A nationwide survey on the epidemiology and clinical features of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) in Japan

Objective. We conducted a cross-sectional nationwide survey to determine eosinophilic granulomatosis with polyangiitis (Churg-Strauss) (EGPA) prevalence and clinical features in Japan. Methods. Data for EGPA patients in 2008 were collected from 1,564 hospitals. In total, 965 patients were reported from 365 departments. In a second survey, clinical data for 473 patients were obtained. Results. We estimated that 1,866 (95% CI: 1,640–2,092) patients have EGPA in Japan (prevalence, 17.8/1,000,000). Of the 473 patients in the second survey, 315 fulfilled American College of Rheumatology (ACR) criteria or Lanham's criteria for EGPA. The mean age (± SD) of the 315 at onset was 55 ± 14 years, male to female ratio 1:2. 93% of patients had neurological manifestations, which were the organ system most frequently involved. Among 277 patients tested for myeloperoxidase (MPO)-/p anti-neutrophil cytoplasmic antibody (ANCA), 139 (50%) were positive, while only 6 of 238 were positive for proteinase3 (PR3)-/cANCA. MPO-ANCA-positive patients had renal involvement, mucous membrane or ophthalmological symptoms, and ENT symptoms more frequently, whereas cutaneous lesions and cardiovascular involvement were less common. Conclusion. The prevalence of EGPA and the frequency of MPO-/p-ANCA-positivity in Japanese EGPA patients were mostly similar to those of Western countries. However, female predominance and a high frequency of neurological manifestations characterized Japanese patients.</p

Dose response of IL-10 inhibition of interferon gamma (IFN-γ) production by CD4T cells after CD3 and CD28 costimulation in patients with rheumatoid arthritis (RA) and in healthy controls (HC)

<p><b>Copyright information:</b></p><p>Taken from "Resistance to IL-10 inhibition of interferon gamma production and expression of suppressor of cytokine signaling 1 in CD4T cells from patients with rheumatoid arthritis"</p><p>Arthritis Research & Therapy 2004;6(6):R567-R577.</p><p>Published online 13 Oct 2004</p><p>PMCID:PMC1064873.</p><p>Copyright © 2004 Yamana et al., licensee BioMed Central Ltd.</p> CD4T cells were purified from peripheral blood mononuclear cells of three RA patients and three HC by positive selection with anti-CD4 antibody. CD4T cells (5 × 10cells in 0.5 ml culture medium with 10% FCS) were stimulated by immobilized anti-CD3 antibody and anti-CD28 antibody in the presence or absence of diluted IL-10 concentrations for 36 hours. Culture supernatants were measured for concentrations of IFN-γ by ELISA. IFN-γ production with IL-10 expressed as % IFN-γ production without IL-10. Values are the mean ± standard error of the mean

Interferon gamma (IFN-γ) production by CD3 and CD28 costimulated CD4T cells in the presence of IL-10 in patients with rheumatoid arthritis (RA) and in healthy controls (HC)

<p><b>Copyright information:</b></p><p>Taken from "Resistance to IL-10 inhibition of interferon gamma production and expression of suppressor of cytokine signaling 1 in CD4T cells from patients with rheumatoid arthritis"</p><p>Arthritis Research & Therapy 2004;6(6):R567-R577.</p><p>Published online 13 Oct 2004</p><p>PMCID:PMC1064873.</p><p>Copyright © 2004 Yamana et al., licensee BioMed Central Ltd.</p> CD4T cells (5 × 10cells in 0.5 ml culture medium with 10% FCS) were stimulated by anti-CD3 antibody and anti-CD28 antibody with or without 1 ng/ml IL-10. Concentrations of IFN-γ in culture supernatants were measured in duplicate by ELISA. RA patients were divided into those with active disease (multiple inflammatory joints and CRP level ≥ 10 mg/l) and inactive disease (in remission and CRP level ≤ 4 mg/l). The results are represented as a box plot; upper and lower bars, 90th and 10th percentiles, respectively; upper, center and lower lines of box, 75th, 50th, and 25th percentiles, respectively. Percentage of IFN-γ production. IFN-γ production with IL-10 expressed as % IFN-γ production without IL-10. Values are the mean ± standard error of the mean. n, number of samples tested

Representative photomicrographs of double immunofluorescent staining in diabetic db/db mice.

<p>NOR1 expression was localized in mesangial, proximal tubular epithelial, and collecting duct cells, but not in podocytes in the kidneys of diabetic db/db mice.</p

Comparative expression levels of NHRs in mouse kidney tissue under high-glucose conditions.

<p>The relative mRNA levels are depicted for streptozotocin-induced diabetic C57BL/6 mouse kidney compared with control C57BL/6 mouse kidney (upper panel), and diabetic db/db mouse kidney compared with control db/m mouse kidney (lower panel). Values depict the means ± SEM of three independent samples.</p

The ELISA of total (A, C, D) and HMW (B, E) adiponectin after stimulation of HMCs with native or deSial/deGal IgA1.

<p>In HMCs, native IgA upregulated the total (A) and high molecular weight (HMW) (B) adiponectin release to the supernatant in a dose- (A, B) and time-dependent manner (C). Native IgA also increased the total and HMW adiponectin concentration in cell lysates in a dose-dependent manner (D, E). HMCs were cultured with different concentrations of native or deSial/deGal IgA1 (0, 6, 12.5, 25 or 50 µg/ml) for 48 h. For the time course study, HMCs were cultured with 25 µg/ml of native or deSial/deGal IgA1 for 0, 1, 6, 24 or 48 h. The concentrations of adiponectin were expressed as the means ± SE. Open diamonds, native IgA; closed circles, deSial/deGal IgA1. *<i>P</i> = 0.05 vs. medium control; #<i>P</i> = 0.01, native IgA vs. deSial/deGal IgA1.</p

Composition of nuclear hormone receptors (NHRs) in the kidney of C57BL/6 mice.

<p>(A) Twenty-five of 49 known NHRs are expressed in C57BL/6 mouse kidney. These include six endocrine receptors that bind hormonal lipids with high-affinity, eight adopted orphan receptors that bind dietary lipids with low-affinity, and 11 orphan receptors. Constituent receptors of each of these classes are listed. (B) Tabular listing of NHRs expressed or unexpressed in C57BL/6 mouse kidney along with their classification and nomenclature. Receptors were deemed unexpressed if cycle threshold (Ct) values exceeded 31.</p

Double staining of HAA lectin and IgA in renal biopsy specimens, and the quantitative analysis of staining.

<p>Renal biopsy specimens from patients with minor glomerular abnormalities (MGA) (A, D and G), lupus nephritis (LN) (B, E and H) and IgA nephropathy (IgAN) (C, F and I) were stained for HAA lectin (red) (A–C), IgA (green) (D–F) and their images were merged (yellow) (G–I). In IgAN patients, the IgA-positive areas were colocalized with HAA lectin-positive area in the glomeruli. On the other hand, there were IgA-positive areas but no HAA lectin-positive areas in the glomeruli of LN patients. The relative double positive intensities in the glomeruli of IgAN patients were increased compared to those of LN or MGA patients (J). The double positive areas in the glomeruli of IgAN patients were increased compared to those with LN or MGA (K). Note that certain segments of tubules and Bowman's capsules were also stained with HAA lectin. Each column consists of the means ± SE. MGA, <i>n</i> = 9; LN, <i>n</i> = 14; and IgAN, <i>n</i> = 17. **<i>P</i><0.01. The scale bars represent 100 µm.</p

The profiles of the patients included for analysis of renal biopsies.

<p>MGA, minor glomerular abnormalities; MCD, minimal change disease; LN, lupus nephritis; IgAN, IgA nephropathy; eGFR, estimated glomerular filtration rate; BMI, body mass index; HbA1c, hemoglobin A1c; HDL, high density lipoprotein; LDL, low density lipoprotein.</p>a<p>: <i>P</i><0.01,</p>b<p>: <i>P</i><0.05 vs. MGA.</p>c<p>: <i>P</i><0.01,</p>d<p>: <i>P</i><0.05 vs. MCNS.</p>e<p>: <i>P</i><0.01,</p>f<p>: <i>P</i><0.05 vs. LN.</p

Suppression of Adiponectin by Aberrantly Glycosylated IgA1 in Glomerular Mesangial Cells In Vitro and In Vivo

<div><p>The pathogenesis of IgA nephropathy (IgAN) may be associated with the mesangial deposition of aberrantly glycosylated IgA1. To identify mediators affected by aberrantly glycosylated IgA1 in cultured human mesangial cells (HMCs), we generated enzymatically modified desialylated and degalactosylated (deSial/deGal) IgA1. The state of deglycosylated IgA1 was confirmed by lectin binding to <em>Helix aspersa</em> (HAA) and <em>Sambucus nigra</em> (SNA). In the cytokine array analysis, 52 proteins were upregulated and 34 were downregulated in HMCs after stimulation with deSial/deGal IgA1. Among them, the secretion of adiponectin was suppressed in HMCs after stimulation with deSial/deGal IgA1. HMCs expressed mRNAs for adiponectin and its type 1 receptor, but not the type 2 receptor. Moreover, we revealed a downregulation of adiponectin expression in the glomeruli of renal biopsy specimens from patients with IgAN compared to those with lupus nephritis. We also demonstrated that aberrantly glycosylated IgA1 was deposited in the mesangium of patients with IgAN by dual staining of HAA and IgA. Moreover, the urinary HAA/SNA ratio of lectin binding was significantly higher in IgAN compared to other kidney diseases. Since adiponectin has anti-inflammatory effects, including the inhibition of adhesion molecules and cytokines, these data suggest that the local suppression of this adipokine by aberrantly glycosylated IgA1 could be involved in the regulation of glomerular inflammation and sclerosis in IgAN.</p> </div