Study Title:

Immunoglobulin A as an anti-inflammatory agent

Study Abstract

Immunoglobulin A (Ig)A is a class of antibodies that shows the highest daily synthesis, at a concentration of approximately 2–3 mg/ml, and is the second most prevalent antibody in the serum after IgG 1. IgA is differentially distributed between the systemic and mucosal immune systems and plays a key role in immune protection. Most IgA circulates as monomers derived from bone marrow plasma cells, whereas the majority of IgA in the secretions is polymeric, mainly in the form of dimers comprising two IgA monomers linked by a J (joining) chain. Secretory IgA (SIgA) is synthesized by local plasma cells before being transported to mucosal surfaces through epithelial cells by the polymeric Ig receptor 2,3. Human IgA is divided into closely related subclasses, IgA1 and IgA2. Only a minor percentage of serum IgA is in a polymeric form. SIgA plays an important role in different functions in the immune system. While high-affinity IgA antibodies are thought to protect intestinal mucosal surfaces against invasion by pathogenic microorganisms, low-affinity IgA antibodies are important to confine commensal bacteria to the intestinal lumen 1. In contrast, the major role of serum monomeric IgA (mIgA) is to promote a powerful anti-inflammatory effect. More than 30 years ago, it was demonstrated by several groups that in the absence of antigen, serum IgA is capable of down-regulating many cellular responses 4.

We have demonstrated that both inflammatory and anti-inflammatory functions of IgA are mediated by a single Fc receptor (FcR), the IgA Fc receptor or FcαRI (CD89). This receptor is expressed exclusively by myeloid cells. Inflammatory responses are mediated following cross-linking of FcαRI by IgA immune complexes which require its association with the FcRγ subunit to initiate immunoreceptor tyrosine-based activation motif (ITAM)-dependent cellular responses. The FcRγ-chain ITAM consists of a conserved stretch of paired tyrosines and leucines separated by seven amino acids in a consensus sequence (YxxLx6–7YxxL). The Src kinase Lyn phosphorylates the tyrosines within the associated FcRγITAM to serve as ‘docking’ sites for the recruitment of the tyrosine kinase Syk; this facilitates the activation of multiple targets including PI3K, ultimately triggering calcium release. Activation of rapidly accelerated fibrosarcoma-1 mitogen-activated protein kinase kinase–mitogen-activated protein (Raf-1–MEK–MAP) kinases by sequential phosphorylation is also induced. The interconnected signalling pathways couple FcRγ-chain ITAM phosphorylation to different cellular processes by the activation of several transcription factors. FcαRI activation may thus trigger specific signalling and functional responses.

We have demonstrated that ITAMs can also propagate inhibitory signals when they are in a conformation named inhibitory ITAM (ITAMi) 5,6. Some of the ITAM-bearing FcRs, such as FcαRI, FcRγRIIA and FcRγRIIIA, can act as bi-functional receptors that may trigger inhibitory signals towards a whole array of activating receptors, and down-regulate IgE- or IgG-FcR-mediated signalling 6–8. The ITAMi function is initiated by targeting these FcRs at a low valency and is operative at a distance, independently of a co-aggregation mechanism. Thus it does not require any signals initiated by the activating receptors. With FcαRI, monomeric serum IgA transduces inhibitory signals through the FcαRI–FcRγ-chain complex. At the molecular level, an initial very low-intensity FcαRI activation step promotes a Syk-dependent recruitment of the tyrosine phosphatase Src homology region 2 domain-containing phosphatase-1 (SHP-1) to the FcRγITAM and the movement of FcαRI to lipid rafts. Following this recruitment, both inhibitory and activating receptors and the inhibitory molecular effector, SHP-1, can be identified in intracellular structures that we have called ‘inhibisomes’, which diminish Syk and ERK phosphorylation and function of the heterologous activating receptors 9. Therefore, similar to immunoreceptor tyrosine-based inhibition motif (ITIM)-mediated signals, down-regulation of the response of the heterologous activating receptor (also recruited into rafts) requires the association of inhibitory receptors with SHP-1. Inhibisome formation also requires the SHP-1-dependent depolarization of actin. Thus, both IgA-induced activating and inhibiting signals depend on FcαRI–FcRγ-chain ITAM, but differ with respect to the recruitment of tyrosine kinases versus tyrosine phosphatases, respectively. It has therefore been proposed that the cross-linking of FcαRI during infection with IgA-opsonized pathogens induces proinflammatory responses, whereas naturally occurring serum IgA (which is not complexed with an antigen) induces inhibitory signals through the FcαRI to dampen excessive immune responses. Indeed, the fact that IgA-deficient patients develop more autoimmune and inflammatory diseases 10 demonstrates the importance of IgA as a natural inhibitor of immunity.

Data from our laboratory have demonstrated that ITAM-induced signalling through FcαRI could prevent disease development in several experimental inflammatory disease models. FcαRI targeting using anti-FcαRI A77 Fab fragments could prevent the development of asthma in FcαRI transgenic (Tg) mice. Pretreatment of FcαRI Tg animals with anti-FcαRI Fab, which monovalently targets FcαRI, reduced symptoms considerably compared to animals that received irrelevant control Fab antibodies 6. We demonstrated the therapeutic potential of an anti-FcαRI Fab treatment for the inhibition of inflammatory responses using two kidney inflammatory models 11. Cross-linking of the receptor worsened these diseases, whereas treatment with anti-FcαRI Fab impaired inflammatory cell infiltration and fibrosis development. These results demonstrate that anti-FcαRI Fab could be used as a new therapeutic tool to prevent the progression of inflammatory diseases.

SIgA also has a powerful anti-inflammatory effect due to its ability to interact with dendritic cells (DC) through the specific intercellular adhesion molecule (ICAM)-3 grabbing non-integrin receptor 1 (SIGNR1) 12. SIGNR1 is a mouse homologue of DC-SIGN, a C-type lectin receptor that was recently described as a receptor for human SIgA on the cell surface of DC. Similar to its interaction to DC-SIGN, SIgA–SIGNR1 interactions are dependent on sugars, notably mannose residues, on calcium and the presence of the secretory component. SIgA prevents activation of the immune system by regulating the function of mouse bone marrow-derived DC (BMDC) through SIGNR1. Pre-incubation with SIgA inhibits the maturation and the production of proinflammatory cytokines by BMDC, which instead harbours a tolerogenic phenotype and produces large amounts of interleukin (IL)-10. Importantly, BMDC pretreated with SIgA promotes the expansion of IL-10-secreting forkhead box protein 3 (FoxP3+) regulatory T cells (Tregs). Moreover, in vivo injection of SIgA-DC, loaded with self-peptides, prevents the development of autoimmune diseases such as experimental autoimmune encephalomyelitis and type 1 diabetes. Therefore, these data suggest that SIgA interaction with lectin-like receptors such as SIGNR1/DC-SIGN has a hitherto unknown regulatory function in the bloodstream, which opens new therapeutic avenues for the treatment of autoimmune and inflammatory diseases.

In summary, naturally occurring serum IgA induces inhibitory signals to dampen excessive immune responses, whereas targeting of DC-SIGN/SIGNR1 by secretory IgA induces tolerogenic immune responses. The manipulation of the IgA receptor functions by different types of IgA (monomers and secretory) or anti-receptor antibodies may thus offer novel promising therapeutic strategies. Further studies are now required to determine whether monomeric or secretory IgA treatment may be beneficial to prevent or reverse an established inflammatory disease and thus whether it constitutes the basis for future development of an intravenous IgA therapeutic approach.

Study Information

Clin Exp Immunol. 2014 Dec; 178(Suppl 1): 108–110. Published online 2014 Dec 29. doi: 10.1111/cei.12531

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