Abstract
IgA is the most abundant immunoglobulin in mucosal areas but is only the second most common antibody isotype in serum because it is catabolized faster than IgG. IgA exists in monomeric and polymeric forms that function through receptors expressed on effector cells. Here, we show that IgA Fc receptor(s) (FcalphaR) are expressed with or without the gamma chain on monocytes and neutrophils. gamma-less FcalphaR represent a significant fraction of surface FcalphaR molecules even on cells overexpressing the gamma chain. The FcalphaR-gamma2 association is up-regulated by phorbol esters and interferon-gamma. To characterize gamma-less FcalphaR functionally, we generated mast cell transfectants expressing wild-type human FcalphaR or a receptor with a point mutation (Arg --> Leu at position 209) which was unable to associate with the gamma chain. Mutant gamma-less FcalphaR bound monomeric and polymeric human IgA1 or IgA2 but failed to induce exocytosis after receptor clustering. The two types of transfectant showed similar kinetics of FcalphaR-mediated endocytosis; however, the endocytosis pathways of the two types of receptor differed. Whereas mutant FcalphaR were localized mainly in early endosomes, those containing FcalphaR-gamma2 were found in endo-lysosomal compartments. Mutant gamma-less FcalphaR recycled the internalized IgA toward the cell surface and protected against IgA degradation. Cells expressing the two forms of FcalphaR, associated or unassociated with gamma chains, may thus have differential functions either by degrading IgA antibody complexes or by recycling serum IgA.
Highlights
In humans, IgA is found in the systemic and mucosal compartments; it is the second most common antibody class in blood and the major immunoglobulin at mucosal surfaces [1, 2]
We show that IgA Fc receptor(s) (Fc␣R) are expressed with or without the ␥ chain on monocytes and neutrophils. ␥-less Fc␣R represent a significant fraction of surface Fc␣R molecules even on cells overexpressing the ␥ chain
We have identified significant amounts of ␥-less Fc␣R in several cell types, including monocytes, neutrophils, and transfected cells overexpressing the ␥ chain. ␥-less Fc␣R and Fc␣R-␥2 are expressed on the same cells, and this constitutes the basis for differential endocytosis pathways of IgA, in which ␥-less receptors recycle IgA toward the cell surface whereas Fc␣R-␥2 undergo endo-lysosomal sorting for IgA degradation
Summary
IgA is found in the systemic and mucosal compartments; it is the second most common antibody class in blood and the major immunoglobulin at mucosal surfaces [1, 2]. Fc␣R are expressed on myeloid cells as heterogeneously glycosylated type I transmembrane proteins that can bind both IgA1 and IgA2 isotypes at the boundary between the C␣2 and C␣3 domains (14 –18). Fc␣R are associated with the disulfide-linked FcR ␥ chain homodimer (26 –28) This interaction is resistant to treatment with Nonidet P-40 detergent, which contrasts with the dissociation of ␥ chains from Fc⑀RI or Fc␥RI in certain detergents [26, 29, 30]. FcR without signaling motifs in their cytoplasmic tails are associated with specialized subunits, such as ␥ or  chains, and depend on their specific retention motifs to be fully expressed on the cell surface [33]. We have identified significant amounts of ␥-less Fc␣R in several cell types, including monocytes, neutrophils, and transfected cells overexpressing the ␥ chain. ␥-less Fc␣R and Fc␣R-␥2 are expressed on the same cells, and this constitutes the basis for differential endocytosis pathways of IgA, in which ␥-less receptors recycle IgA toward the cell surface whereas Fc␣R-␥2 undergo endo-lysosomal sorting for IgA degradation
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