by: Dr. Stephen Pelsue

Overview

Well, it finally happened–the giant snow pile in front of MBS has melted. A time of year in Maine and other snow bound areas enthusiastically celebrate…but then immediately start complaining about the heat (I know, I know: it’s not the heat it’s the humidity). The emergence of spring brings the blooming of flowers and trees, the greening of grass, and a general feeling of rejuvenation.  Oh, and yes…allergy season!  Chances are that you or someone you know suffers from allergies or asthma.  For most of us it is a nuisance that we endure periodically, but for many, it can be debilitating and even life threatening. If the primary function of our immune system is to protect us, why then, are allergies, or more specifically hypersensitivity responses, such a problem?

Allergic Responses

The allergic response is a type (or types) of hypersensitivity responses that are defined by an overactive immune response that leads to tissue damage of the host.  There are five types of hypersensitivity responses, three of which (Type II, III, & V) are characteristic of autoimmune responses and autoimmune diseases, and two (Type I & IV) that are associated with allergy and asthma.  Type I hypersensitivity is an immediate response triggered within minutes of exposure, while type IV hypersensitivity is a late-phase response becoming activated in 6-72 hours following exposure. For the purpose of this presentation, I will be referring to the combination of these two responses as the allergic response.

Before we discuss the allergic response we should pause to talk about IgE.  The IgE class of antibodies is associated with protection against parasites, which are too large to be engulfed by phagocytic cells (neutrophils & macrophages). Distinct from the other classes of antibodies, IgE is produced and has a short half-life in circulation (hours), however, it is captured on the surface of mast cells by the high affinity IgE receptor FcR𝜖I.  The IgE bound to the FcR𝜖I is very stable and remains associated for weeks to months. Mast cells are tissue resident granulocytes that upon activation release tissue destroying enzymes, soluble mediators, cytokines, and chemokines.  The mast cells become activated by the IgE, recognizing its target antigen, and engaging the FcR𝜖I on the mast cell.  Typically multiple receptors would be activated simultaneously, referred to as cross-linking, which transduces a signal to the mast cell to become activated and release the granules and secrete the mediators.  The granules are deposited on the surface of the multicellular pathogen and initiate the destruction of the cellular surface of the pathogen.  The mediators initiate changes in the epithelium, vasculature, and smooth muscle cells as well as recruit and activate other leukocytes (predominantly macrophages, neutrophils, and eosinophils).  This effectively kills and breaks apart the pathogen and recruits the cells to clean up the mess, thereby protecting the host.

While the same general process occurs in an allergic response, the response leads to a destructive inflammatory response that is harmful to the host tissue.  There are three general phases associated with the allergic response: sensitization, activation, and inflammation. Sensitization occurs when an otherwise benign environmental antigen, referred to as an allergen, initiates the development of a Th2 skewed response and the development of allergen specific IgE antibodies (in most cases).  The allergen specific IgE coats the surface of the mast cells and upon a subsequent exposure to the allergen cross-links the IgE-FcR𝜖I complex and within seconds to minutes initiates granule release.  In this case, there is no foreign pathogen to destroy and the granule release results in allergic inflammation and depending on the site of exposure can result in anything from a rash to rhinitis to asthma to anaphylaxis.

Allergens

Allergens are the immunogenic proteins that drive the allergic response. Allergens are typically classified by source: 1) indoor (dust mites, mold, etc); 2) pollens (grass, tree, flower, etc.); insect bite (bee, wasp, mosquito, etc); or food (peanut, shellfish, milk, egg, etc) and have diverse biological structures and functions. It should be noted that not all allergic responses are IgE mediated, such as food and insect allergens.  Structural analysis of the known allergens has identified 120 molecular architectures, indicating there is a structural basis for the development of allergic responses.  In addition, these allergens typically promote a Th2 response which underlies the immunological mechanism of IgE development and the allergic cascade.  The structural basis of this is still under active investigation, however, it is likely that there are epitopes (both B cell and T cell)  as well as individual genetic susceptibility that promotes the development of the Th2 responses and IgE production.

Therapies

For any allergic reaction that has a known allergen source, the primary mechanism of treatment is allergen avoidance.  However, this is not always possible, particularly with outdoor environmental allergens (pollens) and additional therapies must be employed.  Many established therapies target immune suppression (corticosteroids), bronchodilation (asthma, 𝛽2-adrenoceptor agonists), allergen specific therapy (inducing tolerance to specific allergens), or inhibition of allergic mediators.   More recently there has been active development of antibody based biological therapies that target IgE, receptors (FcR𝜖I, cytokine receptors), and cytokine mediators (IL-5) to name a few.  Some have been approved and many more are in clinical trials. As we define the mechanisms associated with the allergic response, it is certain that more small molecule and biologic therapies will be developed to better control allergy and asthma.

Worldwide allergic diseases have become an epidemic.  Development of new therapies and diagnostics will be critical for better management of allergy and asthma.  At MBS, as a custom antibody CRO, we are pleased to have the opportunity to work with companies that are developing allergy and asthma therapeutics and diagnostics.  Whether it is the development of allergy therapeutics, anti-idiotypes for clinical assessment of therapeutics, diagnostics, or antibodies for research, we would be pleased to discuss your future projects and needs for polyclonal or monoclonal antibody development.

 

ABOUT DR. PELSUE

Dr. Pelsue joined MBS as Science Director after 20 years experience in Immunology research.  Dr. Pelsue is providing technical expertise and leadership to address challenging new antibody targets on behalf of our client base.