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Van Der Heijden J.,University of Amsterdam | Geissler J.,University of Amsterdam | Van Mirre E.,University of Amsterdam | Van Deuren M.,Radboud University Nijmegen | And 5 more authors.
Journal of Allergy and Clinical Immunology | Year: 2013

Background: Our index case was a patient with common variable immunodeficiency (CVID). She had anaphylactoid reactions on administration of intravenous immunoglobulin (IVIg) associated with the presence of IgG antibodies against IgA. Objective: We sought to determine the role of Fcγ receptor (FcγR) IIa in IVIg-induced anaphylactoid reactions. Methods: Neutrophils and PBMCs were isolated from healthy subjects and IVIg-treated patients. FcγRIIa mRNA and DNA were analyzed by using real-time PCR and sequencing. IgG-mediated elastase release and intracellular Ca2+ mobilization were determined in neutrophils and transfected cell lines, respectively. Results: A novel splice variant of FcγRIIa containing an expressed cryptic exon 6* (FcγRIIaexon6) was identified in our index patient. This exon is normally spliced out of all FcγRII isoforms, except the inhibitory FcγRIIb1. Compared with healthy control subjects, the heterozygous FCGR2Ac.742+871A>G mutation was more frequent in patients with CVID (n = 53, P < .013). Expression in patients with CVID was associated with anaphylaxis on IVIg infusion (P =.002). On screening of additional IVIg-treated patient cohorts, we identified 6 FCGR2A c.742+871A>G allele-positive patients with Kawasaki disease (n = 208) and 1 patient with idiopathic thrombocytopenia (n = 93). None had adverse reactions to IVIg. Moreover, FcγRIIaexon6 was also demonstrated in asymptomatic family members. Functional studies in primary cells and transfected murine cells demonstrated enhanced cellular activation by FcγRIIaexon6 compared with its native form, as shown by increased elastase release and intracellular calcium mobilization. Conclusion: A novel splice variant, FcγRIIaexon6, was characterized as a low-frequency allele, coding for a gain-of-function receptor for IgG. In the presence of immune complexes, FcγRIIaexon6 can contribute to anaphylaxis in patients with CVID. © 2012 American Academy of Allergy, Asthma & Immunology.

Winzer K.-J.,Charite - Medical University of Berlin | Sauerbrei W.,Albert Ludwigs University of Freiburg | Liersch T.,Universitatsmedizin Gottingen | Dunst J.,Universitatsklinikum Halle | And 2 more authors.
European Journal of Cancer | Year: 2010

To study the role of radiotherapy and tamoxifen after breast-conserving surgery (BCS) in patients with a favourable prognosis, a clinical trial was initiated by the German Breast Cancer Study Group (GBSG-V). Between 1991 and 1998, 361 patients (pT 1pN0M0, aged 45-75 years, receptor positive, grades I and II) were randomised to radiotherapy (yes/no) and tamoxifen for 2 years (yes/no) in a 2 × 2-factorial design; the exclusion of seven centres (14 patients) left 347 patients for the analysis. First results after a median follow-up of 5.9 years were published. Herein we present updated results after a median follow-up of about 10 years. Hundred and eleven events concerning event-free survival (EFS) have been observed. Since a strong interactive effect between radiotherapy and tamoxifen has been established, the results are presented in terms of the treatment effects for all four treatment groups separately. Mainly due to the presence of local recurrences, the event rate was much higher in the group with BCS only than in the other three groups. No significant difference could be established between the four treatment groups for distant disease-free survival rates (DDFS). Updated results give further evidence that even in patients with a favourable prognosis, the avoidance of radiotherapy and tamoxifen after BCS increases the rate of local recurrences substantially. Rates are about three times higher in the BCS only group. For the two outcomes EFS and DDFS, no important difference could be seen between the three groups with an additional treatment. However, because of the limited sample size with corresponding low power the strength of evidence for such a comparison is weak. © 2009 Elsevier Ltd. All rights reserved.

Krawitz P.,Universitatsklinikum Charite
Medizinische Genetik | Year: 2010

Recent advances in sequencing technology have reduced the costs and time required to decode a single genome to the extent that complete sequencing of personal genomes becomes affordable for both private individuals and the health care system. The broad availability of individual genomes will drive medicine further towards an information-based science and the importance of IT solutions in medicine will increase. © 2010 Springer-Verlag.

Janke M.,Deutsches Rheumaforschungszentrum Berlin | Peine M.,Deutsches Rheumaforschungszentrum Berlin | Nass A.,Charite - Medical University of Berlin | Morawietz L.,Universitatsklinikum Charite | And 3 more authors.
European Journal of Immunology | Year: 2010

Recently, IL-17 produced by Th17 cells was described as pro-inflammatory cytokine with an eminent role in autoimmune diseases, e.g. rheumatoid arthritis. A lack of IL-17 leads to amelioration of collagen-induced arthritis. IL-17 induction in naïve CD4+ T cells depends on IL-6 and TGF-β and is enhanced by IL-23. The in vivo inflammatory potential of in vitro-primed Th17 cells however, remains unclear. Here, we show that, although IL-17 neutralisation results in amelioration of murine OVA-induced arthritis, in vitro-primed Th17 cells cannot exacerbate arthritic symptoms after adoptive transfer. Furthermore, Th17 cells cannot induce an inflammatory delayed type hypersensitivity reaction because they fail to migrate into inflamed sites, possibly due to the lack of CXCR3 expression. Also, re-isolated Th17 cells acquired IFN-γ expression, indicating instability of the Th17 phenotype. Taken together, the data show that IL-6, TGF-β and IL-23 might not provide sufficient signals to induce "fully qualified" Th17 cells. © 2010 Wiley-VCH Verlag GmbH & Co. KGaA.

Van Biesen W.,Ghent University | Jorres A.,Universitatsklinikum Charite
Kidney International | Year: 2014

McCafferty and colleagues report on a retrospective analysis in peritoneal dialysis patients in whom fluid status was assessed by multifrequency bioimpedance. During 12 months of follow-up, overhydration, as identified by an increased ratio of extracellular over total body water, was not associated with better preservation of residual renal function (RRF). These findings suggest that running patients 'wet' might not contribute to better preservation of RRF in peritoneal dialysis © 2013 International Society of Nephrology.

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