Reply to Bayry et al.: The anti-inflammatory activity of sialylated IgG Fcs
The letter by Bayry et al. (1) regarding our article (2) purports that ERK1/2 phosphorylation is reduced in LPS-treated human monocyte-derived dendritic cells that are pretreated with IVIG or IVIG-derived F(ab)2 fragments. The authors conclude from this single experiment that Fc fragments are not required for IVIG's in vivo anti-inflammatory activity. These conclusions are problematic for conceptual and technical reasons. The Western blot bands presented in Fig. 1 are inconsistent and lack quantitation, and no dose requirements for IVIG or F(ab)2 fragments are stated. Importantly, cultured dendritic cells pulsed with LPS are not a representative or valid model for autoimmune diseases treated with IVIG.
To mechanistically examine the anti-inflammatory activity of IVIG, our laboratory developed a number of in vivo animal models that mimic the effector stages of human autoimmune diseases and include examples of both cytotoxic and immune complex-triggered inflammation protected by clinical doses of IVIG. Using models of immune-mediated thrombocytopenia (ITP) (3), rheumatoid arthritis (4), and glomerulonephritis (5), we have shown an absolute requirement for the IVIG Fc portions and the dependence of terminal sialic acid moeties (6–8). These studies were extended to show that α2,6-sialic acid linkages (9), splenic SIGN-R1 expression (2), and peripheral FcγRIIb expression (2) are all required for this antiinflammatory activity. Furthermore, IVIG-derived Fcs were demonstrated to be the active component of IVIG and were used to treat ITP in the clinic (10).
The experiment provided by Bayry (1) thus fails to provide a relevant, validated system to study IVIG anti-inflammatory activity, and their results cannot be extrapolated to describe the in vivo activity of this therapeutic.
Footnotes
- 1To whom correspondence should be addressed. E-mail: ravetch{at}rockefeller.edu.
-
Author contributions: J.R., R.A., F.W., and M.K. wrote the paper.
-
The authors declare no conflict of interest.
