IgA, IgA Receptors, and Their Anti-inflammatory Properties

Abstract

Immunoglobulin A (IgA) is the most abundantly produced antibody isotype in mammals. The primary function of IgA is to maintain homeostasis at mucosal surfaces and play a role in immune protection. IgA functions mainly through interaction with multiple receptors including IgA Fc receptor I (FcαRI), transferrin receptor 1 (CD71), asialoglycoprotein receptor (ASGPR), Fcα/μR, FcRL4, and DC-SIGN/SIGNR1. In this review we discuss recent data demonstrating anti-inflammatory functions of IgA through two receptors, the FcαRI and DC-SIGN/SIGNR1 interactions in the regulation of immunity. Serum monomeric IgA is able to mediate an inhibitory signal following the interaction with FcαRI. It results in partial phosphorylation of its FcRγ-ITAM and the recruitment of the tyrosine phosphatase SHP-1, which induces cell inhibition following the formation of intracellular clusters named inhibisomes. In contrast, cross-linking of FcαRI by multimeric ligands induces a full phosphorylation of the FcRγ-ITAM leading to the recruitment of the tyrosine kinase Syk and cell activation. In addition, secretory IgA can mediate a potent anti-inflammatory function following the sugar-dependent interaction with SIGNR1 on dendritic cells which induces an immune tolerance via regulatory T cell expansion. Overall, the anti-inflammatory effect of serum and secretory IgA plays a crucial role in the physiology and in the prevention of tissue damage in multiple autoimmune and inflammatory diseases.

Anti–factor VIII IgA as a potential marker of poor prognosis in acquired hemophilia A: results from the GTH-AH 01/2010 study

“…24,25 In contrast, cross-linking of FcaRI by IgA bound to multimeric antigens or bound in immune complexes results in full phosphorylation of the associated FcgR-ITAM motif followed by the recruitment of the tyrosine kinase Syk, which in turn facilitates the activation of multiple targets, resulting in the downstream activation of proinflammatory effector functions. 25,26 Examples for these proinflammatory effector functions are the induction of oxidative burst activities in neutrophils, an increase in antibody-dependent cytotoxic effector functions in macrophages, an increase in antigen presentation by antigen-presenting cells, a degranulation of neutrophils and eosinophils, or the release of proinflammatory cytokines by different myeloid cell populations. 25,26 It appears that the FcaRI is a molecular switch that determines the proinflammatory or anti-inflammatory function of circulating IgA.…”

“…25,26 Examples for these proinflammatory effector functions are the induction of oxidative burst activities in neutrophils, an increase in antibody-dependent cytotoxic effector functions in macrophages, an increase in antigen presentation by antigen-presenting cells, a degranulation of neutrophils and eosinophils, or the release of proinflammatory cytokines by different myeloid cell populations. 25,26 It appears that the FcaRI is a molecular switch that determines the proinflammatory or anti-inflammatory function of circulating IgA. One can imagine that immune complexes of IgA autoantibodies bound to distinct epitopes of human FVIII can result in cross-linking of FcaRI expressed on myeloid cells, thereby stimulating or amplifying innate immune activation, which could maintain or even deteriorate the autoimmune pathology in patients with AHA.…”

Oral Vaccination with Attenuated Salmonella typhimurium-Delivered TsPmy DNA Vaccine Elicits Protective Immunity against Trichinella spiralis in BALB/c Mice

“…Many lines of evidence support the notion that intestinal sIgA are secreted largely by plasma cells derived from B cells initially activated in gut-associated lymphoid tissue (GALT) after vaccination. After immunization, most naïve B cells migrate to the Peyer’s patches or MLNs and differentiate into plasma cells and return to the intestinal mucosa ( Lamina Propria ) to produce high-affinity sIgA [39, 40]. As we know, the epithelial cells of the small intestine express chemokine CCL25 and CCL28 that play important roles in mucosal immunity by recruiting IgA antibody-secreting cells (ASCs) that express their CCR9 and CCR10 receptors in the mucosal lamina propria [41].…”

Scarcity of autoreactive human blood IgA+ memory B cells

“…Indeed, IgA is the most prevalent isotype of antibodies circulating in human blood after IgG. Unliganded “natural” IgA antibodies circulating in human serum are believed to exert anti‐inflammatory activities, whereas specific IgAs opsonizing pathogens or forming immune complexes would trigger immune responses by activating myeloid cells . In this regard, although individuals with selective IgA deficiency are usually asymptomatic, they are prone to recurrent mucosal infections but also frequently present allergic and autoimmune manifestations .…”