FHR3 Blocks C3d-Mediated Coactivation of Human B Cells.
The autoimmune renal disease deficient for complement factor H-related (CFHR) genes and autoantibody-positive form of hemolytic uremic syndrome is characterized by the presence of autoantibodies specific for the central complement regulator, factor H, combined with a homozygous deficiency, mostly in CFHR3 and CFHR1 Because FHR3 and FHR1 bind to C3d and inactivated C3b, which are ligands for complement receptor type 2 (CR2/CD21), the aim of the current study was to examine whether FHR3-C3d or FHR1-C3d complexes modulate B cell activation. Laser-scanning microscopy and automated image-based analysis showed that FHR3, but not FHR1 or factor H, blocked B cell activation by the BCR coreceptor complex (CD19/CD21/CD81). FHR3 bound to C3d, thereby inhibiting the interaction between C3d and CD21 and preventing colocalization of the coreceptor complex with the BCR. FHR3 neutralized the adjuvant effect of C3d on B cells, as shown by inhibited intracellular CD19 and Akt phosphorylation in Raji cells, as well as Ca(2+) release in peripheral B cells. In cases of CFHR3/CFHR1 deficiency, the FHR3 binding sites on C3d are occupied by factor H, which lacks B cell-inhibitory functions. These data provide evidence that FHR3, which is absent in patients with the autoimmune form of hemolytic uremic syndrome, is involved in B cell regulation.
Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, 07745 Jena, Germany;
Denise
D
Buhlmann
Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, 07745 Jena, Germany;
Hannes U
HU
Eberhardt
Applied Systems Biology, Leibniz Institute for Natural Product Research and Infection Biology, 07745 Jena, Germany;
Anna
0000-0001-5268-713X
A
Medyukhina
Department of Hygiene and Medical Microbiology, Medical University of Innsbruck, A-6020 Innsbruck, Austria; and.
Wolfgang M
WM
Prodinger
Applied Systems Biology, Leibniz Institute for Natural Product Research and Infection Biology, 07745 Jena, Germany; Friedrich Schiller University, 07743 Jena, Germany.
Marc Thilo
0000-0002-4044-9166
MT
Figge
Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, 07745 Jena, Germany; Friedrich Schiller University, 07743 Jena, Germany.
Peter F
0000-0002-6149-2411
PF
Zipfel
Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, 07745 Jena, Germany; christine.skerka@hki-jena.de.
Christine
0000-0003-2374-6473
C
Skerka
D001402:B-Lymphocytes / Q000276:immunology*; D001798:Blood Proteins / Q000276:immunology*; D002469:Cell Separation; D015933:Complement C3d / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006463:Hemolytic-Uremic Syndrome / Q000276:immunology*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008213:Lymphocyte Activation / Q000276:immunology*; D018613:Microscopy, Confocal
D001798:Blood Proteins; C105970:CFHR3 protein, human; D015933:Complement C3d