Short communicationInvolvement of Fcα/μR (CD351) in autoantibody production
Introduction
After binding to an antigen, immunoglobulin (Ig) initiates various immune responses via binding to a certain receptor for the Fc portion, called Fc receptor (FcR) (Daeron, 1997, Ravetch, 1997). Extensive studies demonstrated that FcRs for IgG (FcγRI, FcγRIIb, FcγRIII and FcγRIV) and IgE (FcɛRI and FcɛRII) play pivotal roles in immune responses, such as inflammations, cytotoxicity and allergic reactions (Ravetch and Clynes, 1998, Takai, 2002). In contrast to the FcγR and FcɛR, molecular and functional characteristics of Fc receptor for IgM remain incompletely understood. Fcα/μR (CD351) is an Fc receptor for IgM as well as IgA (Sakamoto et al., 2001, Shibuya et al., 2000). Fcα/μR forms an atypical dimer, for which the cytoplasmic region of Fcα/μR is required (Cho et al., 2010, Takagaki et al., 2013). Fcα/μR is moderately expressed on B cells and macrophages (Sakamoto et al., 2001, Shibuya et al., 2000), and most strongly on follicular dendritic cells (FDCs) (Cho et al., 2006, Honda et al., 2009, Usui et al., 2012), which is involved in germinal center (GC) formation (Chaplin and Zindl, 2006, Park and Choi, 2005). Fcα/μR-deficient mice showed increased GC formation and antibody production after immunization with T-independent (TI), but not T-dependent (TD), antigens (Honda et al., 2009). Thus, Fcα/μR negatively regulates humoral immune responses against TI antigens.
IgM exists in the sera of naïve host as a natural antibody. IgM is also the first antibody to be produced by naive B cells upon antigen recognition. Thus, IgM may play an important role in the early phase of host defenses against variable bacterial and viral infections (Boes et al., 1998, Ochsenbein et al., 1999). In addition, IgM prevents autoantibody production (Boes, 2000, Carroll, 2004, Ehrenstein et al., 2000). Mice deficient in serum IgM showed increased anti-DNA IgG production, leading to glomerulonephritis due to deposition of an immune complex with age (Ehrenstein et al., 2000). Moreover, serum IgM deficiency in MRL/MpJ-Faslpr/lpr mice, which spontaneously develop an autoimmune disease that has many features resembling human systemic lupus erythematosus due to lymphoproliferation (lpr) mutation on the Fas gene, showed significantly increased serum IgG autoantibodies against dsDNA and histone, and shortened life span caused by severe glomerulonephritis, compared with MRL/MpJ-Faslpr/lpr mice with normal serum IgM (Boes et al., 2000). Thus, serum IgM prevents autoantibody production and ameliorates immunological disorders (Boes, 2000, Carroll, 2004, Ehrenstein et al., 2000). However, how IgM is involved in autoantibody production is largely unknown.
Several reports have demonstrated that autoantibodies are produced in a T cell-independent manner (Groom et al., 2007, Herlands et al., 2008). Because Fcα/μR negatively regulates humoral immune responses against TI antigens (Honda et al., 2009), we hypothesized that IgM suppresses autoantibody production via interaction with Fcα/μR. To test this idea, we generated mice deficient in Fcα/μR on the background of MRL/MpJ-Faslpr/lpr (Fcamr−/−Faslpr/lpr) mice, and investigated the role of Fcα/μR in IgM-mediated suppression of autoantibody production.
Section snippets
Mice
Mice deficient in Fcα/μR on BALB/c background were previously described (Honda et al., 2009). The Fcα/μR-deficient mice were bred with MRL/MpJ-Faslpr/lpr (MRL/MpJ-Faslpr/JJmsSlc) mice purchased from Japan SLC, Inc. (Tokyo, Japan), and their offsprings were intercrossed to yield Fcamr+/+Faslpr/lpr and Fcamr−/−Faslpr/lpr mice. In all the experiment, we analyzed littermate mice to exclude the influence of the genetic backgrounds. Mice were maintained under specific pathogen free conditions. All
Results and discussion
To analyze the involvement of Fcα/μR in autoantibody production, we generated Fcamr+/+Faslpr/lpr and Fcamr−/−Faslpr/lpr mice. We collected sera from the both mice at the ages of 12, 16 and 20 weeks old, and measured the titers of IgG autoantibodies against double strand DNA (dsDNA), histone and cardiolipin. Fcamr+/+Faslpr/lpr mice showed elevated the titer of total anti-dsDNA IgG, which was further increased with age (Fig. 1A). However, anti-dsDNA IgG titers of Fcamr−/−Faslpr/lpr mice were
Acknowledgements
We thank S. Mitsuishi and Y. Nomura for secretarial assistances. This research was supported in part by the grants provided by the Ministry of Education, Science and Culture of Japan.
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