An FcRn-dependent role for anti-flagellin immunoglobulin G in pathogenesis of colitis in mice.
OBJECTIVE
The neonatal Fc receptor for immunoglobulin (Ig)G (FcRn) protects monomeric IgG from catabolism in parenchymal and hematopoietic cells during adult life. In dendritic cells, FcRn also promotes presentation of antigens in association with IgG. Because IgGs with anti-bacterial specificity are a hallmark of inflammatory bowel disease, we sought to determine their significance and relationship to FcRn expression in antigen-presenting cells, focusing on IgGs specific for flagellin.


METHODS
Levels of circulating anti-flagellin IgG were induced in wild-type and FcRn(-/-) mice, followed by induction of colitis with dextran sodium sulfate (DSS). Bone marrow chimera models were used to localize the site of FcRn action.


RESULTS
Wild-type mice that received anti-flagellin IgG exhibited more severe colitis following administration of DSS, compared with mice that received control IgG. Wild-type mice immunized with flagellin exhibited significantly more severe colitis in response to DSS administration than that observed in similarly treated FcRn(-/-) mice. In chimera studies, FcRn(-/-) mice given wild-type bone marrow and immunized with flagellin exhibited significantly more colitis than wild-type mice given FcRn(-/-) bone marrow and immunized with flagellin. Serum anti-flagellin IgG levels were similar in both sets of chimeric mice, consistent with the equal participation of hematopoietic and nonhematopoeitic cells in FcRn-mediated IgG protection.


CONCLUSIONS
Anti-bacterial IgG antibodies are involved in the pathogenesis of colitis; this pathway requires FcRn in antigen presenting cells, the major subset of hematopoietic cells that express FcRn.
Kobayashi
Kanna
K
Gastroenterology Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Qiao
Shuo-Wang
SW
Yoshida
Masaru
M
Baker
Kristi
K
Lencer
Wayne I
WI
Blumberg
Richard S
RS
D000818:Animals; D017951:Antigen Presentation; D000942:Antigens, Bacterial / Q000276:immunology; D003092:Colitis / Q000209:etiology*; D016264:Dextran Sulfate; D000939:Epitopes; D005260:Female; D005408:Flagellin / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000502:physiology*; D007074:Immunoglobulin G / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011961:Receptors, Fc / Q000502:physiology*; D012486:Salmonella typhimurium / Q000276:immunology
D000942:Antigens, Bacterial; D000939:Epitopes; D015395:Histocompatibility Antigens Class I; D007074:Immunoglobulin G; D011961:Receptors, Fc; D005408:Flagellin; D016264:Dextran Sulfate; C100688:Fc receptor, neonatal