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Hypersensitivity Reactions and Methods of Detection
David Marc, B.Sc.a, & Kelly Olson Ph.Da.
a
NeuroScience, Inc., 373 280th St., Osceola, WI 54020, United States
[email protected]
ABSTRACT
Hypersensitivity reactions are classified into four groups (Type I, II, III, and IV), each characterized by specific biological actions. Research has
focused on understanding each hypersensitvity to ensure appropriate therapeutic recommendations are made. This overview will present the
defining characteristics of each hypersensitivity and examine the diagnostic methods used to determine the existence of a specific type. Type I
hypersensitivities can be determined by provacation testing, immediate-type skin testing, or radioallergosorbent tests (RASTs); Type II
hypersensitivities can be determined by measuring the level of IgG antibodies to specific host proteins; Type III hypersensitivities may be
detected with serum IgG antibody testing to specific antigens; Type IV hypersensitivities are determined by delayed skin testing or memory
lymphocyte immunostimulation assay (MELISA®). Persistent antigen exposure may contribute to chronic conditions such as autoimmune
diseases, irritable bowel syndrome, asthma, or even psychiatric illnesses.
Through the effective detection of potential hypersensitivities, a
patient’s quality of life can be improved through consequent antigen avoidance.
crystallizable (Fc) receptors, to induce degranulation (Yamasaki &
INTRODUCTION
A hypersensitivity reaction refers to a state of altered
Saito, 2005). Mast cell degranulation can lead to the release of
reactivity in which the body mounts an amplified immune response
inflammatory mediators including histamine, proteoglycans, serine
to a substance.
proteases, and leukotrienes (Yamasaki & Saito, 2005).
In 1963, Gell and Coombs classified
The
hypersensitivity reactions into four different groups (Types I, II,
immediate release of these inflammatory mediators can produce
III, and IV) which depended upon the severity and latency of a
hives, redness, and angioedema (swelling of the lips, eyelids,
reaction (Gell & Coombs, 1963).
Clinically, it is difficult to
throat, or tongue) in what is referred to as an anaphylactic reaction
distinguish between the four types of hypersensitivities as they do
(Noone & Osguthorpe, 2003). In some cases, the anaphylactic
not necessarily occur in isolation from each other. Biologically,
reaction can be severe enough to block airways or cause heart
Types I, II, and III hypersensitivities are mediated by antibodies,
arrhythmias (Noone & Osguthorpe, 2003).
whereas, Type IV is mediated by T cells and macrophages
Type II hypersensitivities, also known as cytotoxic
Hypersensitivities can only manifest
hypersensitivities, are rare reactions that are typically caused by
following a second or subsequent contact with a particular antigen.
IgG and IgM antibodies (Brostoff et al., 1991). A Type II response
Recently, extensive research has been conducted to determine
may occur when the target antigen is part of the surface of a
optimum treatments and to define the specific mechanisms that
specific host cell or tissue (Figure 1B). Type II hypersensitivities
mediate each type of hypersensitivity. This overview will define
can be associated with autoimmune diseases, drug reactions, and
the different types of hypersensitivities and examine different
transplantations (Brostoff et al., 1991). Biochemically, Type II
methods to detect hypersensitivity responses.
reactions occur when IgG and IgM antibodies bind to host cells
(Brostoff et al., 1991).
and tissues to form complexes that activate the complement
TYPES OF HYPERSENSITIVITY
Typically, hypersensitivities are classified into four
different types. Type I hypersensitivity is an immediate immune
reaction to an antigen (Sicherer & Leung, 2009). Mast cells and
basophils play an integral role in Type I hypersensitivity reactions.
Following exposure to an antigen, mast cells and basophils go
through a process called degranulation, where they release
substances that induce inflammation (Figure 1A). Specifically,
antigens interact with IgE molecules that are bound to high affinity
receptors on the surface of mast cells, called fragment
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pathway which, in turn, eliminates the host cells (Brostoff et al.,
1991; Kornbrust et al., 1989). During Type II hypersensitivities,
mediators of acute inflammation, such as B cells, antibodies, and
cytokines are generated to induce cell lysis and death. For
example, a Type II reaction may occur when a drug binds to host
cells, such as red blood cells, causing them to be recognized as
foreign pathogens.
This will induce B cell proliferation and
antibody production as well as activate the complement system
which will ultimately trigger cell death (Kornbrust et al., 1989). A
Type II reaction may take several hours to a full day to develop.
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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
Figure 1.
A.
B.
Type I Hypersensitivity
Type II Hypersensitivity
that are not combined with host tissues but with antibodies in the
IgG Antibody
IgE Antibody
blood which can then lead to inflammatory responses (Brostoff et
Antigen
al., 1991). As the number of antigen-antibody complexes increase,
Mast
Cell
Fc Receptor
T Cell
they can deposit in joints and various tissues such as kidneys, skin,
and eyes leading to an inflammatory response wherever they
Complement
precipitate (Ellsworth et al., 2008). Research has suggested that
Histamine and
other mediators
Type III reactions may contribute to certain systemic diseases such
as systemic lupus erythematosus (SLE), serum sickness, and
C.
Type III Hypersensitivity
Host Cell
D.
Antigen
Type IV Hypersensitivity
farmer lung (Coico & Sunshine, 2009). A Type III reaction can
Antigen
Presenting
Cell
IgG Antibody
take hours, days, or even weeks to develop.
Type IV hypersensitivities are referred to as delayedtype hypersensitivities because a reaction can typically take 12 or
more hours to develop (Brostoff et al., 1991). Type IV responses
Antigen
Antigen
Immune Complexes
Deposited in Tissue
Systemic
Inflammation
are dependent on T cell interactions, which recruit other cells to the
site of exposure (Brostoff et al., 1991). Upon an initial antigen
exposure, naive T cells differentiate into memory T cells which are
Tissue
Destruction
Host Tissue
Activation
Cytokine
Secretion
T Cell
Proliferation
specific to that antigen. The memory T cells remain dormant until
a subsequent exposure of the antigen elicits a faster and stronger
Type I hypersensitivity reactions are traditionally
immune response than the first encounter. Upon future encounters
recognized through provocation testing or immediate-type skin
with the given antigen, memory T cells immediately proliferate
testing (Table 1). Provocation testing involves a masked topical
and differentiate into effector cells to quickly eliminate the antigen.
challenge of certain antigens followed by observation of the
Contact dermatitis is commonly caused by a Type IV reaction in
patient’s dermal responses (Smith, 1992). Clinically, the
which lymphocyte production can produce local inflammation,
provocation testing can pose a danger since some antigens may
such as a rash, which characterizes this skin condition (Nosbaum et
result in a severe anaphylactic reaction (Smith, 1992). Skin testing
al., 2009).
is an alternative method which may include skin pricks or patches
of
to determine hypersensitivity. Both the prick test and scratch test
hypersensitivity in which granulomas, a ball-like collection of
Recent
literature
proposes
a
fifth
type
involves pricking the skin with a needle or pin containing a small
macrophages and epitheloid cells, are formed to encapsulate and
amount of the antigen. A patch test is conducted by applying a
isolate a pathogen (Rajan, 2003; Tercelj et al., 2008). Granulomas
patch that contains known antigens to the skin (Williams et al.,
are formed in response to antigens that escape the early phases of
1992). If there is a visual reddening or swelling at the prick or
an immune response and are often times related to a delayed-type
patch site, the patient is considered allergic to that antigen
hypersensitivity (Tercelj et al., 2008).
(Williams et al., 1992). Type I hypersensitivity reactions can also
Although hypersensitivity reactions appear to be
be determined via radioallergosorbent tests (RASTs), which detect
deleterious, they do serve the purpose to protect the human body
the amount of IgE antibodies that react with suspected or known
through the isolation and elimination of specific antigens. Still,
allergens (Primeau & Adkinson, Jr., 2001; Williams et al., 1992).
identification of hypersensitivity reactions can be beneficial for
If a RAST indicates a high level of IgE to a specific antigen, the
helping patients to avoid reactive antigens and to limit deleterious
person is said to be allergic to that antigen (Primeau & Adkinson,
actions, which will decrease the risk of developing chronic
Jr., 2001).
diseases (Rajan, 2003).
include leuokocyte histamine release assays, surface markers for
Other methods to detect a Type I hypersensitivity
basophil activation, and leukotriene release tests (for review see
METHODS TO IDENTIFY HYPERSENSITIVITY
Primeau & Adkinson, Jr., 2001).
Various methods exist to determine the existence and
Type II hypersensitivity reactions are mediated by IgM
types of hypersensitivity. A summary of methods to detect Type I,
and IgG antibody responses to host tissues (Table 1). For instance,
II, III, and IV is provided.
Goodpasture syndrome is an autoimmune disease characterized by
©NeuroScience, Inc. December, 2009
3
inflammation of the glomeruli in the kidneys and hemorrhaging of
lymphocyte transformation test, called memory lymphocyte
the lungs (Salama et al., 2001).
The measurement of IgG
immuno-stimulation assay (MELISA®), is available for healthcare
antibodies to glomerular basement membrane (anti-GBM) is used
practitioners and can assist in the detection of Type IV
to diagnose Goodpasture syndrome (Salama et al., 2001). In
hypersensitivities, as previously described (Valentine-Thon et al.,
addition, anti-neutrophil cytoplasmic IgG antibodies (ANCAs) are
2006; Stejskal et al., 1996). In summary, a standard number of
used to detect various autoimmune disorders that may be
lymphocytes, with the exclusion of monocytes, are isolated from
associated with Type II hypersensitivities (Radice & Sinico, 2005).
whole blood specimens for cell culture.
Most common Type II reactions occur in transplant and blood
cultured for 5 days then transferred to new plates containing
transfusion patients where the reaction is determined by a tissue
known antigens, which are then pulsed for 4 hours with methyl-3H-
biopsy or by monitoring a patient’s signs and symptoms.
thymidine to quantify cell proliferation. A negative control is also
The lymphocytes are
Although limited data exists about methods for the
obtained via lymphocytes from the same patient, which is not
detection of Type III hypersensitivity reactions, some suggest
added to antigens. After culture, the lymphocytes are harvested
serum IgG antibody testing can be utilized (Table 1; Shamberger,
onto filter paper and dried. The radioactivity present on the filter
2008; Stapel et al., 2008). Research on food sensitivities suggests
paper is measured in a liquid scintillation counter. A stimulation
that the use of enzyme-linked immunosorbent assays (ELISA) can
index (SI) is calculated by dividing the counts per minute (cpm) in
be effectively used to detect IgG antibodies to specific dietary
the test well to the average cpm in the negative control wells
proteins (Shamberger, 2008). Specifically, an increased titer of
(Valentine-Thon et al., 2007; Valentine-Thon & Schiwara, 2003;
IgG antibodies to a specific dietary protein would be indicative of
Stejskal et al., 1996). A positive reaction, indicating Type IV
a Type III hypersensitivity to that protein (Scott et al., 1990).
hypersensitivity, is defined as a SI greater than 3 and an equivocal
Cessation from eating the reactive food would therefore be
reaction is a SI between 2 and 3. A SI less than 2 is considered
recommended. However, further research is warranted to verify
negative.
Clinically, MELISA® has been proven to be an
serum IgG antibody testing as a method to detect Type III
hypersensitivities.
effective tool for the determination of sensitivities to various
In recent years, methods have been developed and
refined
to
detect
Type
IV
hypersensitivities
(Table
1).
metals (Valentine-Thon & Schiwara, 2003) and to bacterial
antigens such as Borrelia burgdorferi (Valentine-Thon et al.,
Historically, the role of T cells in hypersensitivity reactions has
2007).
been neglected; however, recent research has clarified and
intelligently choose to remove or avoid various cleaning
analyzed the role of T cells in hypersensitivity, which has provided
chemicals, drugs, foods, dental amalgams, jewelry, or cosmetics
a better understanding of delayed-type reactions (Primeau &
that contain the hypersensitive antigens (Valentine-Thon et al.,
Adkinson, Jr., 2001). Two primary methods exist to verify a Type
2006; Pichler & Tilch, 2004a). Also, appropriate decisions or
IV hypersensitivity in patients: 1) delayed skin testing and 2)
alternative methods of treatment can be developed for patients that
lymphocyte transformation tests (Primeau & Adkinson, Jr., 2001).
may have hypersensitivities to antigens found in bacteria or
Ultimately, patients who possess hypersensitivities can
Delayed skin testing is similar to an immediate-type
prostheses (Valentine-Thon et al., 2007; Stejskal et al., 2006;
skin test however the reaction is typically read after 24 or 72 hours
Hallab et al., 2005). MELISA® testing may prove to be an
rather than 15 minutes after application of the antigens (Li, 2002).
invaluable tool for the determination of contributing factors to
Still, skin testing can pose the risk of developing adverse systemic
persistent conditions so appropriate treatment may be achieved.
reactions and appropriate training and care must therefore be
practiced to ensure the safety of patients (Reid et al., 1993). In
addition, research has shown that skin testing may be unreliable for
some antigens, such as food allergens (Sampson & Albergo, 1984).
Due to the limitations of skin testing (Rietschel, 1996), alternative
Table 1.
Type
I
II
methods are currently being tested for the detection of Type IV
hypersensitivities
including
such
methods
as
lymphocyte
III
The lymphocyte transformation test is an in vitro assay
IV
transformation tests (Pichler & Tilch, 2004b).
that measures the proliferation of T cells following an antigen
challenge (Warrington & Tse, 1979). An enhanced version of the
©NeuroScience, Inc. December, 2009
Description
An immediate reaction that can
result in an anaphylactic reaction
Cytotoxic reaction mediated by
IgM and IgG antibody responses
to host tissue
IgG and IgM antibodies form
immune complexes with antigens
in the blood
Delayed reaction that is mediated
by memory T cells
Method of Detection
Provocation test, Skin
test, IgE RAST
IgG serum test
IgG serum test
Skin test, MELISA®
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Radice, A. & Sinico, R. A. (2005). Antineutrophil cytoplasmic antibodies (ANCA). Autoimmunity, 38, 93103.
COMPARING HYPERSENSITIVITY TO TOXICITY
Hypersensitivity and toxicity appear to be two related
events, yet they are two distinct responses that can occur in
isolation of each other. Hypersensitivity reactions can transpire
after acute contact with an antigen, whereas toxicity is a harmful
reaction that may occur with exposure to excessive amounts of a
substance
(Hallab
et
al.,
2005).
To
explain
further,
hypersensitivity can occur without a toxic reaction because a
hypersensitive response is not dose-dependent and can take place
Rajan, T. V. (2003). The Gell-Coombs classification of hypersensitivity reactions: a re-interpretation.
Trends Immunol., 24, 376-379.
Reid, M. J., Lockey, R. F., Turkeltaub, P. C., & Platts-Mills, T. A. (1993). Survey of fatalities from skin
testing and immunotherapy 1985-1989. J.Allergy Clin.Immunol., 92, 6-15.
Rietschel, R. L. (1996). Reproducibility of patch-test results. Lancet, 347, 1202.
Roy-Byrne, P. P., Davidson, K. W., Kessler, R. C., Asmundson, G. J., Goodwin, R. D., Kubzansky, L. et al.
(2008). Anxiety disorders and comorbid medical illness. Gen.Hosp.Psychiatry, 30, 208225.
Salama, A. D., Levy, J. B., Lightstone, L., & Pusey, C. D. (2001). Goodpasture's disease. Lancet, 358, 917920.
Sampson, H. A. & Albergo, R. (1984). Comparison of results of skin tests, RAST, and double-blind,
placebo-controlled food challenges in children with atopic dermatitis. J.Allergy
Clin.Immunol., 74, 26-33.
with very low levels of an antigen (Stejskal & Stejskal, 1999).
Scott, H., Fausa, O., Ek, J., Valnes, K., Blystad, L., & Brandtzaeg, P. (1990). Measurements of serum IgA
and IgG activities to dietary antigens. A prospective study of the diagnostic usefulness in
adult coeliac disease. Scand.J.Gastroenterol., 25, 287-292.
Therefore, if a patient presents with a hypersensitivity reaction,
Shamberger, R. (2008). Types of Food Allergy Testing. Townsend Letter, January, 71-72.
even small amounts of the antigen may result in health problems
Sicherer, S. H. & Leung, D. Y. (2009). Advances in allergic skin disease, anaphylaxis, and hypersensitivity
reactions to foods, drugs, and insects in 2008. J.Allergy Clin.Immunol., 123, 319-327.
emphasizing the importance of antigen avoidance.
Smith, T. F. (1992). Allergy testing in clinical practice. Ann.Allergy, 68, 293-301.
Spiller, R. C. (2004). Irritable bowel syndrome. Br.Med.Bull., 72, 15-29.
Stapel, S. O., Asero, R., Ballmer-Weber, B. K., Knol, E. F., Strobel, S., Vieths, S. et al. (2008). Testing for
IgG4 against foods is not recommended as a diagnostic tool: EAACI Task Force Report.
Allergy, 63, 793-796.
CONCLUSION
Hypersensitivity reactions are common yet they aren’t
often
considered
in
treatment
regimens.
Untreated
hypersensitivities can contribute to a myriad of 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
Stejskal, J. & Stejskal, V. D. (1999). The role of metals in autoimmunity and the link to
neuroendocrinology. Neuro.Endocrinol.Lett., 20, 351-364.
Stejskal, V., Hudecek, R., Stejskal, J., & Sterzl, I. (2006). Diagnosis and treatment of metal-induced sideeffects. Neuro.Endocrinol.Lett., 27 Suppl 1, 7-16.
Stejskal, V. D., Forsbeck, M., Cederbrant, K. E., & Asteman, O. (1996). Mercury-specific lymphocytes: an
indication of mercury allergy in man. J.Clin.Immunol., 16, 31-40.
Tercelj, M., Salobir, B., & Rylander, R. (2008). Microbial antigen treatment in sarcoidosis--a new
paradigm? Med.Hypotheses, 70, 831-834.
Valenta, R., Mittermann, I., Werfel, T., Garn, H., & Renz, H. (2009). Linking allergy to autoimmune
disease. Trends Immunol., 30, 109-116.
utilizing appropriate techniques to determine the existence of
Valentine-Thon, E., Ilsemann, K., & Sandkamp, M. (2007). A novel lymphocyte transformation test (LTTMELISA) for Lyme borreliosis. Diagn.Microbiol.Infect.Dis., 57, 27-34.
hypersensitivity reactions, patients can become better aware of
Valentine-Thon, E., Muller, K., Guzzi, G., Kreisel, S., Ohnsorge, P., & Sandkamp, M. (2006). LTTMELISA is clinically relevant for detecting and monitoring metal sensitivity.
Neuro.Endocrinol.Lett., 27 Suppl 1, 17-24.
which antigens to avoid. Ultimately, by minimizing exposure to
potential antigens patients may decrease the likelihood of
Valentine-Thon, E. & Schiwara, H. W. (2003). Validity of MELISA for metal sensitivity testing.
Neuro.Endocrinol.Lett., 24, 57-64.
developing chronic diseases and therefore increase their quality of
Warrington, R. J. & Tse, K. S. (1979). Lymphocyte transformation studies in drug hypersensitivity.
Can.Med.Assoc.J., 120, 1089-1094.
life.
Williams, P. B., Dolen, W. K., Koepke, J. W., & Selner, J. C. (1992). Comparison of skin testing and three
in vitro assays for specific IgE in the clinical evaluation of immediate hypersensitivity.
Ann.Allergy, 68, 35-45.
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