Introduction of Fcα/μR
IgM is the first antibody to be produced in a humoral immune response and may play an important role in the primary stage of immunity. Fc receptors play important roles in a wide array of immune responses. In contrast to the well-defined Fcγ and Fcε receptors, the structural and functional characteristics of Fc receptors for IgM expressed on hematopoietic cells remained incompletely understood for years, although a polymeric immunoglobulin receptor (poly-IgR) that is able to bind IgM and IgA and expressed on epithelial cells was characterized. Functional Fc receptors for IgM were suggested since the early 1980s to exist on subpopulations of human and rodent lymphocytes. However, molecular cloning of an Fcμ receptor gene was not successful for years. Similarly, although a human Fcα receptor (FcαRI) was described, a homologous rodent Fcα receptor had not been identified. In 2000, Fcα/μR became the first Fc receptor for IgM as well as IgA, described in both humans and rodents, and expressed on both hematopoietic and nonhematopoietic cells.
Expression of Fcα/μR
Fcα/μR is expressed on a subset of B cells and macrophages, but not on granulocytes, T cells, or NK cells in the mouse spleen. Although Fcα/μR is closely related to poly-IgR, the expression pattern of Fcα/μR is quite different from that of poly-IgR, which is expressed on epithelial, but not hematopoietic, cells. During developmental stages of B cells in the bone marrow, IgD+, IgM+ mature B lymphocytes expressed significant amounts of the mFcα/μR. In contrast, it was not expressed on the majority of IgD, IgM+ immature B lymphocytes, suggesting that the Fcα/μR might be involved in B cell development. However, recent evidence demonstrated that each lymphocyte population, including B cell subsets, was normal in mice deficient in Fcα/μR gene, suggesting that Fcα/μR defect did not affect lymphocyte development. Unlike mFcα/μR, hFcα/μR is hardly detected on the cell surface of B cells and monocytes in peripheral blood. Immunohistochemical studies demonstrated that the Fcα/μR is expressed in germinal centers in lymphoid tissues, including spleen, lymph nodes, and Peyer s patch, strongly suggesting that Fcα/μR may play an important role in humoral immune responses.
Fig 1. Expression of Fcα/μR in lymphoid tissues. (Shibuya, 2015)
>Endocytosis of IgM-immune Complex by the Fcα/μR
The cytoplasmic domain of the Fcα/μR contains a dileucine motif which has been implicated in endosome and lysosome targeting of diverse proteins and is involved in agonist-induced internalization. A dileucine motif is involved in FcγRIIB-mediated endocytosis. Previous study indicates that the mFcα/μR mediates endocytosis of IgM-coated microbial pathogens, suggesting that Fcα/μR may be involved in protection against microbial infection by stimulating phagocytosis, as well as in antigen processing and presentation to helper T cells, resulting in linkage from innate to adaptive immune responses.
The Role of Fcα/μR in Humoral Immune Responses
Fcα/μR was considered to be involved in humoral immune responses based on the expression pattern of Fcα/μR on B cells and FDCs. Indeed, although Fcα/μR-deficient mice showed normal antibody responses after immunization with a T-dependent (TD) antigen, immunization with either of the T-independent (TI) antigens NP-LPS and NP-Ficoll significantly increased the number of GCs, generation of IgG3-producing memory B cells and affinity maturation of anti-NP IgG3, with Fcα/μR acting on both FDCs and B cells.
Fig 2. A role of Fca/μR in humoral immune responses against the T-independent antigen. (Shibuya, 2015)
Role of the Fca/μR Receptor in Inflammatory Responses
MZ B cells are located at the border between the circulating blood and lymphoid tissues in the spleen. After encountering blood-borne pathogens, MZ B cells rapidly differentiate into plasmablasts for production of a fist wave innate-like antibodies, which dominate the early phase of humoral immune responses for eradication of pathogens. Research found that mice lacking MZ B cells are resistant to LPS-induced endotoxic shock and cecum ligation and puncture, suggesting that MZ B cells likely contribute to systemic inflammatory responses to LPS as well as antibody production. Indeed, MZ B cells produce proinflammatory cytokines and chemokines, including IL-6, TNF-a, MCP-1, MIP-1a, and CXCL10, after LPS injection. Mice deficient in Fca/μR or IL-6 specifically in MZ B cells also showed resistance to LPS-induced endotoxic shock. These results suggest that IL-6 secreted from MZ B cells plays an important role in systemic inflammatory responses and Fca/μR is involved in IL-6 production by MZ B cells.
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Reference
- Shibuya, A., Honda, S. Immune regulation by Fcα/μ receptor (CD351) on marginal zone B cells and follicular dendritic cells. Immunological reviews. 2015, 268(1): 288–295.
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