Intravenous immunoglobulin up‐regulates the expression of the inhibitory FcγIIB receptor on B cells

Abstract

Intravenous immunoglobulin (IVIg) preparations are known to modulate autoimmune/inflammatory diseases through several F(ab') 2 -and Fc-dependent mechanisms. In this study, we show that the in vitro and the in vivo exposure of B lymphocytes from lupus-prone and from healthy mice to IVIg results in an increased expression of their surface inhibitory FccIIB receptors. Further, this exposure enhanced the ability of a chimeric antibody, cross-linking FccRIIB and immunoglobulin receptors on DNA-specific B lymphocytes, to suppress IgG anti-DNA antibody production. F(ab') 2 fragments of IVIg had a similar activity as the intact preparation, whereas Fc fragments had no effect. This study describes a novel approach with clinical relevance for modulating B lymphocyte activity.

Platelet production and platelet destruction: assessing mechanisms of treatment effect in immune thrombocytopenia

“…19,20 Anti-D apparently interacts with the activating Fc␥Rs (Fc␥RIIA, Fc␥RIIIA), 20 whereas IVIG is thought to up-regulate the inhibitory Fc␥RIIB. 16,17,19 The pretreatment and posttreatment A-IPF results verified that the primary effect of anti-D and IVIG is inhibition of platelet destruction, rather than increased platelet production. No patients with platelet responses to anti-D treatment alone had an A-IPF response.…”

“…This explanation was based largely on inferential data demonstrating slower clearance of antibody-coated, chromium-labeled red cells, rather than on direct studies of platelets. 15 Studies in murine ITP have shown various effects of IVIG on ITP: protection against autoantibody-mediated immune destruction of platelets via up-regulation of Fc␥RIIB, the inhibitory Fc␥ receptor 16 ; decreased autoantibody production by B lymphocytes, via up-regulation of Fc␥RIIB 17 ; and inhibition of antibody mediated but not cell-mediated platelet destruction. 18 There is less information describing the mechanism of effect of anti-D, although it is presumed to inhibit platelet destruction via blocking Fc␥RIIA and Fc␥RIIIA activation, as also supported by an animal model.…”

Targeted silencing of DNA-specific B cells combined with partial plasma cell depletion displays additive effects on delaying disease onset in lupus-prone mice

“…This has been achieved by the exposure of splenocytes from non-autoimmune Balb/c as well as from MRL/lpr mice to pooled therapeutic human IgG (IVIg). IVIg pretreatment enhanced significantly the ability of the chimeric antibody to suppress the differentiation of dsDNA-specific B lymphocytes to IgG antibody-producing plasma cells [25,26]. The treatment strategy proposed here could be improved further if a tri-specific chimeric antibody that targets both CD32 (FcγIIb) and CD22 inhibitory receptors on dsDNAspecific B lymphocytes is used, as signalling through the first receptor silences B cells with IgG antigen receptors; and through the second, those with IgM BCRs [12,27].…”

Intravenous immunoglobulin replacement therapy in common variable immunodeficiency induces B cell depletion through differentiation into apoptosis-prone CD21low B cells

“…Similar effects of IVIG on FccRIIB expression were observed with murine B cells [14]. More recently, it was shown that IVIG infusion rapidly induces up-regulation of phosphorylated ERK (pERK) expression in B cells of CVID patients [39], a finding parallel to the in vitro sustained ERK activation induced by treatment of normal B cells with IVIG [5].…”

“…It was recently shown that patients with CIDP have reduced expression of Fcc receptor IIB (FccRIIB) and that in these patients effective IVIG therapy up-regulated FccRIIB expression on monocytes and B cells [13]. These findings were confirmed in a mouse model [14]. Interestingly, it was previously shown that FccRIIB controls plasma cell apoptosis [15]; thus, IVIG may have an impact on autoantibody production.…”