Allergen-Specific IgA Antibodies Block IgE-Mediated Activation of Mast Cells and Basophils

Abstract

Mast cells and basophils have long been implicated in the pathogenesis of IgE-mediated hypersensitivity reactions. They express the high-affinity IgE receptor, FcϵRI, on their surface. Antigen-induced crosslinking of IgE antibodies bound to that receptor triggers a signaling cascade that results in activation, leading to the release of an array of preformed vasoactive mediators and rapidly synthesized lipids, as well as the de novo production of inflammatory cytokines. In addition to bearing activating receptors like FcεRI, these effector cells of allergy express inhibitory ones including FcγR2b, an IgG Fc receptor with a cytosolic inhibitory motif that activates protein tyrosine phosphatases that suppress IgE-mediated activation. We and others have shown that food allergen-specific IgG antibodies strongly induced during the course of oral immunotherapy (OIT), signal via FcγR2b to suppress IgE-mediated mast cell and basophil activation triggered by food allergen challenge. However, the potential inhibitory effects of IgA antibodies, which are also produced in response to OIT and are present at high levels at mucosal sites, including the intestine where food allergens are encountered, have not been well studied. Here we uncover an inhibitory function for IgA. We observe that IgA binds mouse bone marrow-derived mast cells (BMMCs) and peritoneal mast cells. Binding to BMMCs is dependent on calcium and sialic acid. We also found that IgA antibodies inhibit IgE-mediated mast cell degranulation in an allergen-specific fashion. Antigen-specific IgA inhibits IgE-mediated mast cell activation early in the signaling cascade, suppressing the phosphorylation of Syk, the proximal protein kinase mediating FcεRI signaling, and suppresses mast cell production of cytokines. Furthermore, using basophils from a peanut allergic donor we found that IgA binds to basophils and that activation by exposure to peanuts is effectively suppressed by IgA. We conclude that IgA serves as a regulator of mast cell and basophil degranulation, suggesting a physiologic role for IgA in the maintenance of immune homeostasis at mucosal sites.

Peach extract induces systemic and local immune responses in an experimental food allergy model

“…In line with this, levels of total IgE, the pivotal immunoglobulin involved in type I allergy reactions 33 , as well as total levels of IgG in serum and intestinal homogenates of the peach allergic mice were strongly enhanced. In contrast, total IgA levels were significantly decreased in the serum, correlating with reports of a protective role of IgA in allergic diseases by inhibition of IgE-induced mast cell degranulation and cytokine production 34,35 .…”

Expansion of Antigen- Specific Memory Cells as a Potential Booster for Food Tolerance Induction

“…Other studies still need to be performed to comprehend the role of the various immune cell types as well as cytokines and immunoglobulins involved in this process through time. For instance, IgA evaluation was not possible during this work, but previous data from our group as well as in the literature suggest this immunoglobulin may play a significant role in our mouse model [88]. Here, we confirmed that a bystander suppression may occur when the animals were offered the allergenic food associated to the ingestion of tolerogenic food (mouse chow).…”

Autoreactive IgE: Pathogenic role and therapeutic target in autoimmune diseases

“…FcεRI‐mediated activation of mast cells and basophils leads to the immediate release of granular pro‐inflammatory preformed mediators and to neosynthesis and release of arachidonic derivatives, cytokines, and chemokines 18 . These effects can be toned down through co‐engagement of FcγRIIB (CD32B) or other inhibitory receptors that can block degranulation and decrease cytokine production 19,20 …”

“…18 These effects can be toned down through co-engagement of FcγRIIB (CD32B) or other inhibitory receptors that can block degranulation and decrease cytokine production. 19,20 The lower affinity IgE receptor FcεRII (CD23, Kd ≈ 10 −7 -10 −8 M) is mainly expressed by some subsets of B cells and monocytes and is involved in the regulation of IgE synthesis and, together with FcεRI, in IgE-mediated facilitated antigen presentation. 14 Beyond its effects on IgE synthesis, little is known about CD23-mediated pathogenicity of IgE in AbAID.…”