Polymorphic lymphoproliferative disorders in patients with rheumatoid arthritis are associated with a better clinical outcome.

OBJECTIVES: The characteristics of lymphoproliferative disorders (LPD) in patients with rheumatoid arthritis (RA) remain unclear. Therefore, we retrospectively analyzed the clinical characteristics of these patients in our department. METHODS: Twenty RA patients who developed LPD between April 2003 and August 2016 in our department were analyzed. RESULTS: All of the RA patients who developed LPD had been treated with methotrexate (MTX). The median weekly and total dosages of MTX were 6.8 mg/week and 2530 mg, respectively. The median duration of MTX administration was eight years. Nineteen patients (95%) achieved complete remission (CR) and 15 (75%) achieved CR with MTX cessation alone. Based on the pathological findings, we divided MTX-associated LPD patients into two groups (n = 16); polymorphic LPD (31%) and other groups. CR with MTX cessation alone was achieved in 5 (100%) and 6 (54.5%) patients in the polymorphic LPD and other groups, respectively (p = .12). Moreover, the duration from the cessation of MTX to CR was significantly shorter in the polymorphic LPD group than in the other group (5.3 months vs 12.6 months, p = .01, respectively). CONCLUSION: Polymorphic LPD, which was the most frequent pathological diagnosis in this cohort, was associated with a higher incidence of CR and a significantly shorter duration to CR.

Thoracic intradural extramedullary lesions causing progressive myelopathy as an initial manifestation of granulomatosis with polyangiitis: a case report and review of literature.

CONTEXT: To our knowledge, only a few reports regarding the spinal involvement of granulomatosis with polyangiitis (GPA)-also termed as Wegener's granulomatosis-have been published. However, all these cases reportedly exhibited epidural tumor-like lesions or dural thickening. FINDINGS: We report the case of a 57-year-old woman with progressive myelopathy caused by multiple spinal lesions with GPA, which appeared to be protruding inwards, within the dura mater, on magnetic resonance imaging (MRI); these lesions were difficult to distinguish from intradural tumors. Moreover, these lesions exhibited low intensity on both T1- and T2-weighted MRI, and showed prominent enhancement on gadolinium-contrast imaging. Resection biopsy was effective for both diagnosis and the recovery of the neurological deficit. CONCLUSION: Based on these findings, we suggest that GPA lesions can exhibit variable patterns in the spine. Nevertheless, clinicians should consider the possibility of GPA in such cases, particularly when multiple, inwardly protruding tumor-like lesions are detected within the dura mater on MRI.

Neuromyelitis optica spectrum disorder complicated with Sjogren syndrome successfully treated with tocilizumab: A case report.

A 38-year-old woman with relapsing longitudinal extensive transverse myelitis and Sjogren's syndrome (SS) was admitted with lower extremity muscle weakness. Studies showed high serum titer of anti-aquaporin4 antibody and gadolinium-enhanced-MRI T1-weighted lesions within thoracic cord. Clinical findings suggested neuromyelitis optica-spectrum disorder (NMO-SD). High-dose corticosteroids, plasma exchange and cyclophosphamide were not effective. After starting tocilizumab, her neurological findings gradually improved. This report describes the first evidence to show tocilizumab could be effective for NMO-SD with SS.

Tracheobronchitis with dyspnea in a patient with ulcerative colitis.

We herein report the case of a 42-year-old man with a one-year history of ulcerative colitis who presented with exacerbated bloody diarrhea, a productive cough and increasing breathing difficulties. Colonoscopy revealed typical deep ulcers in the rectosigmoid colon and atypical multiple sucker-like ulcers in the transverse colon, and computed tomography of the chest demonstrated wall thickening of the trachea and bronchi. In addition, bronchoscopy showed ulcers in the trachea, and histopathology disclosed findings of necrosis and inflammation of the subepithelial tissue of the trachea. Based on these findings, the patient's respiratory symptoms were strongly suspected to be due to ulcerative colitis-related tracheobronchitis. Treatment with systemic corticosteroids subsequently resulted in a rapid clinical improvement.

A new T-cell activation mode for suboptimal doses of antigen under the full activation of T cells with different specificity.

Loss of tolerance for autoantigens is a common feature in autoimmune diseases. Bystander T-cell activation is the activation of T cells to produce functional changes through TCR-independent stimulation. Although bystander activation may be related to tolerance loss to multiple autoantigens, the activation mechanism of T cells directed to an autoantigen with limited amount is not clear. We investigated an activation mode of T cells (designated as "associator T cells") directed to a suboptimal dose of cognate antigen X in the presence of fully activated T cells (designated as "responder T cells") directed to an optimal dose of antigen Y. In in vitro coculture, the activation of associator T cells was dependent on the presentation of antigen X, and soluble factors from activated responder T cells were not sufficient. Therefore, we conclude this activation mode is different from bystander activation and named it "extended antigen priming (EAP)". T cells with EAP showed a different phenotype compared to conventionally primed cells, suggesting the unique nature of EAP. Intriguingly, EAP was dependent on the CD40-CD40L signaling pathway. Thus, the EAP model is a T-cell activation mode for suboptimal dose of antigen and presumably related to the immune response to autoantigens in autoimmune status.

Characteristics of granulomatosis with polyangiitis patients in Japan.

OBJECTIVES: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a disease with significant ethnic differences. Reports on characteristics of Japanese granulomatosis with polyangiitis (GPA) patients are limited, and this study was undertaken to determine the characteristics of Japanese GPA patients. METHODS: This was a retrospective chart study of 24 Japanese GPA patients. GPA was defined according to the European Medicines Agency algorithm. RESULTS: The percentage of MPO-ANCA-positive patients was 33.3%, higher than the percentages reported in studies from Western countries. MPO-ANCA-positive GPA patients differed from PR3-ANCA-positive GPA patients in organs involved at diagnosis with MPO-ANCA-positive patients having nose and sinus involvement less frequently compared to PR3-ANCA-positive patients. Interstitial lung infiltrates were more common among MPO-ANCA-positive GPA patients compared to PR3-ANCA-positive GPA patients. CONCLUSION: Among Japanese GPA patients, the proportion of MPO-ANCA-positive patients is higher compared to reports from Western countries, and those patients are often different from the classical picture of GPA.

CD4+CD25-LAG3+ regulatory T cells controlled by the transcription factor Egr-2.

Regulatory T cells (Tregs) are engaged in the maintenance of immunological self-tolerance and immune homeostasis. IL-10 has an important role in maintaining the normal immune state. Here, we show that IL-10-secreting Tregs can be delineated in normal mice as CD4(+)CD25(-)Foxp3(-) T cells that express lymphocyte activation gene 3 (LAG-3), an MHC-class-II-binding CD4 homolog. Although approximately 2% of the CD4(+)CD25(-) T cell population consisted of CD4(+)CD25(-)LAG3(+) T cells in the spleen, CD4(+)CD25(-)LAG3(+) T cells are enriched to approximately 8% in the Peyer's patch. They are hypoproliferative upon in vitro antigenic stimulation and suppress in vivo development of colitis. Gene expression analysis reveals that CD4(+)CD25(-)LAG3(+) Tregs characteristically express early growth response gene 2 (Egr-2), a key molecule for anergy induction. Retroviral gene transfer of Egr-2 converts naïve CD4(+) T cells into the IL-10-secreting and LAG-3-expressing phenotype, and Egr-2-transduced CD4(+) T cells exhibit antigen-specific immunosuppressive capacity in vivo. Unlike Foxp3(+) natural Tregs, high-affinity interactions with selecting peptide/MHC ligands expressed in the thymus do not induce the development of CD4(+)CD25(-)LAG3(+) Tregs. In contrast, the number of CD4(+)CD25(-)LAG3(+) Tregs is influenced by the presence of environmental microbiota. Thus, IL-10-secreting Egr-2(+)LAG3(+)CD4(+) Tregs can be exploited for the control of peripheral immunity.

Hepatocyte growth factor significantly suppresses collagen-induced arthritis in mice.

Hepatocyte growth factor (HGF) plays an important role in angiogenesis, cell proliferation, antifibrosis, and antiapoptosis. Moreover, recent studies have highlighted the immunosuppressive effect of HGF in animal models of allogenic heart transplantation and autoimmune myocarditis and in studies in vitro as well. We also reported that HGF significantly suppresses dendritic cell function, thus down-regulating Ag-induced Th1-type and Th2-type immune responses in allergic airway inflammation. However, the immunosuppressive effect of HGF in many other situations has not been fully clarified. In the present study, using a mouse model of collagen-induced arthritis (CIA) and experiments in vitro, we examined the effect of HGF on autoimmune arthritis and then elucidated the mechanisms of action of HGF. To achieve sufficient delivery of HGF, we used biodegradable gelatin hydrogels as a carrier. HGF suppressed Ag-induced T cell priming by regulating the functions of dendritic cells in the Ag-sensitization phase with down-regulation of IL-10. In contrast, under continuous Ag stimulation HGF induced IL-10-producing immunocytes both in vivo and in vitro. Moreover, HGF potently inhibited the development of CIA with enhancing the Th2-type immune response. We also confirmed that HGF significantly suppressed the production of IL-17 by immunocytes. These results indicate that HGF suppresses the development of CIA through different ways at different phases. They also suggest that HGF could be an attractive tool for treating patients with rheumatoid arthritis.