title: Retinoid X receptor beta polymorphisms do not explain functional differences in vitamins D and A response in Antineutrophil cytoplasmic antibody associated vasculitis patients.
abstract: It has been suggested that the retinoid X receptor beta (RXRB) gene is a risk factor for Wegener's granulomatosis. We addressed if there is a functional difference in the response to retinoic acid (RA) and vitamin D in Antineutrophil cytoplasmic antibody (ANCA) associated systemic vasculitis (AASV) patients and if this was associated with RXRB genotypes. TNFalpha and IL-10 production were measured in whole blood assay from AASV patients (n = 51) and healthy controls (HC, n = 67). One micromolar of 1,25-(OH)(2) D3, 9-cis RA (9c-RA) or all-trans RA (ATRA) was added to the assay. Genotyping was performed for exons 7 and 2 of the RXRB gene and for a microsatellite in vicinity of the RXRB gene. Lipopolysaccharide (LPS) mediated TNFalpha production and IL-10 were significantly lower in patients. Addition of 1,25-(OH)(2) D3, ATRA or 9c-RA, blunted TNFalpha production, more pronounced in patients. Although all three compounds inhibited IL-10 production significantly in HC, only 1,25-(OH)(2) D3 was found to be effective in patients. Allele distribution of the RXRB microsatellite differed significantly between patients and HC. This was not found for the SNP in exons 2 and 7. Genotype of the latter correlated with the ability of 1,25-(OH)(2) D3 and ATRA to inhibit IL-10 production. We provide immunological evidence for a functional difference in vitamins D and A responsiveness in AASV patients. Since the inhibition of TNFalpha was more effective in patients, vitamin D supplementation might be an additional therapeutical approach.
authors.affiliation: Fifth Department of Medicine, University Hospital Mannheim, Faculty of Medicine Mannheim, University of Heidelberg, Heidelberg, Germany. anna-isabelle.kaelsch@med5.ma.uni-heidelberg.de
authors.forename: Anna-Isabelle
authors.initials: AI
authors.lastname: Kälsch
authors.forename: Anthea
authors.initials: A
authors.lastname: Peters
authors.forename: Birgit
authors.initials: B
authors.lastname: Buhl
authors.forename: Annette
authors.initials: A
authors.lastname: Breedijk
authors.forename: Katharina
authors.initials: K
authors.lastname: Prem
authors.forename: Wilhelm H
authors.initials: WH
authors.lastname: Schmitt
authors.forename: Christel
authors.initials: C
authors.lastname: Weiss
authors.forename: Peter
authors.initials: P
authors.lastname: Heeringa
authors.forename: Cees
authors.initials: C
authors.lastname: Kallenberg
authors.forename: Rainer
authors.initials: R
authors.lastname: Birck
authors.forename: Benito A
authors.initials: BA
authors.lastname: Yard
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000097:blood*; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D049230:Retinoid X Receptor beta / Q000235:genetics*; D056647:Systemic Vasculitis / Q000235:genetics / Q000276:immunology*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism; D014801:Vitamin A / Q000008:administration & dosage / Q000627:therapeutic use; D014807:Vitamin D / Q000008:administration & dosage / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D049230:Retinoid X Receptor beta; D014409:Tumor Necrosis Factor-alpha; D014801:Vitamin A; D016753:Interleukin-10; D014807:Vitamin D