Ovarian clear cell carcinoma with plasma cell-rich inflammatory stroma: Cytological Findings of a Case.

We report a case of clear cell carcinoma (CCC) of the ovary with plasma cell-rich inflammatory stroma, a recently proposed subtype of CCC, and present the cytological findings. The patient was a 48-year-old woman, who was incidentally found to have a right ovarian tumor during the preoperative work-up for an early-stage adenocarcinoma of the uterine cervix. Cytological examination of an imprint smear of the ovarian tumor and peritoneal washing revealed solid cell clusters of irregular, often dendritic shapes, which were intermingled with many inflammatory cells. "Raspberry bodies" were not found. Histopathological examination of the extirpated ovarian tumor showed the features of CCC with plasma cell-rich inflammatory stroma. This subtype of ovarian CCC poses cytological and histological diagnostic problems, and its differentiation from dysgerminoma is often difficult, because it mostly lacks the hyaline or mucoid stroma. Irregularly shaped clusters of large polyhedral cells, coarsely clumped nuclear chromatin, and plasma cell-rich inflammatory infiltrates suggest CCC, but the cytological differences between dysgerminoma and CCC are often subtle, and immunohistochemical examinations for cytokeratin 7 or epithelial membrane antigen may be necessary. Diagn. Cytopathol. 2017;45:128-132. © 2016 Wiley Periodicals, Inc.

The RNA Binding Protein Mex-3B Is Required for IL-33 Induction in the Development of Allergic Airway Inflammation.

Allergic airway inflammation is one of the primary features of allergic asthma. Interleukin-33 (IL-33) is recognized as a key pro-inflammatory cytokine that mediates allergic airway inflammation, and its expression is elevated in this condition, but little is known about the regulatory mechanisms underlying IL-33 induction. Here, we show that the RNA binding protein Mex-3B plays a critical role in the induction of IL-33 in the development of allergic airway inflammation. We generated Mex3b(-/-) mice and found that they develop significantly less airway inflammation than wild-type mice due to reduced induction of IL-33. Furthermore, we show that Mex-3B directly upregulates IL-33 expression by inhibiting miR-487b-3p-mediated repression of IL-33. Moreover, we show that inhalation of an antisense oligonucleotide targeting Mex-3B suppresses allergic airway inflammation. Our data identify a signaling pathway that post-transcriptionally regulates IL-33 expression and suggest that Mex-3B could be a promising molecular target for the treatment of allergic asthma.

Assessment of risks of pulmonary infection during 12 months following immunosuppressive treatment for active connective tissue diseases: a large-scale prospective cohort study.

OBJECTIVE: Pulmonary infections (PI) are leading causes of death in patients with connective tissue diseases (CTD). The PREVENT study (Pulmonary infections in patients REceiving immunosuppressiVE treatmeNT for CTD) assessed risk of PI in patients with active CTD in the contemporary era of advanced immunosuppressive therapy. METHODS: In patients who started corticosteroids (n = 763), conventional immunosuppressants or biologics for active CTD were enrolled. Clinical and laboratory data, usage of drugs, and occurrence of PI were collected for 12 months. Baseline risk factors were investigated using Cox regression analysis. A nested case-control (NCC) study was performed with 1:2 matched case-control pairs to assess the risk for each drug category. RESULTS: During the observation period, 32 patients died (4.2%) and 66 patients were lost to followup (8.6%). Patients with PI (n = 61, 8%) had a significantly worse accumulated survival rate than patients without (p < 0.01). Cox hazard regression analysis using baseline data showed that these factors were significantly associated with PI: age ≥ 65 years (HR 3.87, 95% CI 2.22-6.74), ≥ 20 pack-years of smoking (2.63, 1.37-5.04), higher serum creatinine level (1.21, 1.05-1.41 per 1.0 mg/dl increase), and maximum prednisolone (PSL) dose during the first 2 weeks of treatment (2.81, 1.35-5.86 per 1.0 mg/kg/day increase). Logistic regression analysis by an NCC study revealed that maximum PSL dose within 14 days before PI (OR 4.82, 95% CI 1.36-17.01 per 1.0 mg/dl increase; 2.57, 1.28-5.16 if ≥ 0.5 mg/kg/day) was significantly associated with the events, while other immunosuppressants were not. CONCLUSION: Physicians should be aware of the higher risks for corticosteroids of PI than other immunosuppressants and assess these risk factors before immunosuppressive treatment, to prevent PI.

Pulmonary infections following immunosuppressive treatments during hospitalization worsen the short-term vital prognosis for patients with connective tissue disease-associated interstitial pneumonia.

OBJECTIVE: Connective tissue disease-associated interstitial pneumonia (CTD-IP) significantly affects the mortality of patients with CTD. The purpose of the present study is to identify causes and risk factors for death during hospitalization for immunosuppressive treatment of CTD-IP. METHODS: A multicenter, retrospective study was conducted that collected data from patients with CTD who had been hospitalized for commencing or intensifying immunosuppressive treatment of CTD-IP using a standardized case report form. Risk factors were identified using the Cox proportional hazard regression model. RESULTS: A total of 322 CTD-IP patients were enrolled with rheumatoid arthritis (n = 84), systemic lupus erythematosus (n = 13), polymyositis (n = 33), dermatomyositis (n = 69), systemic sclerosis (n = 55), mixed connective tissue disease (n = 21), microscopic polyangiitis (n = 19), and overlap syndrome (n = 28). Of the 42 patients who died during hospitalization, 22 died from CTD-IP, 15 from CTD-IP and pulmonary infection, 2 from pulmonary infection, and 3 from other causes. Age ≥ 65 years and development of pulmonary infections after commencing or intensifying immunosuppressive treatments were identified as risk factors for death during hospitalization after adjusting for covariates. CONCLUSION: Careful consideration of the benefit-risk balance of immunosuppressive treatment for CTD-IP is indispensable for improving the short-term vital prognosis of these patients.

Perillyl alcohol suppresses antigen-induced immune responses in the lung.

Perillyl alcohol (POH) is an isoprenoid which inhibits farnesyl transferase and geranylgeranyl transferase, key enzymes that induce conformational and functional changes in small G proteins to conduct signal production for cell proliferation. Thus, it has been tried for the treatment of cancers. However, although it affects the proliferation of immunocytes, its influence on immune responses has been examined in only a few studies. Notably, its effect on antigen-induced immune responses has not been studied. In this study, we examined whether POH suppresses Ag-induced immune responses with a mouse model of allergic airway inflammation. POH treatment of sensitized mice suppressed proliferation and cytokine production in Ag-stimulated spleen cells or CD4(+) T cells. Further, sensitized mice received aerosolized OVA to induce allergic airway inflammation, and some mice received POH treatment. POH significantly suppressed indicators of allergic airway inflammation such as airway eosinophilia. Cytokine production in thoracic lymph nodes was also significantly suppressed. These results demonstrate that POH suppresses antigen-induced immune responses in the lung. Considering that it exists naturally, POH could be a novel preventive or therapeutic option for immunologic lung disorders such as asthma with minimal side effects.

Suppression of experimental autoimmune encephalomyelitis by interleukin-10 transduced neural stem/progenitor cells.

Neural stem/progenitor cells (NSPCs) have the ability to migrate into the central nervous system (CNS) to replace damaged cells. In inflammatory CNS disease, cytokine transduced neural stem cells may be used as vehicles to specifically reduce inflammation and promote cell replacement. In this study, we used NSPCs overexpressing IL-10, an immunomodulatory cytokine, in an animal model for CNS inflammation and multiple sclerosis (MS). Intravenous injection of IL-10 transduced neural stem/progenitor cells (NSPC(IL-10)) suppressed myelin oligodendrocyte glycoprotein aa 35-55 (MOG35-55)- induced experimental autoimmune encephalomyelitis (EAE) and, following intravenous injection, NSPC(IL-10) migrated to peripheral lymphoid organs and into the CNS. NSPC(IL-10 )suppressed antigen-specific proliferation and proinflammatory cytokine production of lymph node cells obtained from MOG35-55 peptide immunized mice. In this model, IL-10 producing NSPCs act via a peripheral immunosuppressive effect to attenuate EAE.

Alendronate attenuates eosinophilic airway inflammation associated with suppression of Th2 cytokines, Th17 cytokines, and eotaxin-2.

Bisphosphonates (BPs) have been widely used to treat osteoporosis. They act by inhibiting farnesyl diphosphate synthase in the mevalonate pathway. This resembles the action of statins, whose immune-modulating effect has recently been highlighted. In contrast, the effect of BPs on immune responses has not been elucidated well. In this study, we examined the effect of alendronate (ALN), a nitrogen-containing BP, on allergic airway inflammation in a mouse model. BALB/c mice were sensitized twice with OVA and challenged three times with nebulized OVA to induce eosinophilic airway inflammation. ALN was administered by an intragastric tube before each inhalation. ALN strongly suppressed airway eosinophilia and Th2, as well as Th17 cytokine production in the lung. ALN also attenuated eotaxin-2 production in the lung. Immunohistochemistry demonstrated that the major cell source of eotaxin-2 was peribronchial/perivascular macrophages, and flow cytometrical studies confirmed that ALN decreased eotaxin-2 expression in these macrophages. Furthermore, ALN attenuated eotaxin-2 production from mouse pleural macrophages and human monocyte/macrophage-like THP-1 cells in vitro. These results suggest that ALN suppressed Ag-induced airway responses in the mouse model. The suppression of eotaxin-2 production from macrophages appears to be one of ALN's immunomodulatory effects, whereas the mechanism by which ALN suppressed Th2 and Th17 responses could not be fully elucidated in this study. Although a clinical study should be conducted, ALN could be a novel therapeutic option for asthma.

A Case of Polymyxin b-Immobilized Fiber Column Treatment for Rapidly Progressive Interstitial Pneumonia Associated with Clinically Amyopathic Dermatomyositis.

We report a case of rapidly progressive interstitial pneumonia associated with clinically amyopathic dermatomyositis who responded to single course of polymyxin b-immobilized fiber column treatment. Initial treatment with pulsed corticosteroids and cyclophosphamide, intravenous immunoglobulin, and cyclosporine seemed to suppress the activity of interstitial lung disease temporarily, but signs of relapse were detected such as elevation of serum KL-6 level and progressing pulmonary shadows in chest computed tomography scan. After polymyxin b-immobilized fiber column treatment, the areas of pulmonary shadows drastically decreased. Gradually, arterial partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) ratio recovered, and serum ferritin level and KL-6 level decreased. These findings indicate that polymyxin b-immobilized fiber column treatment could be promising in combination with conventional therapy for rapidly progressive interstitial pneumonia associated with clinically amyopathic dermatomyositis, especially at the early phase of relapse.

A retrospective study of serum KL-6 levels during treatment with biological disease-modifying antirheumatic drugs in rheumatoid arthritis patients: a report from the Ad Hoc Committee for Safety of Biological DMARDs of the Japan College of Rheumatology.

OBJECTIVE: We investigated associations between treatment with methotrexate (MTX) or biological disease-modifying antirheumatic drugs (DMARDs) and elevation of serum Krebs von den Lungen-6 (KL-6) levels in Japanese patients with rheumatoid arthritis (RA). METHODS: Using a standardized form, data were collected retrospectively from medical records and analyzed descriptively. RESULTS: Of a total of 198 RA patients with KL-6 serum levels measured at initiation of treatment (month 0) and two or more times by month 12, 27 (17.9 %) of 151 RA patients treated with biological DMARDs, including infliximab, etanercept, adalimumab, and tocilizumab (the biological DMARDs group), and 5 (10.6 %) of 47 patients treated without biological DMARDs but with MTX (MTX group), met criterion B (max. KL-6 ≥500 U/ml and >1.5-fold from baseline) by 12 months. The majority of patients (n = 28) meeting criterion B had no apparent interstitial lung disease or malignancy. Of these 28 patients, 21 had serum KL-6 levels available after reaching their maximum level, and 13 (61.9 %) of the 21 then met criterion R [decrease to less than 500 U/ml or to less than (baseline + 0.5 × (maximum - baseline))] by month 12. CONCLUSION: Serum KL-6 levels may increase during treatment with MTX or these biological DMARDs without significant clinical events.

Elevation of KL-6 serum levels in clinical trials of tumor necrosis factor inhibitors in patients with rheumatoid arthritis: a report from the Japan College of Rheumatology Ad Hoc Committee for Safety of Biological DMARDs.

OBJECTIVE: The associations between elevated levels of serum Krebs von den Lungen-6 (KL-6) and treatment of rheumatoid arthritis (RA) with tumor necrosis factor (TNF) inhibitors were investigated in five Japanese clinical trials. METHODS: Percentages and incidence rates were calculated for elevated serum KL-6 levels. Adverse events associated with elevated levels of serum KL-6 were investigated. RESULTS: In RISING, a clinical trial for infliximab, 15.6 % of the enrolled patients met criterion B (KL-6 ≥500 U/ml and >1.5-fold increase over the baseline value) by week 54. In HIKARI, 7.8 % of the certolizumab pegol (CZP) group and 0 % of the placebo group met criterion B during the double-blind (DB) period (p = 0.003). In J-RAPID, 8.4 % of the methotrexate (MTX) + CZP and 3.9 % of the MTX + placebo groups met criterion B during the DB period. In GO-MONO, 1.8 % of the golimumab (GLM) and 1.3 % of the placebo groups met criterion B during the DB period. In GO-FORTH, 7.1 % of the MTX + GLM and 0 % of the MTX + placebo groups met criteron B during the DB period (p = 0.017). No adverse events accompanied the elevation of serum KL-6 levels in 95.7 % of these patients. CONCLUSION: Serum KL-6 levels may increase during anti-TNF therapy without significant clinical events. In these patients, continuing treatment with TNF inhibitors under careful observation is a reasonable option.

cGMP-dependent protein kinase I is involved in neurite outgrowth via a Rho effector, rhotekin, in Neuro2A neuroblastoma cells.

Although the cGMP/cGMP-dependent protein kinase (cGK) signaling is involved in the regulation of neurite outgrowth, its mechanism remains to be clarified. In this study, we identified a Rho effector, rhotekin, as a cGK-I-interacting protein. Rhotekin was also a substrate for cGK-Iα. In neurite-extended Neuro2A neuroblastoma cells, cGK-Iα and rhotekin were colocalized in the plasma membrane and extended neurites, while treatment with cGMP resulted in translocation of rhotekin to the cytoplasm. In addition, we found that cGK-Iα and rhotekin synergistically suppressed Rho-induced neurite retraction. Our findings suggest that cGK-Iα interacts with and phosphorylates rhotekin, thereby contributing to neurite outgrowth regulation.

High expression of IL-22 suppresses antigen-induced immune responses and eosinophilic airway inflammation via an IL-10-associated mechanism.

Allergic inflammation in the airway is generally considered a Th2-type immune response. However, Th17-type immune responses also play important roles in this process, especially in the pathogenesis of severe asthma. IL-22 is a Th17-type cytokine and thus might play roles in the development of allergic airway inflammation. There is increasing evidence that IL-22 can act as a proinflammatory or anti-inflammatory cytokine depending on the inflammatory context. However, its role in Ag-induced immune responses is not well understood. This study examined whether IL-22 could suppress allergic airway inflammation and its mechanism of action. BALB/c mice were sensitized and challenged with OVA-Ag to induce airway inflammation. An IL-22-producing plasmid vector was delivered before the systemic sensitization or immediately before the airway challenge. Delivery of the IL-22 gene before sensitization, but not immediately before challenge, suppressed eosinophilic airway inflammation. IL-22 gene delivery suppressed Ag-induced proliferation and overall cytokine production in CD4(+) T cells, indicating that it could suppress Ag-induced T cell priming. Antagonism of IL-22 by IL-22-binding protein abolished IL-22-induced immune suppression, suggesting that IL-22 protein itself played an essential role. IL-22 gene delivery neither increased regulatory T cells nor suppressed dendritic cell functions. The suppression by IL-22 was abolished by deletion of the IL-10 gene or neutralization of the IL-10 protein. Finally, IL-22 gene delivery increased IL-10 production in draining lymph nodes. These findings suggested that IL-22 could have an immunosuppressive effect during the early stage of an immune response. Furthermore, IL-10 plays an important role in the immune suppression by IL-22.

Dopamine D1-like receptor antagonist attenuates Th17-mediated immune response and ovalbumin antigen-induced neutrophilic airway inflammation.

Allergic airway inflammation is generally considered a Th2-type immune response. Recent studies, however, demonstrated that Th17-type immune responses also play important roles in this process, especially in the pathogenesis of neutrophilic airway inflammation, a hallmark of severe asthma. We previously reported that dendritic cells release dopamine to naive CD4(+) T cells in Ag-specific cell-cell interaction, in turn inducing Th17 differentiation through dopamine D1-like receptor (D1-like-R). D1-like-R antagonist attenuates Th17-mediated diseases such as experimental autoimmune encephalomyelitis and autoimmune diabetes. However, the effect of antagonizing D1-like-R on Th17-mediated airway inflammation has yet to be studied. In this study, we examined whether D1-like-R antagonist suppresses OVA-induced neutrophilic airway inflammation in OVA TCR-transgenic DO11.10 mice and then elucidated the mechanism of action. DO11.10 mice were nebulized with OVA or PBS, and some mice received D1-like-R antagonist orally before OVA nebulization. D1-like-R antagonist significantly suppressed OVA-induced neutrophilic airway inflammation in DO11.10 mice. It also inhibited the production of IL-17 and infiltration of Th17 cells in the lung. Further, D1-like-R antagonist suppressed the production of IL-23 by lung CD11c(+) APCs. In contrast, D1-like-R antagonist did not increase Foxp3(+) regulatory T cells in the lung. D1-like-R antagonist neither suppressed nonspecific LPS-induced neutrophilic airway inflammation nor OVA-induced eosinophilic airway inflammation. These results indicate that D1-like-R antagonist could suppress Th17-mediated neutrophilic airway inflammation, raising the possibility that antagonizing D1-like-R serves as a promising new strategy for treating neutrophil-dominant severe asthma.

Clinical and radiological features of acute-onset diffuse interstitial lung diseases in patients with rheumatoid arthritis receiving treatment with biological agents: importance of Pneumocystis pneumonia in Japan revealed by a multicenter study.

OBJECTIVE: Acute-onset diffuse interstitial lung disease (AoDILD) in patients with rheumatoid arthritis (RA) has been a serious concern, especially for those under treatment with biological agents which may affect the presentation and outcome of AoDILD, including Pneumocystis pneumonia (PCP). Therefore, we conducted a retrospective, multi-center study of AoDILD in RA patients receiving biological agents. METHODS: Patients who developed AoDILD while receiving biological agents (infliximab, etanercept, adalimumab and tocilizumab) were enrolled in the study. Definite PCP was defined as patients who showed either P. jirovecii organisms in their respiratory samples by microscopic examination, or positive tests for both P. jirovicii DNA-PCR with respiratory samples and an elevated serum 1,3-ß-D-glucan level above the cut-off value. Probable PCP was defined as either a positive test for P. jirovicii PCR or an elevated serum ß-D-glucan level. Chest HRCT findings were evaluated and scored by two board-certified radiologists. RESULTS: The final diagnoses for 26 patients examined were definite PCP for 13 patients, probable PCP for 11, and methotrexate-associated pneumonitis in 2 patients. Definite and probable PCP cases were clinically indistinguishable. Generalized, diffuse ground-glass opacity (GGO) is the characteristic HRCT finding in patients with definite or probable PCP, which was different from our previous findings in RA patients, mostly without biologics, showing GGO distributed in a panlobular or multilobular manner. The clinical outcome was favorable by treatment with trimethoprim-sulfamethoxazole and glucocorticoids. CONCLUSION: The possibility of PCP should be intensively investigated in RA patients developing AoDILD while receiving biological agents.

Neutrophil elastase contributes to acute lung injury induced by bilateral nephrectomy.

Acute kidney injury (AKI) is a serious problem in critically ill patients of intensive care units. It has been reported previously that AKI can induce acute lung injury (ALI), as well as cause injuries to other remote organs, including the lungs. Patients with AKI complicated by ALI show remarkably high mortality. ALI is characterized by neutrophil infiltration into the lung. Neutrophil elastase (NE) is a key enzyme for tissue injury caused by activated neutrophils, such as occurs in ALI. Therefore, this study investigated the role of NE in AKI-induced ALI using a specific NE inhibitor, sivelestat sodium hydrate (ONO-5046), in a mouse bilateral nephrectomy model. Bilateral nephrectomy showed not only a remarkable increase in blood urea nitrogen levels, but also demonstrated neutrophil infiltration into the lung, increased pulmonary inflammatory cytokine expression [interleukin-6, neutrophil chemokine keratinocyte-derived chemokine, and tumor necrosis factor-α], and protein leakage with early increases in both systemic and pulmonary NE activity. ONO-5046 treatment reduced NE activity and improved these pulmonary inflammatory responses. Additionally, ONO-5046-treated animals had longer survival times. These data demonstrate that increasing NE activity induces pulmonary inflammatory damage in a bilateral nephrectomy model. Blockade of NE activity will be a useful therapeutic strategy for ALI complications in AKI patients.

Intratracheal delivery of hepatocyte growth factor directly attenuates allergic airway inflammation in mice.

Hepatocyte growth factor (HGF) has an important role in many biological events such as angiogenesis and cell proliferation, as well as anti-fibrotic and anti-apoptotic effects. In addition, we found that HGF suppresses antigen-induced immune responses in the airway by suppressing dendritic cell functions, using a HGF-producing plasmid vector. In the present study, we examined whether delivery of the HGF protein in the lung attenuates allergic airway inflammation in a mouse model. Generally, HGF is rapidly cleared from organs. So, to achieve the efficient delivery of HGF, we prepared a slow-releasing form by mounting recombinant human (rh) HGF protein in biodegradable gelatin hydrogels. BALB/c mice were immunized and then challenged with ovalbumin (OVA) to induce eosinophilic airway inflammation. Intratracheal delivery of a very small amount of gelatin-coupled rhHGF (0.3 microg) just once before the inhalation of OVA significantly suppressed eosinophilic airway inflammation. In addition, cytokine production in thoracic lymph nodes and the antigen-presenting capacity of lung CD11c+ cells were reduced. In contrast, delivery of 1.0 microg of rhHGF did not exhibit any significantly suppressive effect. These results suggest that the controlled release of rhHGF protein can suppress antigen-induced allergic immune responses in the lung. Therefore, HGF could be a novel therapeutic option for asthma.

Upregulation of lung dendritic cell functions in elastase-induced emphysema.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is now considered a chronic inflammatory disease. Although dendritic cells (DCs) are thought to play a key role in immune responses, studies investigating the role of DCs in COPD are quite limited. METHODS: Porcine pancreas elastase was intratracheally administered to C57BL/6J mice on day 0. On days 2, 7 and 14, emphysema formation was evaluated by pressure-volume relationships and microscopic findings, including measurement of the mean linear intercept. Lung DCs were isolated on day 2, and their ability to stimulate allogeneic T cells and to produce cytokines was examined. RESULTS: Pathologic emphysematous change was observed on day 2 and a significant increase in lung volume was observed on day 14. Lung DC function, such as the induction of T-cell proliferation and IL-10 production, was upregulated. CONCLUSIONS: Upregulation of DC function was observed in elastase-induced emphysema. Further investigation on the contribution to emphysema formation may provide a useful target for future therapy.

IFN-gamma attenuates antigen-induced overall immune response in the airway as a Th1-type immune regulatory cytokine.

Allergic inflammation in the airway is generally considered a Th2-type immune response. However, recent studies demonstrated that Th1- and Th17-type immune responses also play important roles in this process. IFN-gamma is a Th1-type cytokine that generally counteracts the Th2 response. Although previous studies suggest that exogenous IFN-gamma suppresses allergic airway inflammation, the mechanism of suppression has not been fully clarified. In this study, we elucidated whether IFN-gamma suppresses Ag-induced immune responses including the production of Th1- and Th17-type cytokines in the lung, and examined its mechanism of action. BALB/c mice were sensitized and challenged with OVA-Ag to induce airway inflammation. An IFN-gamma-producing plasmid vector was delivered before systemic Ag sensitization. IFN-gamma suppressed indicators of Th2-type immune responses such as airway eosinophilia, IL-5 and IL-13 production in the lung, and bronchial mucus production. Moreover, IFN-gamma also suppressed the production of IL-17 and IFN-gamma itself. The suppression was not mediated by inducing regulatory T cells or by inducing apoptosis in immunocytes. Instead, IFN-gamma suppressed the Ag-presenting capacity and cytokine production of splenic dendritic cells and thus subsequently suppressed OVA-induced activation of CD4(+) T cells. Furthermore, IFN-gamma also attenuated allergic airway inflammation when delivered during the OVA challenge. Various functions of lung CD11c(+) APCs and their migration to regional lymph nodes were also suppressed. These results suggest that the Th1 cytokine IFN-gamma has broad immune regulatory potential through suppressing APC functions. They also suggest that delivery of IFN-gamma could be an effective strategy for regulating Ag-induced immune responses in the lung.

Clinical and radiological features of Pneumocystis pneumonia in patients with rheumatoid arthritis, in comparison with methotrexate pneumonitis and Pneumocystis pneumonia in acquired immunodeficiency syndrome: a multicenter study.

OBJECTIVE: To elucidate the clinical and radiological features of Pneumocystis pneumonia (PCP) in patients with rheumatoid arthritis (RA), compared with methotrexate (MTX) pneumonitis in RA and Pneumocystis pneumonia in acquired immunodeficiency syndrome (AIDS). SUBJECTS AND METHODS: Retrospective analysis of 14 PCP cases in RA (RA-PCP), 10 MTX pneumonitis cases in RA (MTX-P) and 11 PCP cases in AIDS (AIDS-PCP) from 9 centers in the Kanto area in the last 6 years. RESULTS: Compared with AIDS-PCP, both RA-PCP and MTX-P developed more rapidly, showing higher serum CRP and lower plasma beta-D-glucan levels, and more severe oxygenation impairment. In most of the RA-PCP cases, a high dose of corticosteroid was administered as adjunctive therapy, resulting in a favorable outcome. The mortality was 14% in RA-PCP, 0% in AIDS-PCP and 0% in MTX-P cases. In RA-PCP patients the CD4 cell count showed only mild suppression, not reaching the predisposing level for PCP in HIV infection, suggesting that there are risk factors for RA-PCP other than immunosuppression. Radiologic analysis revealed some characteristic patterns of each disease. In MTX-P, diffuse homogeneous ground glass opacity (GGO) with sharp demarcation by interlobular septa (type A GGO) was found in 70%, while in AIDS-PCP diffuse, homogeneous or nonhomogeneous GGO without interlobular septal boundaries (type B GGO) was predominant (91%). In RA-PCP, type A GGO was found in 6 cases and type B GGO in 5 cases, showing the complex nature of this disease. CONCLUSION: RA-PCP differed considerably from AIDS-PCP clinically and radiologically. Clinically it occurred without severe immunosuppression, and showed characteristic aspects, with more intense inflammation and less parasite burden. Radiologically it mimicked MTX-P in some cases sharing the conspicuous CT features of MTX-P, rendering the distinction of these two disorders difficult.