An FcRn-Dependent Role for Anti-flagellin Immunoglobulin G in Pathogenesis of Colitis in Mice

Background & Aims

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.

Abbreviations used in this paper: APC, antigen-presenting cell, CD, Crohn's Disease, DC, dendritic cell, DSS, dextran sodium sulfate, FcRn, neonatal Fc receptor for immunoglobulin (Ig)G, IBD, inflammatory bowel disease, KO, FcRn knockout, OVA, ovalbumin, UC, ulcerative colitis, WT, wild type