Reversal of Arthritis by Human Monomeric IgA Through the Receptor-Mediated SH2 Domain-Containing Phosphatase 1 Inhibitory Pathway.

OBJECTIVE: Rheumatoid arthritis (RA), one of the most frequent chronic inflammatory rheumatic disorders, is characterized by the presence of autoantibodies and joint infiltration by activated immune cells, leading to cartilage and bone destruction. IgA occurs predominantly as monomers (mIgA) in plasma and regulates many cell responses through interaction with the Fcα receptor type I (FcαRI). FcαRI targeting by anti-FcαRI Fab inhibits activating receptors by inducing an inhibitory immunoreceptor tyrosine-based activation motif (ITAMi) configuration through SH2 domain-containing phosphatase 1 (SHP-1) recruitment. The aim of this study was to investigate the potential utility of mIgA for the treatment of arthritis by acting as an inducer of ITAMi signaling. METHODS: The effect of plasma-derived human mIgA on inhibition of multiple heterologous receptors was evaluated on FcαRI+ cell transfectants, blood phagocytes from healthy individuals, and synovial cells from RA patients. FcαRI-transgenic mice and wild-type mice treated with mIgA were studied in models of collagen antibody-induced arthritis (CAIA) and collagen-induced arthritis (CIA). The mice were assessed for development of arthritis using an arthritis score, and joint tissue samples were evaluated for the extent of leukocyte infiltration and expression of phosphatase. RESULTS: Treatment with mIgA impaired cell activation in an FcαRI-FcRγ-dependent manner, involving ITAMi signaling. Human mIgA or anti-FcαRI Fab were strongly effective in either preventing or attenuating CAIA or CIA in FcαRI-transgenic mice. Administration of mIgA markedly inhibited the recruitment of leukocytes to the inflamed joints of mice, which was associated with induction of SHP-1 phosphorylation in joint tissue cells. Moreover, mIgA reversed the state of inflammation in the synovial fluid of RA patients by inducing an ITAMi configuration. CONCLUSION: These results demonstrate a therapeutic potential of human mIgA in experimental arthritis. The findings support future clinical exploration of mIgA for the treatment of RA.

IgA, IgA receptors, and their anti-inflammatory properties.

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.

Shifting FcγRIIA-ITAM from activation to inhibitory configuration ameliorates arthritis.

Rheumatoid arthritis-associated (RA-associated) inflammation is mediated through the interaction between RA IgG immune complexes and IgG Fc receptors on immune cells. Polymorphisms within the gene encoding the human IgG Fc receptor IIA (hFcγRIIA) are associated with an increased risk of developing RA. Within the hFcγRIIA intracytoplasmic domain, there are 2 conserved tyrosine residues arranged in a noncanonical immunoreceptor tyrosine-based activation motif (ITAM). Here, we reveal that inhibitory engagement of the hFcγRIIA ITAM either with anti-hFcγRII F(ab')2 fragments or intravenous hIgG (IVIg) ameliorates RA-associated inflammation, and this effect was characteristic of previously described inhibitory ITAM (ITAMi) signaling for hFcαRI and hFcγRIIIA, but only involves a single tyrosine. In hFcγRIIA-expressing mice, arthritis induction was inhibited following hFcγRIIA engagement. Moreover, hFcγRIIA ITAMi-signaling reduced ROS and inflammatory cytokine production through inhibition of guanine nucleotide exchange factor VAV-1 and IL-1 receptor-associated kinase 1 (IRAK-1), respectively. ITAMi signaling was mediated by tyrosine 304 (Y304) within the hFcγRIIA ITAM, which was required for recruitment of tyrosine kinase SYK and tyrosine phosphatase SHP-1. Anti-hFcγRII F(ab')2 treatment of inflammatory synovial cells from RA patients inhibited ROS production through induction of ITAMi signaling. These data suggest that shifting constitutive hFcγRIIA-mediated activation to ITAMi signaling could ameliorate RA-associated inflammation.

Anti-inflammatory role of the IgA Fc receptor (CD89): from autoimmunity to therapeutic perspectives.

The human immunoglobulin A (IgA) plays a key role in immune protection. IgA is the second most prevalent antibody in the serum. IgA-deficient patients frequently develop autoimmune or inflammatory diseases. The IgA function is mainly mediated through its interaction with the myeloid IgA Fc receptor FcαRI (CD89). FcαRI, an immunoreceptor tyrosine-based activation motif (ITAM)-bearing receptor, has a dual function in immunity. Monovalent targeting of FcαRI, by anti-FcαRI Fab or monomeric IgA, triggers potent inhibitory ITAM (ITAMi) signaling through the associated FcRγ chain. This results in a low-intensity signaling cascade promoting recruitment of the tyrosine phosphatase SHP-1, which induces cell inhibition of multiple types of activation signals. In contrast, cross-linking of FcαRI by multimeric ligand induces a high-intensity signaling pathway that leads to the recruitment of the tyrosine kinase Syk and to cell activation. Thus, FcαRI acts as a regulator, which mediates both anti- and pro-inflammatory functions of IgA depending on the type of interaction. This balance is of great importance to prevent tissue damage in immunopathology and to ensure the return of activated cells to a resting state. The role of the IgA-FcαRI interaction in the activation of different signaling pathways and its multifaceted role in immunity are discussed.

IgG1 and IVIg induce inhibitory ITAM signaling through FcγRIII controlling inflammatory responses.

Intravenous immunoglobulin (IVIg) has been used in the treatment of several autoimmune and inflammatory diseases. However, its mechanism of action remains incompletely understood. Here, we investigated the possibility that IVIg induces its anti-inflammatory effects through activating Fcγ receptors bearing an immunoreceptor tyrosine-based activation motif (ITAM) in the FcRγ signaling adaptor. Recently, the concept of inhibitory ITAM (ITAMi) has emerged as a new means to negatively control the immune response. We found that interaction of FcRγ-associated mouse or human FcγRIII with uncomplexed IgG1 or IVIg, or with bivalent anti-FcγRIII F(ab')(2) reduced calcium responses, reactive oxygen species production, endocytosis, and phagocytosis, induced by heterologous activating receptors on monocyte/macrophages and FcγRIII(+) transfectants. Inhibition required the ITAMi configuration of the FcγRIII-associated FcRγ subunit and SHP-1 recruitment involving formation of intracellular "inhibisome" clusters containing FcγRIII, and the targeted heterologous activating receptor. IVIg as well as anti-FcγRIII treatments controlled the development of nonimmune mediated inflammation in vivo independently of FcγRIIB. These results demonstrate that circulating immunoglobulins (Ig)Gs are not functionally inert but act through continuous interaction with FcγRIII-inducing ITAMi signaling to maintain immune homeostasis. These data support a new mechanism of action for IVIg and demonstrate the therapeutic potential of FcγRIIIA targeting in inflammation.