostic and therapeutic approaches in EBV-related lymphoid malignancies.

Ogawa N, Kawanami T, Shimoyama K, Ping L, Sugai S. · Division of Hematology and Immunology, Department of Internal Medicine, Kanazawa Medical University, Kahoku-gun, Ishikawa-ken 920-0293, Japan. · Clin Immunol. · Pubmed #15308116 No free full text.

Abstract: To investigate the possible involvement of interferon-inducible T cell alpha chemoattractant (I-TAC or CXCL11) in the salivary gland lesions of Sjögren's syndrome (SS), I-TAC mRNA expression was assayed in cultured salivary epithelial cells by reverse transcriptase-polymerase chain reaction (RT-PCR). This transcript was not expressed by SS salivary epithelial cells in the absence of IFNgamma, but was expressed after cells were stimulated with IFNgamma. We found that IFNgamma was the only cytokine that induced I-TAC mRNA expression. I-TAC proteins were shown by ELISA to be secreted into the culture supernatants of SS salivary epithelial cells following IFNgamma stimulation. Moreover, immunohistochemical assays of minor salivary glands (MSG) showed that I-TAC was predominantly located in the ductal epithelium adjacent to lymphoid infiltrates in the SS salivary gland, indicating that ductal epithelial cells produce I-TAC proteins in response to stimulation with IFNgamma secreted by lymphocytes that infiltrate into SS salivary glands. In contrast, I-TAC proteins were virtually absent from normal salivary glands. These findings suggest that I-TAC is involved in the development of salivary gland lesions observed in SS.