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Hypersensitivity reactions and methods of detection.

Introduction

A hypersensitivity reaction refers to a state of altered reactivity in which the body mounts an amplified immune response to a substance. Gell and Coombs (1963) classified hypersensitivity reactions into four different groups (types I, II, III, and IV), which depended upon the severity and latency of a reaction. Clinically, it is difficult to distinguish between the four types of hypersensitivities, as they do not necessarily occur in isolation from each other. Biologically, types I, II, and III hypersensitivities are mediated by antibodies, whereas type IV is mediated by T cells and macrophages (Brostoff et al. 1991). Hypersensitivities can only manifest following a second or subsequent contact with a particular antigen. Recently, extensive research has been conducted to determine optimum treatments and to define the specific mechanisms that mediate each type of hypersensitivity. This overview will define the different types of hypersensitivities and examine different methods to detect hypersensitivity responses.

Types of Hypersensitivity

Typically, hypersensitivities are classified into four different types. Type I hypersensitivity is an immediate immune reaction to an antigen mediated by IgE antibodies (Sicherer and Leung 2009). Type II hypersensitivities, also known as cytotoxic hypersensitivities, are rare reactions that are typically caused by IgG and IgM antibodies. A type II response may occur when the target antigen is part of the surface of a specific host cell or tissue (Figure 1B). Type II hypersensitivities can be associated with autoimmune diseases, drug reactions, and transplantations. Type III hypersensitivities are also mediated by IgG and IgM antibodies (Table 1). Unlike a type II response, type III hypersensitivity is associated with responses to soluble antigens that are not combined with host tissues but with antibodies in the blood, which can then lead to inflammatory responses. Type IV hypersensitivities are referred to as delayed-type hypersensitivities because a reaction can typically take 12 or more hours to develop. Type IV responses depend on T cell interactions, which recruit other cells to the site of exposure (Brostoff et al. 1991).

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Table 1

Type Description Method of Detection

I An immediate reaction that can result Provocation test, skin
 in an anaphylactic reaction test, IgE RAST

II Cytotoxic reaction mediated by IgM and IgG serum test
 IgG antibody responses to host tissue

III IgG and IgM antibodies form immune IgG serum test
 complexes with antigens in the blood

IV Delayed reaction mediated by memory T Skin test, MELISA
 cells


Although hypersensitivity reactions appear to be deleterious, they do serve to protect the human body through the isolation and elimination of specific antigens. Still, identification of hypersensitivity reactions can be beneficial for helping patients avoid reactive antigens and to limit deleterious actions, which will decrease the risk of developing chronic diseases (Rajan 2003).

Methods to Identify Hypersensitivity

Various methods exist to determine the existence and types of hypersensitivities. Type I hypersensitivity reactions are traditionally recognized through provocation testing or immediate-type skin testing (Table 1). Provocation testing involves a masked topical challenge of certain antigens followed by observation of the patient's dermal responses. Clinically, the provocation testing can pose a danger since some antigens may result in a severe anaphylactic reaction (Smith 1992). Skin testing may include skin pricks or patches to determine hypersensitivity. Both the prick test and scratch test involves pricking the skin with a needle or pin containing a small amount of the antigen. A patch test is conducted by applying a patch that contains known antigens to the skin. If there is a visual reddening or swelling at the prick or patch site, the patient is considered allergic to that antigen (Williams et al. 1992). Other methods to detect a type I hypersensitivity include radioallergosorbent tests (RASTs), leuokocyte histamine release assays, surface markers for basophil activation, and leukotriene release tests (for review, see Primeau and Adkinson Jr. 2001).

Type II hypersensitivity reactions are mediated by IgM and IgG antibody responses to host tissues (Table 1). Most common type II reactions occur in transplant and blood transfusion patients, wherein the reaction is determined by a tissue biopsy or by monitoring a patient's signs and symptoms.

Although limited data exists about methods for the detection of type III hypersensitivity reactions, some suggest that serum IgG antibody testing can be utilized (Shamberger 2008; Stapel et al. 2008). Research on food sensitivities suggests that the use of enzyme-linked immunosorbent assays (ELISA) can be effectively used to detect IgG antibodies to specific dietary proteins (Shamberger 2008). Specifically, an increased titer of IgG antibodies to a specific dietary protein would indicate a type III hypersensitivity to that protein (Scott et al. 1990). Cessation from eating the reactive food would therefore be recommended.

In recent years, methods have been developed and refined to detect type IV hypersensitivities (Table 1). Historically, the role of T cells in hypersensitivity reactions has been neglected; however, recent research has clarified and analyzed the role of T cells in hypersensitivity, which has provided a better understanding of delayed-type reactions. Two primary methods exist to verify a type IV hypersensitivity in patients: (1) delayed skin testing and (2) lymphocyte transformation tests (Primeau and Adkinson Jr. 2001).

Delayed skin testing is similar to an immediate-type skin test; however, the reaction is typically read after 24 or 72 hours rather than 15 minutes after application of the antigens (Li 2002). Still, skin testing can pose the risk of developing adverse systemic reactions, and appropriate training and care must therefore be practiced to ensure patients' safety (Reid et al. 1993). In addition, research has shown that skin testing may be unreliable for some antigens, such as food allergens (Sampson and Albergo 1984). Due to the limitations of skin testing (Rietschel 1996), alternative methods are currently being tested for the detection of type IV hypersensitivities, including such methods as lymphocyte transformation tests (Pichler and Tilch 2004).

The lymphocyte transformation test is an in vitro assay that measures the proliferation of T cells following an antigen challenge (Warrington and Tse 1979). An enhanced version of the lymphocyte transformation test, called memory lymphocyte immuno-stimulation assay (MELISA), can help detect type IV hypersensitivities, as previously described (Valentine-Thon et al. 2006; Stejskal et al. 1996). A standard number of lymphocytes, with the exclusion of monocytes, are isolated from whole blood specimens for cell culture. The lymphocytes are cultured for 5 days, then transferred to new plates containing known antigens, which are then pulsed for 4 hours with methyl-[.sup.3]H-thymidine to quantify cell proliferation. A negative control is also obtained via lymphocytes from the same patient, which is not added to antigens. After culture, the lymphocytes are harvested onto filter paper and dried. The radioactivity present on the filter paper is measured in a liquid scintillation counter. A stimulation index (SI) is calculated by dividing the counts per minute (cpm) in the test well to the average cpm in the negative control wells (Valentine-Thon et al. 2007; Valentine-Thon et al. 2003; Stejskal et al. 1996). A positive reaction, indicating type IV hypersensitivity, is defined as a SI greater than 3 and an equivocal reaction is a SI between 2 and 3. A SI less than 2 is considered negative.

Clinically, MELISA has been proved an effective tool for determining sensitivities to various metals (Valentine-Thon and Schiwara 2003) and to bacterial antigens such as Borrelia burgdorferi (Valentine-Thon et al. 2007). Ultimately, patients with hypersensitivities can intelligently choose to remove or avoid various cleaning chemicals, drugs, foods, dental amalgams, jewelry, or cosmetics that contain the hypersensitive antigens (Valentine-Thon et al. 2006; Pichler and Tilch 2004). Also, appropriate decisions or alternative methods of treatment can be developed for patients who may have hypersensitivities to antigens found in bacteria or prostheses (Valentine-Thon et al. 2007; Stejskal et al. 2006; Hallab et al. 2005). MELISA testing may prove to be an invaluable tool to determine contributing factors to persistent conditions to help ensure appropriate treatment.

Conclusion

Hypersensitivity reactions are common, yet they aren't often considered in treatment regimens. Untreated hypersensitivities can contribute to myriad conditions including autoimmune diseases (Valenta et al. 2009), irritable bowel syndrome (Spiller 2004), asthma (Fernandez-Nieto et al. 2006), and psychiatric illnesses (Roy-Byrne et al. 2008). By utilizing appropriate techniques to determine the existence of hypersensitivity reactions, patients can become better aware of which antigens to avoid. Ultimately, by minimizing exposure to potential antigens, patients may decrease the likelihood of developing chronic diseases and therefore increase their quality of life.

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David Marc, BSc, and Kelly Olson, PhD

NeuroScience Inc.

373 280th St.

Osceola, Wisconsin 54020

david.marc@neurorelief.com

David Marc is clinical scientist at NeuroScience Inc. He received his bachelor's degree from the University of Wisconsin-Eau Claire and is currently pursuing his master's degree in biological sciences from the University of Minnesota with a focus in biochemistry and health informatics. Mr. Marc's research interests include the development of decision support systems for health-care practitioners, clinical database mining for biomarker development, and evaluating medical therapeutics through database management.

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Dr. Kelly Olson is a pharmacologist with a primary focus in neuroscience. She received her PhD in 2007 from the University of Manitoba, Winnipeg, Manitoba, Canada, in pharmacology and therapeutics. Dr. Olson initially studied proteomics to uncover the presence and utility of various proteins. Her research continued with a focus on Alzheimer's disease whereby she employed the use of a transgenic murine model of Alzheimer's disease. Dr. Olson has collaborated with various research groups to examine intracellular activity of proteins such as transforming growth factor beta-1, and associations with various disease states, such as multiple sclerosis. Currently, Dr. Olson is the director of research and development at NeuroScience Inc., developing patents, giving presentations to the medical community, and coordinating research for new products that can correct imbalances in neurotransmitter and hormone levels.
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Publication:Townsend Letter
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Geographic Code:1USA
Date:Jan 1, 2011
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