IgG-mediated immune suppression in mice is epitope specific except during high epitope density conditions

Hui Xu,Birgitta Heyman,Lu Zhang

doi:10.1038/s41598-018-33087-6

Hui Xu, Birgitta Heyman + Show 1 more

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https://doi.org/10.1038/s41598-018-33087-6

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Journal: Scientific Reports	Publication Date: Oct 16, 2018
Citations: 21	License type: open-access

Affiliation: Uppsala University

Abstract

Specific IgG antibodies, passively administered together with erythrocytes, suppress antibody responses against the erythrocytes. Although used to prevent alloimmunization in Rhesus (Rh)D-negative women carrying RhD-positive fetuses, the mechanism behind is not understood. In mice, IgG suppresses efficiently in the absence of Fcγ-receptors and complement, suggesting an Fc-independent mechanism. In line with this, suppression is frequently restricted to the epitopes to which IgG binds. However, suppression of responses against epitopes not recognized by IgG has also been observed thus arguing against Fc-independence. Here, we explored the possibility that non-epitope specific suppression can be explained by steric hindrance when the suppressive IgG binds to an epitope present at high density. Mice were transfused with IgG anti-4-hydroxy-3-nitrophenylacetyl (NP) together with NP-conjugated sheep red blood cells (SRBC) with high, intermediate, or low NP-density. Antibody titers and the number of single antibody-forming cells were determined. As a rule, IgG suppressed NP- but not SRBC-specific responses (epitope specific suppression). However, there was one exception: suppression of both IgM anti-SRBC and IgM anti-NP responses occurred when high density SRBC-NP was administered (non-epitope specific suppression). These findings answer a longstanding question in antibody feedback regulation and are compatible with the hypothesis that epitope masking explains IgG-mediated immune suppression.

Highlights

Passive administration of specific antibodies together with the antigen they recognize can result in dramatic changes in the antibody response as compared to administration of antigen alone
We found that administration to mice of IgG anti-4-hydroxy-3-nitrophenylacetyl (NP), or IgG anti-sheep red blood cells (SRBC), together with SRBC-NP invariably resulted in epitope-specific suppression of the serum IgG response[11]
In mice immunized with SRBC-NP, germinal center (GC) B cells (GL7high CD95high) and non-GC B cells were increased as compared to negative controls immunized with unconjugated SRBC or IgG anti-NP alone (Fig. 2B)

Summary

Introduction

Passive administration of specific antibodies together with the antigen they recognize can result in dramatic changes in the antibody response as compared to administration of antigen alone (reviewed in[1,2,3]) This so called antibody feedback regulation can be either positive, resulting in several 100-fold stronger antibody responses, or negative, resulting in more than 99% suppression. Several reports have confirmed that IgG-mediated immune suppression occurs in the absence of FcγRs13,15,32,33 and in the absence of complement factor C3 (C3), complement factor C1q (C1q), or complement receptors 1 and 2 (CR1/2)[15,33]. In a majority of previous studies demonstrating non-epitope specific suppression, the read-out was a direct plaque forming cell (PFC) assay which detects single IgM (but not IgG) anti-SRBC-producing cells within a week after immunization

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