Shoko Matsui

Proposal for a new clinical entity, IgG4-positive multiorgan lymphoproliferative syndrome: analysis of 64 cases of IgG4-related disorders

Background: Mikulicz’s disease (MD) has been considered as one manifestation of Sjögren’s syndrome (SS). Recently, it has also been considered as an IgG4-related disorder. Objective: To determine the differences between IgG4-related disorders including MD and SS. Methods: A study was undertaken to investigate patients with MD and IgG4-related disorders registered in Japan and to set up provisional criteria for the new clinical entity IgG4-positive multiorgan lymphoproliferative syndrome (IgG4+MOLPS). The preliminary diagnostic criteria include raised serum levels of IgG4 (>135 mg/dl) and infiltration of IgG4+ plasma cells in the tissue (IgG4+/IgG+ plasma cells >50%) with fibrosis or sclerosis. The clinical features, laboratory data and pathologies of 64 patients with IgG4+MOLPS and 31 patients with typical SS were compared. Results: The incidence of xerostomia, xerophthalmia and arthralgia, rheumatoid factor and antinuclear, antiSS-A/Ro and antiSS-B/La antibodies was significantly lower in patients with IgG4+MOLPS than in those with typical SS. Allergic rhinitis and autoimmune pancreatitis were significantly more frequent and total IgG, IgG2, IgG4 and IgE levels were significantly increased in IgG4+MOLPS. Histological specimens from patients with IgG4+MOLPS revealed marked IgG4+ plasma cell infiltration. Many patients with IgG4+MOLPS had lymphocytic follicle formation, but lymphoepithelial lesions were rare. Few IgG4+ cells were seen in the tissue of patients with typical SS. Thirty-eight patients with IgG4+MOLPS treated with glucocorticoids showed marked clinical improvement. Conclusion: Despite similarities in the involved organs, there are considerable clinical and pathological differences between IgG4+MOLPS and SS. Based on the clinical features and good response to glucocorticoids, we propose a new clinical entity: IgG4+MOLPS.

A novel clinical entity, IgG4-related disease (IgG4RD): general concept and details

IgG4-related disease (IgG4RD) is a novel clinical disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4-positive plasma cells. IgG4RD may be present in a certain proportion of patients with a wide variety of diseases, including Mikulicz’s disease, autoimmune pancreatitis, hypophysitis, Riedel thyroiditis, interstitial pneumonitis, interstitial nephritis, prostatitis, lymphadenopathy, retroperitoneal fibrosis, inflammatory aortic aneurysm, and inflammatory pseudotumor. Although IgG4RD forms a distinct, clinically independent disease category and is attracting strong attention as a new clinical entity, many questions and problems still remain to be elucidated, including its pathogenesis, the establishment of diagnostic criteria, and the role of IgG4. Here we describe the concept of IgG4RD and up-to-date information on this emerging disease entity.

International consensus guidance statement on the management and treatment of IgG4-related disease

A. Khosroshahi, Z. S. Wallace, J. L. Crowe, T. Akamizu, A. Azumi, M. N. Carruthers, S. T. Chari, E. Della-Torre, L. Frulloni, H. Goto, P. A. Hart, T. Kamisawa, S. Kawa, M. Kawano, M. H. Kim, Y. Kodama, K. Kubota, M. M. Lerch, M. L€ ohr, Y. Masaki, S. Matsui, T. Mimori, S. Nakamura, T. Nakazawa, H. Ohara, K. Okazaki, J. H. Ryu, T. Saeki, N. Schleinitz, A. Shimatsu, T. Shimosegawa, H. Takahashi, M. Takahira, A. Tanaka, M. Topazian, H. Umehara, G. J. Webster, T. E. Witzig, M. Yamamoto, W. Zhang, T. Chiba, and J. H. Stone

Cutoff Values of Serum IgG4 and Histopathological IgG4+ Plasma Cells for Diagnosis of Patients with IgG4-Related Disease.

IgG4-related disease is a new disease classification established in Japan in the 21st century. Patients with IgG4-related disease display hyper-IgG4-gammaglobulinemia, massive infiltration of IgG4+ plasma cells into tissue, and good response to glucocorticoids. Since IgG4 overexpression is also observed in other disorders, it is necessary to diagnose IgG4-related disease carefully and correctly. We therefore sought to determine cutoff values for serum IgG4 and IgG4/IgG and for IgG4+/IgG+ plasma cells in tissue diagnostic of IgG4-related disease. Patients and Methods. We retrospectively analyzed serum IgG4 concentrations and IgG4/IgG ratio and IgG4+/IgG+ plasma cell ratio in tissues of 132 patients with IgG4-related disease and 48 patients with other disorders. Result. Serum IgG4 >135  mg/dl demonstrated a sensitivity of 97.0% and a specificity of 79.6% in diagnosing IgG4-related disease, and serum IgG4/IgG ratios >8% had a sensitivity and specificity of 95.5% and 87.5%, respectively. IgG4+cell/IgG+ cell ratio in tissues >40% had a sensitivity and specificity of 94.4% and 85.7%, respectively. However, the number of IgG4+ cells was reduced in severely fibrotic parts of tissues. Conclusion. Although a recent unanimous consensus of all relevant researchers in Japan recently established the diagnostic criteria for IgG4-related disease, findings such as ours indicate that further discussion is needed.

Immunoglobulin G4-related lung disease: Clinicoradiological and pathological features

Immunoglobulin G4 (IgG4)‐related disease is a multi‐organ disorder that can include the lungs. IgG4‐related lung disease can present in various forms; the clinical, radiological and pathological features of patients with this disease have been assessed.

Reactive oxygen intermediates stimulate interleukin-6 production in human bronchial epithelial cells

Reactive oxygen intermediates (ROIs) play an important role in the initiation and progression of lung diseases. In this study, we investigated whether ROIs were involved in the induction of interleukin (IL)-6 in human bronchial epithelial cells. We exposed normal human bronchial epithelial cells as well as a human bronchial epithelial cell line, HS-24, to ROIs. We measured the amount of IL-6 in the culture supernatants using ELISA and the IL-6 mRNA levels using RT-PCR. Superoxide anions (O-2), but not hydrogen peroxide (H2O2), increased IL-6 production. To examine whether it is a cell type-specific mechanism of airway epithelial cells, the experiments were also performed in human lung fibroblasts, WI-38-40. In WI-38-40 cells, neither O-2 nor H2O2 increased IL-6 production. In contrast, tumor necrosis factor (TNF)-alpha (200 U/ml) induced IL-6 at the protein and mRNA levels in both airway epithelial cells and lung fibroblasts. This cytokine-induced IL-6 production was significantly suppressed by several antioxidants, including dimethyl sulfoxide (DMSO), in airway epithelial cells. In WI-38-40 cells, DMSO was not able to suppress IL-6 production induced by TNF-alpha. Pretreatment with DMSO recovered the TNF-alpha-induced depletion of intracellular reduced glutathione in HS-24 cells. These findings indicate that oxidant stress specifically induces IL-6 production in human bronchial epithelial cells and that in these cells ROIs may be involved in IL-6 production after stimulation with cytokines such as TNF-alpha. Presumably, ROIs participate in the local immune response in lung diseases via IL-6 release from bronchial epithelial cells.

SRT1720, a SIRT1 activator, promotes tumor cell migration, and lung metastasis of breast cancer in mice

Silent information regulator 2 (SIR2) is a highly conserved protein, the mammalian orthologue of which, SIRT1, exhibits histone deacetylase activity. SIRT1 is involved not in only longevity due to caloric restriction but in a variety of diseases such as diabetes, cardiovascular dysfunction and neurodegeneration. However, accumulating evidence shows that SIRT1 is overexpressed in various types of malignant cells, and its inhibitors suppress the growth of tumor cells. The relationship between SIRT1 and metastasis remains to be clarified. Here, we examined the effect of SRT1720, a SIRT1 activator, on lung metastasis of breast cancer cells. 4T1 breast cancer cells were subcutaneously implanted into syngeneic BALB/c mice and SRT1720 was administered alone or with an antitumor agent, cisplatin. As expected, cisplatin decreased the lung metastasis score, whereas SRT1720 increased metastasis irrespective of cisplatin. In the primary tumors, cisplatin suppressed the mRNA level of angiopoietin-like protein 4 (angptl4), a lung metastasis-promoting gene product of breast cancer, but SRT1720 reduced the effectiveness of cisplatin. The results obtained with animal experiments were in accordance with those in human cancer cells; SRT1720 significantly increased the amount of VEGF secreted from MDA-MB-231 cells. Moreover, a transendothelial cell migration assay showed that SRT1720 promotes the migration of MDA-MB-231 cells across an endothelial cell layer despite the presence of cisplatin. These findings imply that SRT1720 promotes the pulmonary metastasis of breast cancer cells and SIRT1 may be an important target for suppressing metastasis to the lung.

Sirtuin 1 activator SRT1720 suppresses inflammation in an ovalbumin-induced mouse model of asthma.

Background and objective:  In asthma, reduced histone deacetylase activity and enhanced histone acetyltransferase activity in the lungs have been reported. However, the precise function of Sirtuin 1 (Sirt1), a class III histone deacetylase, and the effect of the Sirt1 activator SRT1720 on allergic inflammation have not been fully elucidated.

Doxorubicin induces expression of multidrug resistance-associated protein 1 in human small cell lung cancer cell lines by the c-jun N-terminal kinase pathway.

Multidrug resistance (MDR) is a major impediment to successful chemotherapy for lung cancer. Overexpression of multidrug resistance‐associated protein 1 (MRP1) appears to be involved in MDR development in lung cancer cells. A number of chemotherapeutic agents including doxorubicin (DOX) were reported to induce MRP1 expression in human lung cancer cells. In our study, we investigated the mechanism by which DOX induces MRP1 expression in human small cell lung cancer (SCLC) cell lines, GLC4 and NCI‐H82. These cells expressed MRP1 protein at low levels and were sensitive to DOX. Doxorubicin at 50 nM induced a marked increase in MRP1 expression in 24 hr, and stimulated c‐jun N‐terminal kinase (JNK) activity. Treatment with a JNK inhibitor, SP600125, significantly inhibited MRP1 induction. Furthermore, transfection with JNK1 and JNK2 antisense oligonucleotides markedly inhibited DOX‐induced MRP1 expression. Chromatin immunoprecipitation assays revealed an enhanced recruitment of phosphorylated c‐jun to the MRP1 promoter containing the AP‐1 site upon DOX stimulation, which was inhibited by pretreatment with SP600125. Surprisingly, GLC4 cells exposed to DOX for 24 hr maintained increased MRP1 expression and resistance to DOX for at least 3 weeks. Pretreatment with SP600125 before DOX stimulation blocked the appearance of the MDR phenotype as well as MRP1 induction in GLC4 cells. These findings suggest that JNK activation may play an essential role for the induction of MRP1 protein in human SCLC cells by chemotherapeutic agents and that combined treatment of a JNK inhibitor with anticancer drugs may prevent the development of MDR by the abrogation of MRP1 induction.

Association between IgG4-related disease and progressively transformed germinal centers of lymph nodes

Progressively transformed germinal centers is a benign condition of unknown pathogenesis characterized by a distinctive variant form of reactive follicular hyperplasia in lymph nodes. We recently reported Ig G4-related disease in progressively transformed germinal centers. However, no large case series has been reported and clinicopathologic findings remain unclear. Here, we report 40 Japanese patients (28 men, 12 women; median age, 56 years) with progressively transformed germinal centers of the lymph nodes who fulfilled the histological diagnostic criteria for IgG4-related disease (IgG4+ progressively transformed germinal centers), with asymptomatic localized lymphadenopathy involving the submandibular nodes in 24, submandibular and cervical nodes in 14, cervical nodes only in 1, and cervical and supraclavicular nodes in 1. In all, 16 (52%) of 31 examined patients had allergic disease. Histologically, the lymph nodes demonstrated uniform histological findings, namely marked follicular hyperplasia with progressively transformed germinal centers, and localization of the majority of IgG4+ plasma cells in the germinal centers. Serum IgG4, serum IgE and peripheral blood eosinophils were elevated in 87%, 92% and 53% of examined patients, respectively. Eighteen patients subsequently developed extranodal lesions (including five who developed systemic disease), which on histological examination were consistent with IgG4-related disease. IgG4+ progressively transformed germinal centers presents with uniform clinicopathological features of asymptomatic localized submandibular lymphadenopathy, which persists and/or relapses, and sometimes progresses to extranodal lesions or systemic disease. Nine patients were administered steroid therapy when the lesions progressed, to which all responded well. We suggest that IgG4+ progressively transformed germinal centers should be included in the IgG4-related disease spectrum.