Thus, active secretion of IgA Ab does not contribute to its ability to protect against anaphylaxis

Thus, active secretion of IgA Ab does not contribute to its ability to protect against anaphylaxis. Open in a separate window Figure 3 IgA does not need to be secreted into the gut to inhibit systemic oral antigen-induced anaphylaxisA. systemic anaphylaxis induced by ingested allergens in normal mice, mice deficient in the ability to secrete IgA into the intestines, and mice BAN ORL 24 in which intestinal IL-9 overexpression has induced intestinal mastocytosis and increased intestinal permeability. Results IgE-mediated systemic anaphylaxis and mast cell degranulation induced by antigen ingestion are suppressed by both serum antigen-specific IgA and IgG, but not by IgA within the gut lumen. Conclusion Systemic, rather than enteric antibodies protect against systemic anaphylaxis induced by ingested antigen. This BAN ORL 24 implies that ingested antigens must be absorbed systemically to induce anaphylaxis and suggests that immunization protocols that increase serum levels of antigen-specific, non-IgE antibodies should protect against severe food allergy. Clinical Implications Induction of a systemic IgG or IgA antibody response against a food allergen should protect against induction of systemic anaphylaxis by ingestion of that allergen. Keywords: Mouse, food allergy, IgE, IgA, IgG, allergic diarrhea, blocking antibodies Introduction Systemic anaphylaxis, which can be characterized by urticaria, angioedema, bronchospasm, diarrhea, dysrhythmias and cardiovascular collapse, is responsible for approximately 150,000 emergency department visits 1, 15,000 hospital admissions 2C3 and 1,500 deaths 4C6 each year in the United States. Although parenteral allergen administration is more likely to trigger systemic anaphylaxis than ingestion of the same allergen, the high prevalence of food allergy, coupled with the much greater likelihood CDC42 of eating an allergenic protein than being injected with an allergenic protein makes food allergy responsible for ~one third to BAN ORL 24 one-fifth of the emergency department visits for anaphylaxis 1, 7 and 100C200 deaths annually 4, 7C8 in the U.S. The immune mechanisms that cause food-induced systemic anaphylaxis and the immune mechanisms that may protect against food-induced systemic anaphylaxis are not as well understood as those BAN ORL 24 that promote and protect against parenteral allergen-induced anaphylaxis and are likely different. Systemic anaphylaxis elicited by allergen injection, for example, can be induced in mice by either an IgE/FcRI/mast cell-dependent mechanism or an IgG/FcRIII/basophil- or macrophage-dependent mechanism 9C10, while triggering of systemic anaphylaxis by allergen ingestion appears to be always or nearly always IgE, FcRI and mast cell dependent 11C12. In addition, while histamine is the predominant mediator responsible for IgE-dependent anaphylaxis induced by injected allergen, PAF and serotonin appear to have a more important role in IgE-dependent anaphylaxis induced by ingested allergen 9, 11. The evidence that Ig isotypes other than IgE have little or no role in food allergen-induced systemic anaphylaxis, when coupled with evidence that non-IgE antibodies(Abs) can protect against IgE-mediated anaphylaxis caused by injected antigens (Ags) by binding allergen epitopes before they can react with mast cell-associated, allergen-specific IgE 13, raises questions about whether these other isotypes can also protect against food allergen-induced anaphylaxis. Furthermore, if allergen-specific non-IgE Abs are protective, do they protect by binding ingested allergen in the gut lumen, before it has been absorbed, in the same way that IgA neutralizes intestinal toxins and blocks bacterial binding to epithelial receptors14C18, or by binding to allergen after it has been adsorbed systemically. This question is related to an additional issue C does ingested allergen induce systemic anaphylaxis predominantly by activating mucosal mast cells that are interspersed with mucosal epithelial cells at the interface of intestinal villi with the gut lumen, in which case systemic allergen absorption may not be necessary, or by interacting with mast cells that are associated with lymphatics and blood vessels, in which case systemic absorption is likely to be important. These questions have clinical implications: if ingested allergens do not have to be absorbed systemically to induce systemic anaphylaxis, allergen-specific Ab, presumably of the IgA isotype, would have to be secreted into the gut lumen to intercept allergen before it could activate mast cells and induce anaphylaxis. In contrast, if induction of systemic anaphylaxis by ingested allergens requires their systemic absorption, then IgG and non-secretory IgA Abs should be able to inhibit systemic anaphylaxis induced by ingested allergens. These alternative possibilities should influence strategies for the optimal induction of Abs able to inhibit food allergy-related systemic anaphylaxis. To address these issues, we have used both passive and active anaphylaxis models to study the ability of secreted vs. non-secreted IgA Abs and IgG Abs to inhibit systemic anaphylaxis induced by ingested allergens in three models: 1) normal mice that have been sensitized passively by injection of a TNP-specific IgE antibody; 2) IgE anti-TNP mAb passively sensitized mice in which intestinal IL-9 overexpression has induced intestinal mastocytosis; and 3) normal mice in which.