Complement Receptors 1 and 2 in Murine Antibody Responses to IgM-Complexed and Uncomplexed Sheep Erythrocytes

Christian Rutemark,Frida Henningsson,Birgitta Heyman,Anna Bergman,Andrew Getahun,Jenny Hallgren

doi:10.1371/journal.pone.0041968

Christian Rutemark, Frida Henningsson + Show 4 more

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https://doi.org/10.1371/journal.pone.0041968

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Abstract

Early complement components are important for normal antibody responses. In this process, complement receptors 1 and 2 (CR1/2), expressed on B cells and follicular dendritic cells (FDCs) in mice, play a central role. Complement-activating IgM administered with the antigen it is specific for, enhances the antibody response to this antigen. Here, bone marrow chimeras between Cr2−/− and wildtype mice were used to analyze whether FDCs or B cells must express CR1/2 for antibody responses to sheep erythrocytes (SRBC), either administered alone or together with specific IgM. For robust IgG anti-SRBC responses, CR1/2 must be expressed on FDCs. Occasionally, weak antibody responses were seen when only B cells expressed CR1/2, probably reflecting extrafollicular antibody production enabled by co-crosslinking of CR2/CD19/CD81 and the BCR. When SRBC alone was administered to mice with CR1/2+ FDCs, B cells from wildtype and Cr2−/− mice produced equal amounts of antibodies. Most likely antigen is then deposited on FDCs in a way that optimizes engagement of the B cell receptor, making CR2-facilitated signaling to the B cell superfluous. SRBC bound to IgM will have more C3 fragments, the ligands for CR1/2, on their surface than SRBC administered alone. Specific IgM, forming a complex with SRBC, enhances antibody responses in two ways when FDCs express CR1/2. One is dependent on CR1/2+ B cells and probably acts via increased transport of IgM-SRBC-complement complexes bound to CR1/2 on marginal zone B cells. The other is independent on CR1/2+ B cells and the likely mechanism is that IgM-SRBC-complement complexes bind better to FDCs than SRBC administered alone. These observations suggest that the immune system uses three different CR1/2-mediated effector functions to generate optimal antibody responses: capture by FDCs (playing a dominant role), transport by marginal zone B cells and enhanced B cell signaling.

Highlights

Complement is central to a well functioning immune defense
Lack of C1q [5,11], but not of factor B in the alternative pathway [12,13] or of MBL in the lectin pathway [14,15] leads to impaired antibody responses, suggesting that the classical pathway is of major importance
To determine whether expression of complement receptors 1 and 2 (CR1/2) on B cells or on follicular dendritic cells (FDCs) are required for a normal antibody response, bone marrow chimeric mice were generated

Summary

Introduction

Complement is central to a well functioning immune defense. Its most well known role is to induce lysis of target cells which occurs when the end product of complement activation, the membrane attack complex, forms pores in the target cell membrane. Lack of C1q [5,11], but not of factor B in the alternative pathway [12,13] or of MBL in the lectin pathway [14,15] leads to impaired antibody responses, suggesting that the classical pathway is of major importance. The enhancing effect of IgM depends on its ability to activate complement [20,21] but enhancement is unperturbed in mice lacking the lytic pathway of complement activation owing to lack of factor C5 [21], excluding that increased lysis of antigen explains the immunostimulatory effect of IgM. Ability to enhance correlates with deposition of C3 fragments on the surface of the IgM-complexed antigen [11]

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