Before coming to the in-class session, please read the following chapter from Basic Immunobiology and the introduction below.
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Allergy is exploding as a medical problem. The prevalence of allergic diseases, such as asthma, allergic rhinitis (“hay fever”), and food or drug allergies has grown in a near exponential rate. The growth in allergic disease seems to have occurred only in the last century and only in “industrialized” societies. One hundred years ago, allergic disease was rare. Now, nearly one in three people in the U.S. experience allergic disease of some sort, be it asthma, allergic rhinitis, or potentially fatal food or drug allergy. Allergic sensitization is of great importance in clinical medicine because of the potential for rapidly fatal systemic allergic responses (“anaphylaxis”) that can result from exposure after sensitization.
Allergy is a unique pathological immune response in that it is directed generally against harmless non-self proteins encountered in everyday life. These include proteins derived from inhaled animal danders, insect products, and pollen granules, as well as proteins from foods that humans have been consuming from time immemorial.
Most allergic sensitization occurs by episodic low dose exposure on mucosal surfaces, although systemic exposure (as by food or medicines) also can sensitize. Allergic sensitization requires cytokines that characterize T cells polarized in the Th2 direction. Th2 T cells produce cytokines that foster isotype switching of antibody production to IgE, eosinophil production and chemotaxis, and alterations in the physiology of airways and blood vessels, such as bronchospasm, that characterize the allergic response. IgE antibody has the unique ability to “arm” mast cells by binding to the IgE receptor on these cells. This leaves the IgE variable region open to bind epitopes on allergens, leading to the immediate release of allergic mediators, the most potent of which is histamine. This very rapid cascade of events characterizes the allergic, or "immediate hypersensitivity", response.
Th2 responses of extreme vigor, including enormously high IgE levels, are seen in response to parasitic infestations, largely in non-industrialized societies. In non-industrialized societies, therefore, it seems that this same response is orchestrated in response to parasitic infestations, suggesting that allergic disease is a pathological response that occurs in the absence of genuine parasitic infestations. The observation that infections other than parasitic infestations, such as hepatitis A, can protect against allergic disease has fostered a broader hypothesis to explain the allergy epidemic, termed the “hygiene hypothesis.” Recent evidence has linked regulatory T cells and the products of infections, such as endotoxin, with resistance to allergic disease in the absence of parasitic infestations.
Non-allergic hypersensitivity reactions, meaning those not involving IgE, can occur through a variety of means. For these, we shall recall the classification of pathological immune responses put forth by Gell and Coombs. So far, we have discussed type I, or immediate hypersensitivity, which requires prior IgE sensitization. Type II hypersensitivity reactions consist of IgG reactions against tissue-bound antigens, such as antibodies against the TSH receptor in Grave’s disease. Type III reactions are those in which IgG antibodies bind free-floating or “soluble” antigens in the blood stream, and cause damage by immune complex deposition, as seen in serum sickness and systemic lupus erythematosus. Type IV, or delayed hypersensitivity reactions, are ultimately CD4+ T cell- mediated reactions that occur one or more days after exposure to an antigen to which the immune system has been sensitized. Poison ivy reactions and the PPD reaction are prominent clinical examples of this hypersensitivity.
The main allergens that trigger asthma and nasal allergies are derived from common environmental particulates such as birch pollen, house dust mite feces, and other common components of inhalable microscopic particles. The allergen is a protein contained in each of these transmissible particles, and is inhaled at very low amounts over time. The key features of most allergens is their protein nature, their small size (typical allergens are about 100 amino acids long), their solubility in the aqueous environment of the upper and lower airways, and their resistance to proteolysis, which may be accounted for by the frequent finding that allergens are themselves proteases. They are inhaled at incredibly low doses, bind very strongly to class II HLA proteins, and are delivered to local lymph nodes in the respiratory tree by a continuous stream of dendritic cells.
Myeloid dendritic cell presentation of low dose allergen tightly bound to MHC class II favors activation of Th2 like cells. These cells produce several molecules that contribute to the allergic response. These include the cytokine IL-4, which is unique in its ability to stimulate isotype switching to antibody of the IgE isotype. These cells also produce the chemokine eotaxin, which is strongly chemotactic to eosinophils. The also produce the cytokines IL-3, IL-5 and GM-CSF, which collectively enhance the production of eosinophils. Thus, priming of Th2 cells by allergens in the airways leads to all the elements needed to produce an allergic reaction, characterized by IgE-dependent mast cell activations and massive eosinophilic infiltrates.
Allergy appears to be a disease of modern times and of industrialized societies. Epidemiological studies have linked the eradication of parasites and drastic alteration in other microbial exposures in these societies with the development of allergies. An early attempt to explain this phenomenon, termed the hygiene hypothesis, relied on the counterbalance of Th1 and Th2 polarized T cells, and the role of infections in fostering strong Th1 responses. However, recent studies reveal that allergic responses are controlled in non-allergic individuals by active responses from allergen-specific regulatory T cells that control both Th1 and Th2 responses through cytokines such as IL-10 and TGF-β. A dramatic illustration of this is found in a congenital defect of Treg development (Fox-P3 deficiency), which results in severe allergic and non-allergic hypersensitivity responses. The links between infection and regulatory T cell responses are now emerging.
There are other important targets of Type I hypersensitivity, such as drug allergies, the most prominent of which are allergies against penicillin and other β-lactam antibiotics. These drug molecules generally must modify native proteins binds binding to them chemically in order to form a hapten on the native protein. This haptenated protein becomes the target for the IgE antibody response.
There are, however, several other types of non-IgE hypersensitivity reactions. Type II allergic reactions are mediated by IgG antibodies directed against antigens fixed on the cell surface, an example of which is the formation of IgG antibodies to certain drugs that modify the surface proteins of platelets or red blood cells to cause thrombocytopenia or hemolytic anemia. The Type III hypersensitivity reactions are caused by IgG binding to soluble proteins circulating in peripheral blood. The classic example of this reaction is serum sickness, in which IgG antibodies directed against horse serum proteins form complement-fixing immune complexes with those proteins, leading to damage of vascular beds in which the complexes land. Finally, Type IV delayed-type hypersensitivity reactions are those characterized by reactivity by previously primed T cells against foreign proteins (as in the PPD reaction) or modified self proteins (as in urishiol modification of native proteins after poison ivy contact).