The purpose of the immune system is to protect the individual from disease states, whether infectious, parasitic, or cancerous, through both cellular and humoral mechanisms. In so doing, the ability to distinguish “self” from “nonself” plays a predominant role. However, situations arise in which the individual's immune system responds in a manner producing tissue damage, resulting in a self-induced disease, either (1) hypersensitivity, or allergy, or (2) autoimmunity. Hypersensitivity reactions result from the immune system responding in an exaggerated or inappropriate manner. In the case of autoimmunity, mechanisms of self-recognition break down and Igs and TCRs react with self-antigens, resulting in tissue damage and disease.
Classification of Hypersensitivity Reactions
All four types of hypersensitivity reactions require prior exposure leading to sensitization in order to elicit a reaction on subsequent challenge. Figure 12–6 illustrates the mechanisms of hypersensitivity reactions as classified by Coombs and Gell.
Schematic of classification of hypersensitivity reactions.
Type I (Immediate Hypersensitivity)
Sensitization occurs as the result of exposure to appropriate antigens through the respiratory tract, dermally, or by exposure through the gastrointestinal tract and is mediated by IgE production. IgE binds to appropriate cells and sensitizes an individual; reexposure to the antigen results in degranulation of the mast cells with the release of preformed mediators and cytokines that promote vasodilatation, bronchial constriction, and inflammation.
Type II (Antibody-Dependent Cytotoxic Hypersensitivity)
Type II hypersensitivity is IgG-mediated. Tissue damage may result from the direct action of cytotoxic cells or by antibody activation of the classic complement pathway. Complement activation may result in cell lysis.
Type III (Immune Complex-Mediated Hypersensitivity)
Type III hypersensitivity reactions also involve IgG Igs. Ig may form complexes with soluble antigen and the complex may deposit (lodge) in various tissues, causing tissue damage. The most common location is the vascular endothelium in the lung, joints, and kidneys. Macrophages, neutrophils, and platelets attracted to the deposition site contribute to the tissue damage.
Type IV (Cell-Mediated Hypersensitivity)
Type IV is a DTH response. Contact hypersensitivity is initiated by topical exposure, and consists of two phases: sensitization and elicitation. Sensitization results in development of activated and memory T cells when the chemical is presented on an APC to T-helper cells in local lymph nodes, leading to generation of memory T cells.
On second contact, antigen-presenting Langerhans–dendritic cells present the processed hapten–carrier complex to memory T cells. These activated T cells then secrete cytokines that bring about further proliferation of T cells and facilitate the movement of inflammatory cells into the skin, resulting in erythema and the formation of papules and vesicles. Cells of the cell-mediated immune response may cause local tissue damage.
Whereas separation of hypersensitivity responses into types I to IV is helpful in understanding the involved mechanisms, it is important to realize that often pathology is the result of a combination of these mechanisms.
Assessment of Hypersensitivity Responses
Assessment of Respiratory Hypersensitivity in Experimental Animals
Methods for detecting pulmonary hypersensitivity can be divided into two types: (1) those for detecting immunologic sensitization and (2) those for detecting pulmonary sensitization. In the case of types I to III, immunologic sensitization occurs when antigen-specific Ig is produced in response to exposure to an antigen or, in the case of type IV, when a population of sensitized T lymphocytes is produced. Pulmonary sensitization is determined by a change in respiratory function subsequent to the challenge of a sensitized animal.
Guinea pig models have been most frequently used because the lung is the major shock organ for anaphylactic response. Immunologic sensitization may be determined by obtaining sequential blood samples throughout the induction period and measuring antibody titer. Pulmonary sensitization is evaluated by detecting the presence of pulmonary reactivity (either visible respiratory distress or changes in respiratory function) following challenge.
Assessment of IgE-Mediated Hypersensitivity Responses in Humans
Two skin tests available for immediate hypersensitivity testing measure a “wheal and flare” reaction. The prick–puncture test introduces very small amounts of antigen under the skin. For test compounds not eliciting a reaction in the less sensitive skin test, the intradermal test using dilute concentrations of antigen may be used, but there is a higher risk of systemic reactions.
In vitro serologic tests, ELISAs, and radioallergosorbent tests (RASTs) may also be used to detect the presence of antigen-specific antibody in the patient's serum.
Bronchial provocation tests may be performed by having the patient inhale an antigen into the bronchial tree and evaluating his or her pulmonary response.
Assessment of Contact Hypersensitivity in Experimental Animals—The two most commonly utilized guinea pig models are the Büehler test and the guinea pig maximization test. In the Büehler test, the test article is applied to the shaven flank and covered with an occlusive bandage for 6 h once a week for 3 weeks. On day 28, a challenge dose of the test article is applied to a shaven area on the opposite flank; the area is evaluated for signs of edema and erythema for 2 days afterwards. In the guinea pig maximization test, the test article is administered by intradermal injection, an adjuvant is employed, and irritating concentrations are used. These assays evaluate the elicitation phase of the response in previously sensitized animals.
The mouse local lymph node assay is a stand-alone alternative to the guinea pig assays for use in hazard identification of chemical sensitizers. Animals are dosed by topical application of the test article to the ears for 3 consecutive days. A few days later, the animals are injected with radiolabeled thymidine, which is incorporated into proliferating lymphocytes. Later, the animals are sacrificed and the local lymph nodes assayed for radiolabeled lymphocytes to see if the test article induced an immune response.
Assessment of Contact Hypersensitivity in Humans
Human testing for contact hypersensitivity reactions is by skin patch testing. Patches containing specified concentrations of the allergen in the appropriate vehicle are applied under an occlusive patch for 48 h. Once the patch is removed, the area is read for signs of erythema, papules, vesicles, and edema. Generally, the test is read again at 72 h and in some cases signs may not appear for up to 1 week or more.
Hypersensitivity Reactions to Xenobiotics
Numerous xenobiotics illicit hypersensitivity reactions. Polyisocyanates, and toluene diisocyanate in particular, used in the production of adhesives and coatings are known to induce the full spectrum of hypersensitivity responses, types I to IV, as well as nonimmune inflammatory and neuroreflex reactions in the lung. Inhaled acid anhydrides, which are used in the manufacturing of paints, varnishes, coating materials, adhesives, and casting and sealing materials, may conjugate with serum albumin or erythrocytes leading to type I, II, or III hypersensitivity reactions on subsequent exposure.
Metals and metallic substances, including metallic salts, are responsible for producing contact and pulmonary hypersensitivity reactions. Platinum, nickel, chromium, beryllium, and cobalt are commonly implicated.
Hypersensitivity responses to drugs are among the major types of unpredictable drug reactions. Drugs are designed to be reactive in the body and multiple treatments are common. This type of exposure is conducive to producing an immunologic reaction. Immunologic mechanisms of hypersensitivity reactions to drugs include types I to IV. Penicillin is the most common agent involved in drug allergy.
Pesticides have been implicated as causal agents in both contact and immediate hypersensitivity reactions.
Natural rubber latex is used in the manufacture of over 40,000 products from balloons to surgical gloves. Dermatologic reactions to latex include irritant dermatitis and contact dermatitis.
Cosmetics and Personal Hygiene Products
Contact dermatitis and dermatoconjunctivitis may result from exposure to many cosmetic and personal hygiene products. These agents contain paraben esters, sorbic acid, phenolics, organomercurials, quaternary ammonium compounds, and formaldehyde.
Subtilin and papain are enzymes capable of eliciting type I hypersensitivity responses. Subtilin is used in laundry detergents. Both individuals working where the product is made and those using the product may become sensitized. Subsequent exposure may produce signs of rhinitis, conjunctivitis, and asthma. Papain is another enzyme known to induce IgE-mediated disease. It is most commonly used as a meat tenderizer and a clearing agent in beer production.
Formaldehyde exposure occurs in the cosmetics and textile industries, and in the furniture, auto upholstery, and resins industries. Occupational exposure to formaldehyde has been associated with the occurrence of asthma.
In cases of autoimmunity, self-antigens are the target, and in the case of chemical-induced autoimmunity, the disease state is induced by a modification of host tissues or immune cells by the chemical and not the chemical acting as an antigen/hapten.
Mechanisms of Autoimmunity
Three types of molecules are involved in the process of self-recognition: Igs, TCRs, and the products of MHC. Igs and TCRs are expressed clonally on B and T cells, respectively, whereas MHC molecules are present on all nucleated cells.
The process of negative selection against autoreactive T cells in the thymus is important in the prevention of autoimmune disease. T cells expressing receptors that bind to self-antigens undergo apoptosis (negative selection), whereas those that do not recognize self-proteins proliferate (positive selection) and migrate to the peripheral lymph organs. Some cells that recognize self-molecules do not die, but undergo anergy, where they stay in the body but are inactive.
Several mechanisms may break down self-tolerance, leading to autoimmunity. First, if exposure to antigens is not available in the thymus during embryonic development, such as to myelin, which is not produced until later in development, then antigen-specific T-cell-reactive lymphocytes not subjected to negative selection could induce an autoimmune reaction. Breakdown of self-tolerance to these antigens may be induced by exposure to adjuvants, chemicals used to enhance immunogenicity, or to another antigenically related protein. Second, T-cell anergy can be overcome with chronic lymphocyte stimulation. Third, interference with normal immunoregulation by CD8+ T-cell suppressor cells may create an environment conducive to the development of autoimmune disease.
As is the case with hypersensitivity reactions, autoimmune disease is often the result of more than one mechanism working simultaneously. Therefore, pathology may be the result of antibody-dependent cytotoxicity, complement-dependent antibody-mediated lysis, or direct or indirect effects of cytotoxic T cells.
Autoimmune Reactions to Xenobiotics
Table 12–5 lists chemicals known to be associated with autoimmunity, showing the proposed self-antigenic determinant or stating adjuvancy as the mechanism of action. Table 12–6 shows chemicals that have been implicated in autoimmune reactions, but in these cases the mechanism of autoimmunity has not been as clearly defined or confirmed.
Table 12–5 Chemical agents known to be associated with autoimmunity. ||Download (.pdf)
Table 12–5 Chemical agents known to be associated with autoimmunity.
Proposed Antigenic Chemical
Liver microsomal proteins
Abnormal protein synthesized in liver
Glomerular basement membrane protein
Most likely acts as an adjuvant
Table 12–6 Chemicals implicated in autoimmunity.
Multiple Chemical Sensitivity Syndrome
Multiple chemical sensitivity syndrome (MCS) has been associated with hypersensitivity responses to chemicals. The syndrome is characterized by multiple subjective symptoms related to more than one system. The more common symptoms are nasal congestion, headaches, lack of concentration, fatigue, and memory loss. Many mechanisms have been suggested to explain how chemicals cause these symptoms. A major hypothesis is that MCS occurs when chemical exposure sensitizes certain individuals, and, on subsequent exposure to exceedingly small amounts of these or unrelated chemicals, the individual exhibits an adverse response.