Increased serum IgA in Fcα/μR-deficient mice on the (129 x C57BL/6) F1 genetic background
Introduction
IgA is an antibody produced most abundantly among the classes of immunoglobulins and mainly secreted to the mucosal lumen (Kerr et al., 1990, Macpherson et al., 2012). Secreted IgA prevents penetration of pathogens into the mucosal lumen, neutralizes toxins and pathogens (Monteiro and Van De Winkel, 2003), and anchors the pathogenic bacteria to the mucus, leading to down-modulation of their pro-inflammatory epitopes (Fernandez et al., 2003). In Peyer's patches (PP), antigen-stimulated B cells form germinal centers (GC) with T cell help, leading to class switch recombination to IgA (IgA-CSR) in the presence of IgA-CSR-inducing factors, such as TGF-β and retinoic acid (Cazac and Roes, 2000). IgA+ B cells then circulate through the bloodstream and home to the intestinal lamina propria via expressions of α4β7 integrin and CCR9 (Mora and von Andrian, 2009). In addition, IgA+ B cells are also generated in the intestinal lamina propria (Fagarasan and Honjo, 2004). These in situ IgA-CSR does not require T cells, but does DC (Litinskiy et al., 2002) or epithelial cells (Xu et al., 2007), which secrete IgA-CSR-inducing factors (He et al., 2007). IgA produced in the lamina propria is transported and secreted into the mucosal lumen via binding to polymeric Ig receptor (pIgR) expressed on the mucosal epithelial cells (Kaetzel, 2005). Although the molecular mechanisms for IgA secretion into the mucosal lumen have well been studied, little is known about the maintenance of IgA in the sera.
Fc receptors are expressed on immune cells and play pivotal roles in immune responses. Several Fc receptors for IgG [FcγRI (CD64), FcγRII (CD32), FcγRIII (CD16) and FcγRIV] and IgE [FcɛRI and FcɛRII (CD23)] have been identified and shown to be pivotal for host immunity, allergy and autoimmune diseases (Ravetch, 1997, Takai, 2002). We have previously identified an Fc receptor for both IgA and IgM (Fcα/μR) (Shibuya et al., 2000). Fcamr that encodes Fcα/μR was mapped on chromosome 1, in which other Fc receptor genes are closely located each other (Shibuya et al., 2000, Shimizu et al., 2001). Although Fcα/μR is abundantly expressed in the small intestine (Sakamoto et al., 2001), its role in the mucosal tissue is largely unknown. Here, we found that Fcα/μR was preferentially expressed on FDCs in PP and negatively regulate the serum IgA level in response to gut-oriented antigens.
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Mice
Two lines of Fcα/μR-deficient mice were generated, as described previously (Honda et al., 2009). One line was E14 ES origin and backcrossed to one generation to C57BL/6J mice [Fcα/μR-deficient mice on (129 x C57BL/6) F1 genetic background]. Another line was BALB/c ES origin and then backcrossed to C57BL/6J mice for more than 12 generations [Fcα/μR-deficient mice on BALB/c and C57BL/6 genetic backgrounds, respectively]. BALB/c and C57BL/6J mice were purchased from Clea Japan, Inc. (Tokyo,
Increased serum IgA in Fcα/μR-deficient mice on the (129 x C57BL/6) F1 genetic background
Previous reports demonstrated that Fcamr transcript was abundantly expressed in the small intestine (Sakamoto et al., 2001). By using immunohistochemical analyses, we observed that Fcα/μR was strongly expressed on FDCs in Peyer's patches (PP) of the small intestine (Fig. 1A). Since FDCs are involved in mucosal IgA production (Suzuki et al., 2010), IgA concentration in the serum and feces was analyzed. We found that serum IgA was significantly increased in Fcα/μR-deficient mice on the (129 x
Discussion
We observed that naïve Fcα/μR-deficient mice on the (129 x B6) F1 background, but not on the BALB/c or C57BL/6 genetic backgrounds, showed increased serum IgA level. It was previously reported that immune responses, including antibody production, are influenced by genetic background of mice (Dorf et al., 1974, Lipes et al., 2002). Along with this notion, involvement of Fcα/μR in serum IgA level seemed to be influenced by the genetic background of mice. Although we found that Fcα/μR on FDCs was
Acknowledgements
We thank S. Mitsuishi for secretarial assistance. This research was supported in part by Grants provided by the Ministry of Education, Culture, Sports, Science and Technology of Japan.
References (27)
- et al.
TGF-beta receptor controls B cell responsiveness and induction of IgA in vivo
Immunity
(2000) - et al.
Molecular characteristics of IgA and IgM Fc binding to the Fcalpha/muR
Biochem. Biophys. Res. Commun.
(2006) - et al.
Regulation of IgA synthesis at mucosal surfaces
Curr. Opin. Immunol.
(2004) - et al.
Anti-inflammatory role for intracellular dimeric immunoglobulin a by neutralization of lipopolysaccharide in epithelial cells
Immunity
(2003) - et al.
Intestinal bacteria trigger T cell-independent immunoglobulin A(2) class switching by inducing epithelial-cell secretion of the cytokine APRIL
Immunity
(2007) - et al.
Homeland security: IgA immunity at the frontiers of the body
Trends Immunol.
(2012) - et al.
Role of retinoic acid in the imprinting of gut-homing IgA-secreting cells
Semin. Immunol.
(2009) - et al.
Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis
Cell
(2004) Fc receptors
Curr. Opin. Immunol.
(1997)- et al.
The sensing of environmental stimuli by follicular dendritic cells promotes immunoglobulin A generation in the gut
Immunity
(2010)
Human Fcalpha/muR and pIgR distribute differently in intestinal tissues
Biochem. Biophys. Res. Commun.
Genetic control of the immune response: the effect of non-H-2 linked genes on antibody production
J. Immunol.
Follicular dendritic cells: dynamic antigen libraries
Nat. Rev. Immunol.
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