The MHC class I–like Fc receptor promotes humorally mediated autoimmune disease
Shreeram Akilesh, … , Gregory J. Christianson, Derry Roopenian
Shreeram Akilesh, … , Gregory J. Christianson, Derry Roopenian
Published May 1, 2004
Citation Information: J Clin Invest. 2004;113(9):1328-1333. https://doi.org/10.1172/JCI18838.
View: Text | PDF
Article Autoimmunity

The MHC class I–like Fc receptor promotes humorally mediated autoimmune disease

Abstract

The MHC class I family–like Fc receptor, FcRn, is normally responsible for extending the life span of serum IgG Ab’s, but whether this molecule contributes to autoimmune pathogenesis remains speculative. To determine directly whether this function contributes to humoral autoimmune disease, we examined whether a deficiency in the FcRn heavy chain influences autoimmune arthritis in the K/BxN mouse model. FcRn deficiency conferred either partial or complete protection in the arthritogenic serum transfer and the more aggressive genetically determined K/BxN autoimmune arthritis models. The protective effects of an FcRn deficiency could be overridden with excessive amounts of pathogenic IgG Ab’s. The therapeutic saturation of FcRn by high-dose intravenous IgG (IVIg) also ameliorated arthritis, directly implicating FcRn blockade as a significant mechanism of IVIg’s anti-inflammatory action. The results suggest that FcRn is a potential therapeutic target that links the initiation and effector phases of humoral autoimmune disease.

Authors

Shreeram Akilesh, Stefka Petkova, Thomas J. Sproule, Daniel J. Shaffer, Gregory J. Christianson, Derry Roopenian

×

Figure 2

Options: View larger image (or click on image) Download as PowerPoint
FcRn-deficient K/BxN mice are protected from genetically-induced arthrit...
FcRn-deficient K/BxN mice are protected from genetically-induced arthritis. (A) Ankle width measurements and overall arthritis scores (mean ± SE) were performed as in Figure 1. All WT FcRn+/_ littermates (filled diamonds; n = 21; 13 males and 8 females) showed rapid disease onset. Of 21 FcRn_/_ littermates, the mice that remained healthy (open circles; n = 10; 4 males and 6 females) at approximately the 16-week duration of the experiment are plotted separately from FcRn_/_ mice (n = 11; 3 males and 8 females) that became sick (filled circles). The time of disease onset of healthy mice versus WT FcRn+/_ littermates versus FcRn_/_ sick mice was significant at P < 0.0001 by the ANOVA repeated measures test. (B) H&E sections of representative 16-week K/BxN-FcRn+/_ (+/_), sick FcRn_/_ (_/_ sick), and healthy FcRn_/_ (_/_ healthy) mice at ∞20 magnification. (C) Total serum IgG and (D) anti-GPI activity of each cohort from A was measured by ELISA at the weekly time points indicated. IgG levels of FcRn_/_ healthy versus WT FcRn+/_ mice and FcRn_/_ sick versus WT FcRn+/_ mice was significant at P _ 0.0001 by the Scheffe test. FcRn_/_ healthy versus FcRn_/_ sick (filled circles) mice did not differ significantly by the Scheffe test. Anti-GPI levels of FcRn_/_ healthy mice versus WT FcRn+/_ mice versus FcRn_/_ sick mice was significant at P _ 0.0004 by the Scheffe test. conc, concentration.