title: Immunomodulatory effects of 25-hydroxyvitamin D3 on monocytic cell differentiation and influence of vitamin D3 polymorphisms in type 1 diabetes.
abstract: BACKGROUND
  Preventive measures and a causal therapy for type 1 diabetes (T1D) remain elusive. An imbalance between different dendritic cells (DC) with increased immunogenic DC and decreased tolerogenic DC (tDC) may lead to T1D. Furthermore, 25(OH)D3 is associated with less adverse effects than 1,25(OH)2D3.
  
  
  OBJECTIVE
  The present study was performed to clarify the remaining issues about the cellular effects of 25(OH)D3 in patients with T1D and the role of genetic polymorphisms of the vitamin D3 (VD3) metabolism on a functional cellular level.
  
  
  METHODS
  Twelve patients with T1D were case-matched to twelve healthy controls (HC). Monocytes (MC) were either not supplemented or supplemented with 25(OH)D3 in vitro and phenotyped with fluorescence-activated cell sorting. In vitro synthesis and plasma levels of 25(OH)D3 and 1,25(OH)2D3 were analyzed as well as twelve gene polymorphisms of the VD3 metabolism.
  
  
  RESULTS
  25(OH)D3 significantly inhibited differentiation of MC into DC and led to an increase of intermediate cells (IC), which show a similar phenotype as tDC. The patient with a recent onset of T1D showed a higher increase in MC and IC compared to patients with long-standing T1D. There were significant differences for the increase of IC with supplementation of 25(OH)D3 between different genotypes within the polymorphisms of VDR-BsmI-rs1544410, VDR-TaqI-rs731236 and CYP24A1-rs927650.
  
  
  CONCLUSIONS
  This study suggests that 25(OH)D3 shows immunomodulatory effects on a cellular level in patients with T1D and HC by inhibiting the differentiation of MC into DC and promoting the formation of IC, which are similar to tDC, thereby shifting immunity to self-tolerance. The potency of 25(OH)D3 did not differ between patients with T1D and HC. Increased plasma levels of 25(OH)D3 may inhibit a proinflammatory cell milieu. Despite of the limited patient number, this study generates the hypothesis that the immunmodulatory effects may be influenced by genotypes of the VDR and CYP24A1 illustrating their functional role in T1D susceptibility, which is worth further investigation.
authors.affiliation: Division of Endocrinology & Metabolism, Department of Internal Medicine, Goethe-University Hospital, Theodor-Stern-Kai, Frankfurt am Main, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Mauf
authors.affiliation: Division of Endocrinology & Metabolism, Department of Internal Medicine, Goethe-University Hospital, Theodor-Stern-Kai, Frankfurt am Main, Germany.
authors.forename: Marissa
authors.initials: M
authors.lastname: Penna-Martinez
authors.affiliation: Division of Trauma Surgery, Department of Surgery, University Hospital Zürich, Switzerland.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Jentzsch
authors.affiliation: Institute of Biostatistics and Mathematical Modeling, Center of Health Sciences, Goethe-University, Frankfurt am Main, Germany.
authors.forename: Hanns
authors.initials: H
authors.lastname: Ackermann
authors.affiliation: Department of Trauma, Hand and Reconstructive Surgery, Department of Surgery, Goethe-University Hospital, Frankfurt am Main, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Henrich
authors.affiliation: Center for Drug Research, Development and Safety, Goethe-University, Frankfurt am Main, Germany.
authors.forename: Heinfried H
authors.initials: HH
authors.lastname: Radeke
authors.affiliation: Division of Hematology and Oncology, Department of Internal Medicine, University Hospital Giessen and Marburg, Marburg, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Brück
authors.affiliation: Division of Endocrinology & Metabolism, Department of Internal Medicine, Goethe-University Hospital, Theodor-Stern-Kai, Frankfurt am Main, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Badenhoop
authors.affiliation: Division of Endocrinology & Metabolism, Department of Internal Medicine, Goethe-University Hospital, Theodor-Stern-Kai, Frankfurt am Main, Germany.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Ramos-Lopez
mesh_terms: D000293:Adolescent; D000328:Adult; D054337:Cell Dedifferentiation; D002762:Cholecalciferol / Q000097:blood / Q000276:immunology*; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000097:blood / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D011110:Polymorphism, Genetic; D018167:Receptors, Calcitriol / Q000235:genetics; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics; D055815:Young Adult
chemical_list: D007155:Immunologic Factors; D018167:Receptors, Calcitriol; C579457:VDR protein, human; D002762:Cholecalciferol; D065668:Vitamin D3 24-Hydroxylase
keywords: 25(OH)D(3); Cell differentiation; Dendritic cells; Monocytes; Polymorphisms; Type 1 diabetes (T1D); Vitamin D(3)