Inroads Being Made to Prevent and Treat Anaphylaxis
Many visits to the emergency room are a result of allergic reactions, some of which result in anaphylaxis, an acute and potentially fatal allergic reaction that occurs when an allergen is introduced systemically. A recent study by Richard Strait, MD, et al, produced findings that may lead to new avenues for the prevention and treatment of anaphylaxis in humans.
An allergic reaction that can cause shortness of breath, wheezing, rash and hypotension, anaphylaxis affects the whole body whereas most other allergic reactions affect just one area of the body. As allergic diseases become more prevalent throughout the world, it is important to study the reactions to determine why some resolve and others develop into anaphylaxis.
"The majority of the anaphylaxis that occurs in humans is still not well understood," says Dr. Strait, attending physician in the Cincinnati Children's Division of Emergency Medicine. "This study was designed to analyze the reactions that occur in anaphylaxis in an animal model, so that we can get a better handle on the reactions that occur in humans."
Anaphylaxis has classically been defined as a process that is mediated primarily by IgE, FcεRI, mast cells and histamine. However, several recent studies have suggested that an alternative pathway involving IgG, FcγRII, macrophages and platelet-activating factor (PAF) may be more important than the classical pathway in rodent models of antigen-induced anaphylaxis. Dr. Strait's study sheds new light on these two pathways and their respective roles in a mouse model of antigen-induced anaphylaxis.
The authors immunized mice with an anti-mouse IgD antibody, which cross-links IgD on the surface of B cells. This cross-linking causes B cells to mount massive IgG and IgE responses and induces them to secrete cytokines that induce mastocytosis. These mice were then challenged 14 days later by injecting them with either antigen or with a rat anti-mouse IgE monoclonal antibody that effectively cross-links IgE. Severity of anaphylaxis was measured by changes in body temperature, physical activity and mortality.
Surprising Findings
The investigators found that antigen-based challenge was physically indistinguishable from anti-IgE challenge in terms of kinetics, severity, target organs or dose requirements. Despite these similarities, however, striking differences were noted at the cellular and molecular level.
As might be expected, challenge with an anti-IgE antibody resulted in a response that was FcεRI and mast cell dependent, and was mediated by histamine. This is the classically defined anaphylaxis pathway. In contrast, challenge with antigen resulted in a response that was FcγRII and macrophage dependent, and was mediated primarily by PAF. Mast cells, platelets and histamine appeared to be unimportant in this alternative pathway.
Dr. Strait says that these results were somewhat unexpected. "One surprise was the involvement of only the macrophage in the alternative pathway. When we eliminated the macrophage we got no response at all. The lack of involvement of histamine in that pathway was also somewhat surprising."
The authors conclude that antigen-induced anaphylaxis proceeds primarily through the alternative IgG/FcγRII pathway, even in an animal model that is characterized by strong mast cell and IgE responses. Furthermore, the authors speculate that the presence of FcγRII on human macrophages suggests that this alternative pathway may be important in human anaphylaxis.
Clinical Significance
From a clinical standpoint, this discovery suggests a careful re-thinking of current prevention strategies and treatments for allergy. One example, says Dr. Strait, is the use of anti-IgE antibody to enhance serial desensitization therapy. In this treatment, allergic patients are given increasing doses of allergen coupled with antibody that binds and neutralizes IgE.
"By using anti-IgE," he says, "you may actually be promoting the alternative [IgG] pathway and could potentially induce anaphylaxis via the macrophage."
Although these findings have yet to be validated in humans, Dr. Strait says the mouse studies give important clues about the complexity of the reactions that occur in anaphylaxis.
"The take-home message is that anaphylaxis occurs by at least two different pathways, and they may be occurring simultaneously. It's not as simple as one pathway for one response."
This study appeared in the Journal of Allergy and Clinical Immunology (109[4]:658-668, 2002 April) and was supported by a Merit Award from the Veteran's Administration and grants from the National Institutes of Health.
