The IgA receptor family comprises a number of surface receptors including the polymeric Ig receptor involved in epithelial transport of IgA/IgM, the myeloid specific IgA Fc receptor (FcαRI or CD89), the Fcα/μR, and at least two alternative IgA receptors. These are the asialoglycoprotein receptor and the transferrin receptor, which have been implicated in IgA catabolism, and tissue IgA deposition. In this reviewwe focus on the biology of FcαRI (CD89). FcαRI is expressed on neutrophils, eosinophils, monocytes/macrophages, dendritic cells, and Kupffer cells. This receptor represents a heterogeneously glycosylated transmembrane protein that binds both IgA subclasses with low affinity. A single gene encoding FcαRI has been isolated, which is located within the leukocyte receptor cluster on chromosome 19. The FcαRI α chain lacks canonical signal transduction domains but can associate with the FcR γ-chain that bears an activation motif (ITAM) in the cytoplasmic domain, allowing activatory functions. FcαRI expressed alone mediates endocytosis and recyling of IgA. No FcαRI homologue has been defined in the mouse, and progress in defining the in vivo role of FcαRI has been made using human FcαRI transgenic (Tg) mice. FcαRI-Tg mice demonstrated FcαRI expression on Kupffer cells and so defined a key role for the receptor in mucosal defense. The receptor functions as a second line of antibacterial defense involving serum IgA rather than secretory IgA. Studies in FcαRI-Tg mice, furthermore, defined an essential role for soluble FcαRI in the development of IgA nephropathy by formation of circulating IgA-FcαRI complexes. Finally, recent work points out a role for human IgA in treatment of infectious and neoplastic diseases.

Progression to destructive insulitis in nonobese diabetic (NOD) mice is linked to the failure of regulatory cells, possibly involving T helper type 2 (Th2) cells. Natural killer (NK) T cells might be involved in diabetes, given their deficiency in NOD mice and the prevention of diabetes by adoptive transfer of α/β double-negative thymocytes. Here, we evaluated the role of NK T cells in diabetes by using transgenic NOD mice expressing the T cell antigen receptor (TCR) α chain Vα14-Jα281 characteristic of NK T cells. Precise identification of NK1.1⁺ T cells was based on out-cross with congenic NK1.1 NOD mice. All six transgenic lines showed, to various degrees, elevated numbers of NK1.1⁺ T cells, enhanced production of interleukin (IL)-4, and increased levels of serum immunoglobulin E. Only the transgenic lines with the largest numbers of NK T cells and the most vigorous burst of IL-4 production were protected from diabetes. Transfer and cotransfer experiments with transgenic splenocytes demonstrated that Vα14-Jα281 transgenic NOD mice, although protected from overt diabetes, developed a diabetogenic T cell repertoire, and that NK T cells actively inhibited the pathogenic action of T cells. These results indicate that the number of NK T cells strongly influences the development of diabetes.

Immunoglobulin A vasculitis (IgAV), also referred to as Henoch-Schönlein purpura, is the most common form of childhood vasculitis. The pathogenesis of IgAV is still largely unknown. The disease is characterized by IgA1-immune deposits, complement factors and neutrophil infiltration, which is accompanied with vascular inflammation. Incidence of IgAV is twice as high during fall and winter, suggesting an environmental trigger associated to climate. Symptoms can resolve without intervention, but some patients develop glomerulonephritis with features similar to IgA nephropathy that include hematuria, proteinuria and IgA deposition in the glomerulus. Ultimately, this can lead to end-stage renal disease. In IgA nephropathy immune complexes containing galactose-deficient (Gd-)IgA1 are found and thought to play a role in pathogenesis. Although Gd-IgA1 complexes are also present in patients with IgAV with nephritis, their role in IgAV is disputed. Alternatively, it has been proposed that in IgAV IgA1 antibodies are generated against endothelial cells. We anticipate that such IgA complexes can activate neutrophils via the IgA Fc receptor FcαRI (CD89), thereby inducing neutrophil migration and activation, which ultimately causes tissue damage in IgAV. In this Review, we discuss the putative role of IgA, IgA receptors, neutrophils and other factors such as infections, genetics and the complement system in the pathogenesis of IgA vasculitis.

Fc receptors (FcRs) belong to the ITAM-associated receptor family. FcRs control the humoral and innate immunity which are essential for appropriate responses to infections and prevention of chronic inflammation or auto-immune diseases. Following their crosslinking by immune complexes, FcRs play various roles such as modulation of the immune response by released cytokines or of phagocytosis. Here, we review FcR involvement in pathologies leading notably to altered intracellular signaling with functionally relevant consequences to the host, and targeting of Fc receptors as therapeutic approaches. Special emphasis will be given to some FcRs, such as the FcαRI, the FcγRIIA and the FcγRIIIA, which behave like the ancient god Janus depending on the ITAM motif to inhibit or activate immune responses depending on their targeting by monomeric/dimeric immunoglobulins or by immune complexes. This ITAM duality has been recently defined as inhibitory or activating ITAM (ITAMi or ITAMa) which are controlled by Src family kinases. Involvement of various ITAM-bearing FcRs observed during infectious or autoimmune diseases is associated with allelic variants, changes in ligand binding ability responsible for host defense perturbation. During auto-immune diseases such as rheumatoid arthritis, lupus or immune thrombocytopenia, the autoantibodies and immune complexes lead to inflammation through FcR aggregation. We will discuss the role of FcRs in autoimmune diseases, and focus on novel approaches to target FcRs for resolution of antibody-mediated autoimmunity. We will finally also discuss the down-regulation of FcR functionality as a therapeutic approach for autoimmune diseases.

Celiac disease (CD) is an enteropathy resulting from an abnormal immune response to gluten-derived peptides in genetically susceptible individuals. This immune response is initiated by intestinal transport of intact peptide 31-49 (p31-49) and 33-mer gliadin peptides through an unknown mechanism. We show that the transferrin receptor CD71 is responsible for apical to basal retrotranscytosis of gliadin peptides, a process during which p31-49 and 33-mer peptides are protected from degradation. In patients with active CD, CD71 is overexpressed in the intestinal epithelium and colocalizes with immunoglobulin (Ig) A. Intestinal transport of intact p31-49 and 33-mer peptides was blocked by polymeric and secretory IgA (SIgA) and by soluble CD71 receptors, pointing to a role of SIgA–gliadin complexes in this abnormal intestinal transport. This retrotranscytosis of SIgA–gliadin complexes may promote the entry of harmful gliadin peptides into the intestinal mucosa, thereby triggering an immune response and perpetuating intestinal inflammation. Our findings strongly implicate CD71 in the pathogenesis of CD.