Adult dermatomyositis with bleeding ulcer in the pharynx.

Dermatomyositis (DM) is one of the idiopathic inflammatory myopathies caused by complement-mediated vasculopathy or vasculitis in the muscle. Although the gastrointestinal (GI) mucosa has been reported to be involved as a result of vasculitis or vasculopathy, ulceration in the pharynx is a rare manifestation of DM. A 54-year-old woman complaining of muscle weakness in the extremities, low-grade fever, and dysphagia was diagnosed as having DM. Despite medical treatment with corticosteroids and immunosuppressive agents, her DM progressed rapidly, leading to exacerbation of the dysphagia. About 3 weeks after undergoing tracheostomy as a preventive measure against aspiration, the patient developed intractable respiratory tract hemorrhage. Repeated laryngoendoscopy revealed a bleeding ulceration in the pharynx that required hemostasis with electric cautery under general anesthesia. No bleeding recurred thereafter. Histopathologically, the pharynx exhibited nonspecific inflammatory cell infiltration in the muscle tissue. This rare manifestation may be considered in cases of DM with unexplainable airway bleeding.

Clinical usefulness of anti-RNA polymerase III antibody measurement by enzyme-linked immunosorbent assay.

OBJECTIVE: To evaluate the clinical usefulness of measuring anti-RNA polymerase (RNAP) III antibody with a commercially available ELISA in Japanese patients with SSc. METHODS: This multicentre study involved 354 patients with SSc, 245 with non-SSc CTDs and 102 healthy controls. ELISAs were used to detect anti-RNAP III antibody, anti-topo I antibody and ACA. The presence of anti-RNAP III antibody in selected serum samples was confirmed by immunoprecipitation (IP) assay. RESULTS: By ELISA, anti-RNAP III antibody was detected in 38 (10.7%) patients with SSc, 3 (1.2%) with non-SSc CTD and no healthy controls. The clinical specificity for SSc was excellent (98.8%), although a small number of false positives occurred. The sensitivity of the anti-topo I and ACA ELISAs for SSc was 59.9%, which increased to 68.2% without a reduction in specificity when the anti-RNAP III measurement was added. Clinical features associated with positivity for the anti-RNAP III antibody include dcSSc, a high total skin score and a trend towards high prevalence of renal crisis, consistent with previous studies that used an IP assay. Furthermore, on clinical severity scales, SSc patients with anti-RNAP III antibody scored highest for skin and renal involvement among patients subgrouped by the presence of individual SSc-related antibodies. CONCLUSIONS: The measurement of anti-RNAP III antibody by ELISA is useful in routine clinical practice, because it helps diagnose SSc and identify a disease subset with severe skin and renal involvement.

Myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitis with diffuse tubulointerstitial nephritis.

Renal involvement in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is characterized by focal segmental crescentic and/or necrotizing glomerulonephritis. Here, we report the case of a 66-year-old woman showing myeloperoxidase (MPO)-ANCA positivity and mononeuritis multiplex whose kidney biopsy revealed severe and diffuse tubulointerstitial nephritis despite the fact that crescentic necrotizing glomerulonephritis was focal. The mechanism of tubulointerstitial injury in ANCA-associated vasculitis remains unclear. Further studies are necessary to confirm the relationship between diffuse tubulointerstitial nephritis and ANCA-associated vasculitis.

Severe airflow limitation in two patients with systemic lupus erythematosus: effect of inhalation of anticholinergics.

Airway involvement clinically presenting as dyspnea and an obstructive ventilatory defect is a rare but clinically important complication in systemic lupus erythematosus (SLE), since the airway manifestation is often progressive and resistant to systemic immunosuppressive therapy. Here we report two SLE patients with slowly progressive airflow limitation, which was clinically thought to be bronchiolitis obliterans. Both patients showed obvious improvement after inhalation of anticholinergics was started. Because anticholinergics are highly safe and never immunosuppressive, inhalation of these drugs might be useful in the therapeutic strategies for airflow limitation accompanying SLE or other collagen diseases.

Polymyositis associated with focal mesangial proliferative glomerulonephritis with depositions of immune complexes.

A 58-year-old man concurrently developed polymyositis (PM), interstitial lung disease, and nephrotic-range proteinuria. Renal biopsy revealed focal mesangial proliferative glomerulonephritis (mesPGN) with depositions of immunoglobulin and complements. A combination therapy of corticosteroid, intravenous immunoglobulin, and cyclosporine was found very effective for the patient. Glomerulonephritis associated with PM/dermatomyositis (DM) is rare. In our review of related literature, mesPGN was exclusively observed in polymyositis while membranous nephropathy in DM. The mechanism underlying the association between myositis and glomerulonephritis remains to be elucidated.

Wegener's granulomatosis with eosinophilia.

Wegener's granulomatosis with eosinophilia both in blood and tissue samples has been rarely reported. A 25-year-old woman developed fever, granulomatous inflammation of nasal mucosa, pulmonary hemorrhage, suprascleritis, and cutaneous vasculitis. She showed eosinophilia in blood and biospy samples of skin, nasal mucosa, and lung. She was positive for proteinase 3-antineutrophil cytoplasmic antibody. She had no history of asthma. We diagnosed her as Wegener's granulomatosis with eosinophilia rather than Churg-Strauss syndrome. Her mucocutaneous and pulmonary lesions were successfully treated with high-dose corticosteroid and methotrexate, but her suprascleritis required pulsed cyclophosphamide.

Suppression of T cell responses by chondromodulin I, a cartilage-derived angiogenesis inhibitory factor: therapeutic potential in rheumatoid arthritis.

OBJECTIVE: Chondromodulin I (ChM-I), a cartilage matrix protein, promotes the growth and proteoglycan synthesis of chondrocytes. However, it also inhibits angiogenesis. Since ChM-I is expressed not only in cartilage, but also in the thymus, we investigated the modulation of T cell function by ChM-I to assess its therapeutic potential in rheumatoid arthritis (RA). METHODS: The localization of ChM-I expression in mouse thymus tissue was examined by in situ hybridization. The proliferative response of peripheral blood T cells and synovial cells obtained from patients with RA was evaluated by (3)H-thymidine incorporation assay. The effects of ChM-I were examined using recombinant human ChM-I (rHuChM-I). Modulation of the antigen-specific immune response was evaluated by the recall response of splenic T cells and the delayed-type hypersensitivity response induced in the ear of mice primed with ovalbumin (OVA). Antigen-induced arthritis (AIA) was induced in mice by injecting methylated bovine serum albumin into the ankle joints 2 weeks after the priming. RESULTS: ChM-I was expressed in the cortex of the thymus. Recombinant human ChM-I suppressed the proliferative response of mouse splenic T cells and human peripheral blood T cells stimulated with anti-CD3/CD28 antibodies, in a dose-dependent manner. Production of interleukin-2 was decreased in rHuChM-I-treated mouse CD4 T cells. Ten micrograms of rHuChM-I injected intraperitoneally into OVA-primed mice suppressed the induction of the antigen-specific immune response. Finally, rHuChM-I suppressed the development of AIA, and also suppressed the proliferation of synovial cells prepared from the joints of patients with RA. CONCLUSION: These results suggest that ChM-I suppresses T cell responses and synovial cell proliferation, implying that this cartilage matrix protein has a therapeutic potential in RA.

T cells accumulating in the inflamed joints of a spontaneous murine model of rheumatoid arthritis become restricted to common clonotypes during disease progression.

Although a number of studies have revealed that T cells expand clonally in the joints of patients suffering from rheumatoid arthritis (RA), the kinetics of T cell clonality in multiple joints of an individual throughout progression of the disease is not known. By employing a TCR beta chain gene-specific RT-PCR and subsequent single-strand conformation polymorphism, which enables us to monitor T cell clonality, we analyzed transgenic mice (Tg) carrying the human T cell leukemia virus type I env-pX region. These mice spontaneously develop destructive progressive arthritis similar to RA as they age. In the early stage, the majority of accumulating T cell clones differed in each of four affected feet analyzed. However, in the advanced stage, many of the clones were common to all four feet. The total number of distinct clones gradually decreased as the disease progressed. When splenocytes from arthritic elder Tg were adoptively transferred into either nude mice or young Tg, the clones common to all four feet of the donor were detected again in four feet of the recipients. These findings suggest that, as arthritis progresses, the T cell clones accumulating in the arthritic joints are gradually restricted to certain common clonotypes, some of which are arthrotropic.

Analysis of accumulating clonotypes of T cell in joints of a spontaneous murine model of rheumatoid arthritis.

SKG mouse, as a model of spontaneous rheumatoid arthritis (RA) bred recent years, is similar to the patients with RA. We analyzed the clonotypes of T cell infiltrating into joints of SKG mice in initial stage and late stage of RA by using reverse transcriptase-polymerase chain reaction (RT-PCR) and subsequent single-strand conformation polymorphism (SSCP). The results indicated that the percentages of clonotypes TCR Vbeta2 and Vbeta8.2 of T cell clonotypes increased obviously to 72.3% and 60.2%, respectively. Mice number with identical TCR Vbeta2 and Vbeta8.2 clonotypes also clearly increased in late stage of disease to 100% and 75%, respectively. These results mean that T cells with TCR Vbeta2 and Vbeta8.2 clonotypes probably play an important role in RA progression of SKG mouse. Sequencing of the extracted DNA verified that common bands on SSCP gel were derived from the same T cell clones among samples from different joints. The results we obtained implied that RT-PCR/SSCP method was a sensitive and credible method for analyzing T cell clonotypes. When the T cells of SKG mouse were adoptively transferred to a nude mouse, it was verified that the T cells infiltrating into joints were related to morbid formation of RA.

[A case of eosinophilic lung disease presenting asthma-like symptoms and centrilobular shadows in both lung fields].

This case, in a 23-year-old man presenting with cough, sputum, dyspnea on effort and wheezing, had been diagnosed as bronchial asthma at another hospital. Because inhaled steroid and theophylline were far from effective, he was admitted to our hospital for further evaluation. A blood test revealed marked eosinophilia. Chest radiography showed diffuse, small nodular shadows in both lung fields, and a chest CT scan demonstrated diffuse centrilobular nodules and thickening of the bronchi and bronchioles. A spirometric test showed obstructive and restrictive ventilatory impairment, but the depressed forced vital capacity failed to show improvement in response to bronchodilator inhalation, discouraging a diagnosis of asthma. Eosinophilic lung disease with prominent eosinophilic bronchiolitis was diagnosed on the basis of BAL eosinophilia and thoracoscopic lung biopsy findings. The symptoms and blood eosinophilia were responsive to administration of oral prednisolone (30 mg daily); radiographic and CT findings also showed improvement. This case showed a marked similarity to the recently reported "eosinophilic bronchiolitis", and was probably not a type of bronchial asthma.

Reconstitution of CD8+ T cells by retroviral transfer of the TCR alpha beta-chain genes isolated from a clonally expanded P815-infiltrating lymphocyte.

Gene transfer of TCR alphabeta-chains into T cells may be a promising strategy for providing valuable T lymphocytes in the treatment of tumors and other immune-mediated disorders. We report in this study the reconstitution of CD8(+) T cells by transfer of TCR alphabeta-chain genes derived from an infiltrating T cell into P815. Analysis of the clonal expansion and Vbeta subfamily usage of CD8(+) TIL in the tumor sites demonstrated that T cells using Vbeta10 efficiently infiltrated and expanded clonally. The TCR alpha- and beta-chain sequences derived from a tumor-infiltrating CD8(+)/Vbeta10(+) single T cell clone (P09-2C clone) were simultaneously determined by the RT-PCR/single-strand conformational polymorphism method and the single-cell PCR method. When P09-2C TCR alphabeta-chain genes were retrovirally introduced into CD8(+) T cells, the reconstituted T cells positively lysed the P815 tumor cells, but not the A20, EL4, or YAC-1 cells, in vitro. In addition, the CTL activity was blocked by the anti-H2L(d) mAb. Furthermore, T cells containing both TCR alpha- and beta-chains, but not TCR beta-chain alone, accumulated at the tumor-inoculated site when the reconstituted CD8(+) T cells were adoptively transferred to tumor-bearing nude mice. These findings suggest that it is possible to reconstitute functional tumor-specific CD8(+) T cells by transfer of TCR alphabeta-chain genes derived from TIL, and that such T cells might be useful as cytotoxic effector cells or as a vehicle for delivering therapeutic agents.

Evaluation of functional disability using the health assessment questionnaire in Japanese patients with systemic sclerosis.

OBJECTIVE: To assess whether the functional disability in Japanese patients with systemic sclerosis (SSc) can be adequately evaluated by the Health Assessment Questionnaire (HAQ) developed in the United States. METHODS: The HAQ was completed by 121 Japanese patients with SSc, in whom SSc-specific physical examinations and laboratory tests were performed at the same time. Clinical findings associated with the disability index (DI) and individual components of the HAQ were examined using Student's t tests and Pearson's correlation tests. Logistic regression analysis was used to identify clinical findings that independently contributed to the increase in the HAQ-DI score. RESULTS: Japanese patients with SSc had significant functional disability, especially in the categories of eating and gripping, but the degree of disability was much less than was reported in previous studies carried out in the US. The increase in the HAQ-DI score was strongly correlated with increased total skin score, reduced oral aperture, reduced hand extension, increased finger flexion, subcutaneous calcinosis, flexion contractures, increased erythrocyte sedimentation rates, decreased percent vital capacity, and vascular involvement (p < 0.001 for all correlations). Multivariate logistic regression analysis showed that hand extension was the most important and an independent correlate of the HAQ-DI. CONCLUSION: Our multicenter, cross-sectional study has demonstrated that the self-administered HAQ is a valuable assessment tool of functional disability in Japanese SSc patients, who have social customs different from Americans, but functional disability measured by the HAQ is potentially influenced by ethnic variability.

Generation of CD4(+)CD25(+) regulatory T cells from autoreactive T cells simultaneously with their negative selection in the thymus and from nonautoreactive T cells by endogenous TCR expression.

Normal T cell repertoire contains regulatory T cells that control autoimmune responses in the periphery. One recent study demonstrated that CD4(+)CD25(+) T cells were generated from autoreactive T cells without negative selection. However, it is unclear whether, in general, positive selection and negative selection of autoreactive T cells are mutually exclusive processes in the thymus. To investigate the ontogeny of CD4(+)CD25(+) regulatory T cells, neo-autoantigen-bearing transgenic mice expressing chicken egg OVA systemically in the nuclei (Ld-nOVA) were crossed with transgenic mice expressing an OVA-specific TCR (DO11.10). Ld-nOVA x DO11.10 mice had increased numbers of CD4(+)CD25(+) regulatory T cells in the thymus and the periphery despite clonal deletion. In Ld-nOVA x DO11.10 mice, T cells expressing endogenous TCR alpha beta chains were CD4(+)CD25(-) T cells, whereas T cells expressing autoreactive TCR were selected as CD4(+)CD25(+) T cells, which were exclusively dominant in recombination-activating gene 2-deficient Ld-nOVA x DO11.10 mice. In contrast, in DO11.10 mice, CD4(+)CD25(+) T cells expressed endogenous TCR alpha beta chains, which disappeared in recombination-activating gene 2-deficient DO11.10 mice. These results indicate that part of autoreactive T cells that have a high affinity TCR enough to cause clonal deletion could be positively selected as CD4(+)CD25(+) T cells in the thymus. Furthermore, it is suggested that endogenous TCR gene rearrangement might critically contribute to the generation of CD4(+)CD25(+) T cells from nonautoreactive T cell repertoire, at least under the limited conditions such as TCR-transgenic models, as well as the generation of CD4(+)CD25(-) T cells from autoreactive T cell repertoire.

Peripheral tolerance to a nuclear autoantigen: dendritic cells expressing a nuclear autoantigen lead to persistent anergic state of CD4+ autoreactive T cells after proliferation.

It remains unknown why the T cell tolerance to nuclear autoantigens is impaired in systemic autoimmune diseases. To clarify this, we generated transgenic mice expressing OVA mainly in the nuclei (Ld-nOVA mice). When CD4+ T cells from DO11.10 mice expressing a TCR specific for OVA(323-339) were transferred into Ld-nOVA mice, they were rendered anergic, but persisted in vivo for at least 3 mo. These cells expressed CD44(high), CD45RB(low), and were generated after multiple cell divisions, suggesting that anergy is not the result of insufficient proliferative stimuli. Whereas dendritic cells (DCs) from Ld-nOVA (DCs derived from transgenic mice (TgDCs)), which present rather low amount of the self-peptide, efficiently induced proliferation of DO11.10 T cells, divided T cells stimulated in vivo by TgDCs exhibited a lower memory response than T cells stimulated in vitro by peptide-pulsed DCs. Furthermore, we found that repeated transfer of either TgDCs or DCs derived from wild-type mice pulsed with a lower concentration of OVA(323-339) induced a lower response of DO11.10 T cells in Ag-free wild-type recipients than DCs derived from wild-type mice. These results suggest that peripheral tolerance to a nuclear autoantigen is achieved by continuous presentation of the self-peptide by DCs, and that the low expression level of the peptide might also be involved in the induction of hyporesponsiveness.

[Acute exacerbation of interstitial pneumonia associated with active systemic lupus erythematosus in a patient with rheumatoid arthritis].

A 36-year-old woman with rheumatoid arthritis was admitted to our hospital for evaluation of newly developed active systemic lupus erythematosus (SLE). After hospitalization, she showed progressive respiratory failure. Chest CT revealed exacerbation of interstitial pneumonia, showing acute development of air-space consolidation and ground-glass opacity in addition to intensified reticular shadows. Administration of high-dose corticosteroids and cyclosporine A resulted in recovery from respiratory failure, accompanied by obvious improvement in the chest radiographs and CT, as demonstrated by the disappearance of air-space consolidation and ground-glass opacity. Clinically, the exacerbation of her interstitial pneumonia was compatible with acute lupus pneumonitis, a rare complication with active SLE.