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Additional file 1: Supplementary Table 1. Demographic and clinical features of SSc patients recruited for the in vitro T or B cell-depletion. Supplementary Table 2. Overview on medications given to all individual SSc patients with SSc treated with or without immunosuppressive drugs in the present and previous study [5]. Supplementary Figure 1. Efficiency of depletion of human T or B cells from PBMC. Levels of CD3+ T cells (A), CD4+ T cells (B), CD8+ T cells (C), and CD20+ B cells (D) were determined by FACS analysis and presented as % of total human leukocytes in PBMC. Statistical significance of comparison was determined using the paired t test. Supplementary Figure 2. Levels of human leukocytes in peripheral blood of recipient mice. Mice were transferred with whole PBMC, T-cell depleted, or B-cell depleted PBMC, and peripheral blood was taken at the 6th week (A, B) and 12th week (C, D) after the transfer. Subsequently, human CD45+ leukocytes, CD3+ T cells, CD4+ T cells, CD8+ T cells and CD20+ B cells were identified by flow cytometry. Levels of human leukocytes are presented as percentage of total leukocytes including murine and human leukocytes in murine blood. Comparison on levels of human leukocytes indicated between mice transferred with whole PBMC (n = 7) and mice transferred with T-cell depleted PBMC (n = 7) (A) and between mice transferred with whole PBMC (n = 10) and mice transferred with B-cell depleted PBMC (n = 10) (B) by week by the 6th week after the transfer. Comparison on levels of human leukocytes indicated between mice transferred with whole PBMC (n = 4) and mice transferred with T-cell depleted PBMC (n = 4) (C) and between mice transferred with whole PBMC (n = 16) and mice transferred with B-cell depleted PBMC (n = 6) (D) by week by the 12th week after the transfer. P values reflect comparisons between mice transferred with whole PBMC and mice transferred with T- or B-cell depleted PBMC. Statistical significance was determined using the Wilcoxon matched pairs test. Supplementary Figure 3. Presence of ANA in sera of PBMC-transferred mice. Antinuclear antibody (ANA) pattern of murine sera were detected using (HEp-2) cell-based immunofluorescence staining (EUROPattern Suite, Euroimmun, Germany). Two out of 7 mice which received whole PBMC from SSc patients scored positive for ANA, and their ANA patterns were consistent with those of two corresponding SSc patients. By contrast, mice which received T cell-depleted or B cell-depleted PBMC isolated from the 2 SSc patients were ANA negative. Representative micrographs of the ANA test for mice received whole PBMC, T cell-depleted PBMC (PBMC T-/-) or B cell-depleted PBMC (PBMC B-/-) are shown. Supplementary Figure 4. Matrix of Spearman’s correlation coefficients between immunological and histopathological variables. Severity of inflammation in the lung, kidney and liver as well as levels of circulating human CD45+ leukocytes, CD3+ T cells, CD4+ T cells, CD8+ T cells and CD20+ B cells at 6th week after the cell transfer, and levels of total IgG, anti-AT1R IgG and anti-ETAR IgG in sera obtained after the sacrifice of mice were used for the analysis. Samples were tested for normal distribution by using Shapiro-Wilk normality test. Since most variables were not normally distributed, Spearman correlation was applied for the analysis. A color-coded correlation scale is provided on the right of the plot. Blue and ellipses represent negative and positive correlations, respectively, and darker color tones representd larger correlation coefficient magnitudes. Statistically significant differences are indicated by asterisks (*p

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA.

Patienten mit Wegenerscher Granulomatose (WG) zeigen signifikant häufiger eine nasale Kolonisation mit S. aureus. Dies ist mit einer erhöhten Rezidivrate vergesellschaftet. Ein möglicher Zusammenhang zwischen Besiedlung und der Sekretion Antimikrobieller Peptide (AMP) ist bislang nicht[for full text, please go to the a.m. URL], 81. Jahresversammlung der Deutschen Gesellschaft für Hals-Nasen-Ohren-Heilkunde, Kopf- und Hals-Chirurgie

Einleitung: Die Ribonuclease (RNase) 7 ist ein kationisches Peptid mit breiter antimikrobieller Wirksamkeit auch gegen Staphylococcus (S.) aureus, welches u.a. in Oberflächenepithelien der Haut sowie des Gastrointestinaltraktes nachgewiesen wurde. Der Nachweis in der Nase fehlt bislang. Patienten und Methoden: Nasale Sekrete von Patienten mit Wegenerscher Granulomatose (WG) (n=12), Polyposis nasi (PP) (n=11) und gesunden Kontrollen (n=12) sowie Serumproben von 14 WG-, 12 PP-Patienten und 13 Kontrollen wurden mittels ELISA auf RNase 7 getestet. Primäre nasale Epithelzellkulturen (NEC) gesunder Probanden wurden mit abgetöteten S. aureus-Zellen stimuliert und die RNase 7 Konzentration im Überstand bestimmt. Ergebnisse: In nasalen Sekreten aller drei Gruppen ließ sich RNase 7 nachweisen. Die Unterschiede waren nicht signifikant. Im Serum war RNase 7 nur bei 14 von 35 Proben nachweisbar und unter den Gruppen gleichverteilt. Nach Stimulation der NEC mit steigenden S. aureus Konzentrationen zeigte sich eine Abnahme der RNase 7 Konzentration. Diskussion: RNase 7 ist Bestandteil des angeborenen Immunsystems, auch der nasalen Mucosa, lässt sich systemisch jedoch nur selten nachweisen. Ein diesbezüglicher Defekt der nasalen Barriere lässt sich quantitativ für WG und PP nicht nachweisen. Funktionell erscheint eine hemmende Wirkung für steigende Konzentrationen bakterieller Stimuli möglich. Weitere Untersuchungen insbesondere hinsichtlich möglicher Interaktionen von Mikroorganismen und Epithelzellen (bakterielle Peptidasen, inhibierende Komponenten im nasalen Sekret, Interaktionen antimikrobieller Peptide) erfolgen. Unterstützt durch: Deutsche Forschungsgemeinschaft; Klinische Forschergruppe 170, GMS Current Posters in Otorhinolaryngology - Head and Neck Surgery; 6:Doc88; ISSN 1865-1038