title: Complement drives Th17 cell differentiation and triggers autoimmune arthritis.
abstract: Activation of serum complement triggers Th17 cell-dependent spontaneous autoimmune disease in an animal model. In genetically autoimmune-prone SKG mice, administration of mannan or beta-glucan, both of which activate serum complement, evoked Th17 cell-mediated chronic autoimmune arthritis. C5a, a chief component of complement activation produced via all three complement pathways (i.e., lectin, classical, and alternative), stimulated tissue-resident macrophages, but not dendritic cells, to produce inflammatory cytokines including IL-6, in synergy with Toll-like receptor signaling or, notably, granulocyte/macrophage colony-stimulating factor (GM-CSF). GM-CSF secreted by activated T cells indeed enhanced in vitro IL-6 production by C5a-stimulated macrophages. In vivo, C5a receptor (C5aR) deficiency in SKG mice inhibited the differentiation/expansion of Th17 cells after mannan or beta-glucan treatment, and consequently suppressed the development of arthritis. Transfer of SKG T cells induced Th17 cell differentiation/expansion and produced arthritis in C5aR-sufficient recombination activating gene (RAG)-/- mice but not in C5aR-deficient RAG-/- recipients. In vivo macrophage depletion also inhibited disease development in SKG mice. Collectively, the data suggest that complement activation by exogenous or endogenous stimulation can initiate Th17 cell differentiation and expansion in certain autoimmune diseases and presumably in microbial infections. Blockade of C5aR may thus be beneficial for controlling Th17-mediated inflammation and autoimmune disease.
authors.affiliation: Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
authors.forename: Motomu
authors.initials: M
authors.lastname: Hashimoto
authors.forename: Keiji
authors.initials: K
authors.lastname: Hirota
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yoshitomi
authors.forename: Shinji
authors.initials: S
authors.lastname: Maeda
authors.forename: Shin
authors.initials: S
authors.lastname: Teradaira
authors.forename: Shuji
authors.initials: S
authors.lastname: Akizuki
authors.forename: Paz
authors.initials: P
authors.lastname: Prieto-Martin
authors.forename: Takashi
authors.initials: T
authors.lastname: Nomura
authors.forename: Noriko
authors.initials: N
authors.lastname: Sakaguchi
authors.forename: Jörg
authors.initials: J
authors.lastname: Köhl
authors.forename: Birgitta
authors.initials: B
authors.lastname: Heyman
authors.forename: Minoru
authors.initials: M
authors.lastname: Takahashi
authors.forename: Teizo
authors.initials: T
authors.lastname: Fujita
authors.forename: Tsuneyo
authors.initials: T
authors.lastname: Mimori
authors.forename: Shimon
authors.initials: S
authors.lastname: Sakaguchi
mesh_terms: D000818:Animals; D001168:Arthritis / Q000276:immunology* / Q000473:pathology*; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D049109:Cell Proliferation / Q000187:drug effects; D015936:Complement C5a / Q000276:immunology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008351:Mannans / Q000494:pharmacology; D051379:Mice; D011951:Receptors, Complement / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000276:immunology*; D051193:Toll-Like Receptors / Q000378:metabolism
chemical_list: D008351:Mannans; D011951:Receptors, Complement; D051193:Toll-Like Receptors; D015936:Complement C5a; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
references.citation: Nat Immunol. 2002 Apr;3(4):360-5
references.pmid: 11896391
references.citation: Immunity. 2006 Feb;24(2):179-89
references.pmid: 16473830
references.citation: Nat Rev Immunol. 2002 May;2(5):346-53
references.pmid: 12033740
references.citation: Blood. 2007 Jul 1;110(1):228-36
references.pmid: 17363730
references.citation: N Engl J Med. 2007 Sep 20;357(12):1199-209
references.pmid: 17804836
references.citation: J Exp Med. 2007 Jan 22;204(1):41-7
references.pmid: 17227914
references.citation: N Engl J Med. 2007 Sep 6;357(10):977-86
references.pmid: 17804842
references.citation: Eur J Immunol. 2005 Oct;35(10):3064-73
references.pmid: 16180250
references.citation: J Immunol. 2006 Dec 15;177(12):8626-32
references.pmid: 17142762
references.citation: Annu Rev Immunol. 2005;23:821-52
references.pmid: 15771587
references.citation: Nature. 2003 Nov 27;426(6965):454-60
references.pmid: 14647385
references.citation: Eur J Immunol. 2010 Mar;40(3):710-21
references.pmid: 20017191
references.citation: J Exp Med. 2005 Mar 21;201(6):949-60
references.pmid: 15781585
references.citation: Nat Immunol. 2005 Nov;6(11):1123-32
references.pmid: 16200070
references.citation: J Immunol. 2008 May 1;180(9):6132-8
references.pmid: 18424734
references.citation: Immunity. 2008 Mar;28(3):425-35
references.pmid: 18328742
references.citation: Science. 1986 Apr 25;232(4749):506-8
references.pmid: 3083507
references.citation: Nat Genet. 2005 Dec;37(12):1317-9
references.pmid: 16273109
references.citation: J Exp Med. 2003 May 5;197(9):1183-90
references.pmid: 12732659
references.citation: Immunology. 2006 Jul;118(3):372-83
references.pmid: 16827898
references.citation: EMBO J. 2007 Jan 24;26(2):623-33
references.pmid: 17215869
references.citation: J Exp Med. 2008 Sep 29;205(10):2281-94
references.pmid: 18779348
references.citation: J Immunol. 2008 May 1;180(9):5882-9
references.pmid: 18424707
references.citation: Annu Rev Immunol. 2009;27:485-517
references.pmid: 19132915
references.citation: Nat Immunol. 2007 Jun;8(6):630-8
references.pmid: 17450144
references.citation: Immunity. 2005 Apr;22(4):415-26
references.pmid: 15845447
references.citation: Eur J Immunol. 2007 Jan;37(1):224-34
references.pmid: 17154261
references.citation: Nat Immunol. 2006 Dec;7(12):1258-65
references.pmid: 17110942
references.citation: Nature. 1996 Sep 5;383(6595):86-9
references.pmid: 8779720
references.citation: Blood. 2009 Jul 30;114(5):1005-15
references.pmid: 19491392
references.citation: J Exp Med. 1996 Dec 1;184(6):2385-92
references.pmid: 8976192