title: The presence of FCGR2B promoter or transmembrane region variant alleles leads to reduced serum IL-6 levels in rheumatoid arthritis.
abstract: The inhibitory FcγRIIB plays an important role for the peripheral B cell tolerance and plasma cell homeostasis, and any malfunctioning is predicted to result in humoral autoimmunity. An association between rheumatoid arthritis (RA) and FCGR2B promoter and TM region variant alleles, both of which result in a reduced functionality, is only insufficiently elucidated. We here set out to investigate the impact of these variants on disease progression in European RA patients. One hundred and five ACPA-positive RA patients were genotyped for the FCGR2B -386G>C promoter and the 695T>C transmembrane region variants. Moreover, serum titers for IL-6, TNFα, CTX-1 and ACPAs were measured and peripheral blood T cell and B cell populations analyzed for expression of the activation markers CTLA-4 and CD86. The presence of an FCGR2B variant allele results in reduced serum IL-6, a trend toward later disease onset and reduced requirement for biological treatment, but does not seem to aggravate RA. Likewise, the presence of the TM region variant allele is associated with a lower activation state of the Tregs and of naïve and memory B cells. The observation of a malfunctioning FcγRIIb not aggravating RA is counterintuitive at first. However, the etiology of RA is linked to inflammatory episodes, and the lack of B cell inhibition may support an accelerated antibody-mediated clearance of the disease initiating and perpetuating agents. It would thereby shorten inflammatory episodes, postpone the onset of disease and result in a less severe course of RA in carriers of FCGR2B variant alleles.
authors: Institute of Immunology, University Medicine Rostock, Schillingallee 69, 18057, Rostock, Germany.
authors: Stefanie
authors: S
authors: Meister
authors: Robby
authors: R
authors: Engelmann
authors: Christian
authors: C
authors: Kneitz
authors: Brigitte
authors: B
authors: Müller-Hilke
mesh_terms: D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology; D001402:B-Lymphocytes; D051940:B7-2 Antigen / Q000276:immunology; D060908:CTLA-4 Antigen / Q000276:immunology; D015331:Cohort Studies; D024042:Collagen Type I / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D005838:Genotype; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000378:metabolism; D010456:Peptides, Cyclic / Q000276:immunology; D011401:Promoter Regions, Genetic; D017452:Receptors, IgG / Q000235:genetics*; D013601:T-Lymphocytes; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
chemical_list: D001323:Autoantibodies; D051940:B7-2 Antigen; C497964:CD86 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D024042:Collagen Type I; C499173:FCGR2B protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D010446:Peptide Fragments; D010456:Peptides, Cyclic; D017452:Receptors, IgG; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; C487763:cyclic citrullinated peptide
references: Nature. 1996 Jan 25;379(6563):346-9
references: 8552190
references: Hum Mol Genet. 2005 Oct 1;14(19):2881-92
references: 16115811
references: Lupus. 2009 Jul;18(8):727-34
references: 19502269
references: Hum Genet. 2005 Jul;117(2-3):220-7
references: 15895258
references: Nat Immunol. 2007 Apr;8(4):419-29
references: 17322888
references: Proc Natl Acad Sci U S A. 2010 Apr 27;107(17 ):7881-5
references: 20385827
references: Indian J Med Res. 2011 Aug;134:181-5
references: 21911970
references: J Immunol. 2014 Apr 1;192(7):3021-8
references: 24563255
references: Proc Natl Acad Sci U S A. 2011 Jan 18;108(3):1122-7
references: 21187399
references: Nat Rev Immunol. 2002 Aug;2(8):580-92
references: 12154377
references: J Exp Med. 2006 Sep 4;203(9):2157-64
references: 16923849
references: Arthritis Rheum. 2006 Dec;54(12):3908-17
references: 17133600
references: J Exp Med. 2008 Apr 14;205(4):883-95
references: 18362174
references: Autoimmunity. 2007 Sep;40(6):409-17
references: 17729034
references: Proc Natl Acad Sci U S A. 2007 Apr 24;104(17):7169-74
references: 17435165
references: Immunol Rev. 2010 Jan;233(1):233-55
references: 20193003
references: Ann Rheum Dis. 2010 Dec;69(12):2062-6
references: 21097657
references: Curr Opin Rheumatol. 2014 Jul;26(4):424-9
references: 24807405
references: Nat Rev Immunol. 2010 May;10(5):328-43
references: 20414206
references: Rheumatology (Oxford). 2015 Mar;54(3):545-53
references: 25193807
references: Arthritis Rheum. 2006 Dec;54(12):3828-37
references: 17133580
references: Immunity. 2006 Jan;24(1):19-28
references: 16413920
references: Eur J Immunol. 2013 Mar;43(3):770-8
references: 23280344
references: Nat Rev Immunol. 2008 Jan;8(1):34-47
references: 18064051