Human DC-SIGN and CD23 do not interact with human IgG

Abstract

The precise mechanisms underlying anti-inflammatory effects of intravenous immunoglobulin (IVIg) therapies remain elusive. The sialylated IgG fraction within IVIg has been shown to be therapeutically more active in mouse models. Functionally, it has been suggested that IgG undergoes conformational changes upon Fc-sialylation which sterically impede binding to conventional FcγRs, but simultaneously allow binding to human DC-SIGN (SIGN-R1 in mice) and also CD23. These latter C-type lectins have been proposed responsible for the immunomodulatory effects in mouse models. However, there is conflicting evidence supporting direct interactions between sialylated human IgG and CD23/DC-SIGN. While cells expressing human CD23 and DC-SIGN in their native configuration bound their natural ligands IgE and ICAM-3, respectively, no IgG binding was observed, regardless of Fc-glycan sialylation in any context (with or without bisection and/or fucosylation) or presence of sialylated Fab-glycans. This was tested by both by FACS and a novel cellular Surface Plasmon Resonance imaging (cSPRi) approach allowing for monitoring low-affinity but high-avidity interactions. In summary, we find no evidence for human CD23 or DC-SIGN being bona fide receptors to human IgG, regardless of IgG Fc- or Fab-glycosylation status. However, these results do not exclude the possibility that either IgG glycosylation or C-type lectins affect IVIg therapies.

High-Dose Intravenous Immunoglobulins in the Treatment of Severe Acute Viral Pneumonia: The Known Mechanisms and Clinical Effects

“…However, other studies have challenged this hypothesis. The evidence of a direct interaction between sialylated IgG and DC-SIGN is not fully supported in the literature (66,67). Moreover, there is conflicting evidence suggesting that the sialylated Fc fragment of IgG is dispensable for the anti-inflammatory mechanisms of high-dose IVIg (68)(69)(70)(71)(72).…”

“…It has been proposed that sialylated IgG binds to DC-SIGN in addition to CD23, a C-type lectin which is also a known low-affinity IgE receptor characteristically expressed on B cells, inducing the suppression of B cells (189). However, there has been disagreement as to whether there is a direct interaction between IgG and DC-SIGN/CD23 (67,190). A further proposed mechanism of action of high-dose IVIg is the interaction between the sialylated Fc fragment of IgG and CD22, an I-type lectin expressed on B cells, which results in the activation of the ITIM signaling cascade, subsequently promoting B cell apoptosis (183,191,192).…”

Impact of Plasma Membrane Domains on IgG Fc Receptor Function

“…All of them belong to the superfamily of CLRs unified by the structural feature of the C-type lectin domain. Nevertheless, it has at least to be noted that the IgG binding capability of DC-SIGN and FcεRII has recently been challenged (125).…”

“…They further differ in their intracellular motifs responsible for receptor internalization, cycling and signaling [summarized in ( 121 )]. Because of this complexity, here we will focus only on the three so far described type II FcRs, DC-SIGN (CD209), Dectin-1 (CLEC7A) and Fcε receptor II (FcεRII; CD23) characterized by the ability to bind immunoglobulins ( Figure 2 ) although this is a current matter of debate ( 119 , 122 – 125 ).…”

Molecular Recognition in C‐Type Lectins: The Cases of DC‐SIGN, Langerin, MGL, and L‐Sectin

“…Recent reports have thoroughly screened these effects making use of large glycan arrays, evidencing striking affinity changes sometimes arising from remote chemical modifications. [91][92][93] As examples, the presence of terminal sialylation completely abrogates recognition, [92] as well as the elongation of the GlcNAc 2 Man 3 GlcNAc 2 scaffold with Galβ1-4, although the negative effect is asymmetric, given that the presence of one unique Gal moiety at the α1-6 branch still permits a weak binding (Figure 4, left). [91,93] Similarly, bisecting residues and double core fucosylation at the reducing end of the chitobiose disaccharide also produce an affinity loss in general.…”