No evidence for a role of FcgammaRIIB in suppression of in vivo antibody responses to erythrocytes by passively administered IgG.

Abstract

SETTING THE STAGEIn a paper in this issue of Scandinavian Journal ofImmunology, Sinclair addresses the role of Fc-signalling inthe modulation of immune responses by passive antibody [1].This is a broad field, encompassing aspects of immuneresponses from autoimmune disease models to cell signallingin vitro. A substantial part of the paper deals in a critical waywith recent results from our laboratory concerning the abilityof immunoglobulin (Ig)G to feedback-regulate in vivo anti-body responses in mice [2,3] and we will limit our reply tothis area. In a field as complicated as antibody feedbackregulation, it is important to define exactly what is discussed.Antibodies of many classes have the capacity to modulateantibody responses, either positively or negatively [4]. IgGhas a dual role, suppressing the response to particulateantigens such as erythrocytes [5–9], and enhancing theresponse to soluble antigens such as keyhole limpethemocyanine (KLH), bovine serum albumin (BSA), andovalbumin (OVA) [3,9–11]. The same monoclonal IgG anti-trinitriphenyl (anti-TNP) can suppress or enhance, dependingon whether TNP is conjugated to an erythrocyte or a solubleantigen [9,11]. Considering the strikingly different structure ofthese two types of immune complexes this is not surprising.While an IgG molecule is much smaller than an erythrocyte(10 nm versus 7 mm in diameter), IgG is on average twice aslarge as BSA. When discussing IgG-mediated immunoregula-tion, it is therefore vital to keep apart studies using particulateversus soluble antigens. Major differences between in vitroand in vivo systems for studying antibody responses exist(e.g., lack of lympoid organ structure in vitro) and unlessspecifically stated, only in vivo systems will be consideredhere.NO EVIDENCE FOR A ROLE OF FCgRIIB INSUPPRESSION OF IN VIVO ANTIBODYRESPONSES TO SRBC BY PASSIVELYADMINISTERED IgGWhy IgG has the capacity to completely inhibit a response toSRBC is a question that has been debated extensively over theyears. Hypotheses put forward are: (i) epitope masking by IgG,preventing recognition of the antigen by B cells, (ii) effectiveelimination of IgG-coated antigen via Fc-dependent phago-cytosis, and (iii) central inhibition of B-cell activation viacocrosslinking of the B-cell receptor and the inhibitoryFcgRIIB. Sinclair argues that the mechanism behind the IgG-mediated suppression of erythrocyte-specific responses wasresolved 30 years ago and that his so called TripartiteInactivation Model ((iii) see above) explains the phenomenon[12]. Some textbooks and reviews also state for a fact that themechanism behind the IgG-mediated suppression has beenproven to be FcgRIIB-mediated negative signalling to B cells.We do not share this opinion. Although this receptorundoubtedly plays an inhibitory role in many experimentalsystems, there are many observations calling for scepticismabout its role in inhibition of erythrocyte responses by passivelyadministered IgG. Firstly, data regarding the Fc-dependence ofsuppression are conflicting. The efficiency of F(ab