title: Cγ1 Deficiency Exacerbates Collagen-Induced Arthritis.
abstract: IgG antibodies protect by aggregating pathogens and activating complement and stimulatory Fcγ receptors (FcγR). Although IgG1 accounts for a large percentage of murine serum antibodies, it poorly activates complement, binds more avidly to inhibitory FcγRIIb than to stimulatory FcγRIII, and has a relatively low aggregating ability. We previously demonstrated that IgG1 protects against complement- and FcγR-independent renal disease by inhibiting immune complex obstruction of glomerular capillaries. The purpose of this study was to determine whether IgG1 also protects against the complement- and FcγR-dependent disorder, collagen-induced arthritis (CIA).
  
  
  
  CIA was induced by injecting mice with type II collagen (CII) (active model) or with IgG2a and IgG2b anti-CII monoclonal antibodies (ArthritoMab) (passive model). Arthritis severity was assessed, and CII-specific IgG was titered.
  
  
  
  Cγ1-deficient C57BL/6 mice lack IgG1 (IgG1(-/-) ); in these mice, arthritis developed at a higher frequency and was more severe compared with IgG1(+/+) mice in the active model. Disease was FcγRIII- and C3-dependent in both the IgG(+/+) and IgG(-/-) mouse strains and was not influenced by interleukin-4 receptor α in either strain. CII-specific IgG2a/c titers were considerably higher in IgG1(-/-) than in IgG1(+/+) mice and correlated with CIA incidence and severity. IgG1(+/+) mice that developed CIA had higher CII-specific IgG1 and IgG2a/c levels than did those without CIA. CII-inoculated BALB/c IgG1(+/+) and IgG1(-/-) mice had much lower CII-specific IgG2a/c titers than did C57BL/6 mice and failed to develop CIA but developed passive CIA when given ArthritoMab.
  
  
  
  The absence of a functional Cγ1 gene indirectly promotes the development of CIA, likely through increased production of IgG2a/c, an isotype that strongly activates complement and stimulatory FcγR.
authors.affiliation: Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Strait
authors.affiliation: Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Sherry
authors.initials: S
authors.lastname: Thornton
authors.affiliation: Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, and Cincinnati Veterans Affairs Medical Center, Cincinnati, Ohio.
authors.forename: Fred D
authors.initials: FD
authors.lastname: Finkelman
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology*; D003094:Collagen / Q000502:physiology*; D007074:Immunoglobulin G / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000172:deficiency*; D017452:Receptors, IgG / Q000502:physiology*
chemical_list: D007074:Immunoglobulin G; D016692:Receptors, Antigen, T-Cell, gamma-delta; D017452:Receptors, IgG; D003094:Collagen