eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology
Delayed-type Hypersensitivity
Updated: Jun 2, 2009
Introduction
Background
Cell-mediated immunity (CMI) is a T-cell–mediated defense mechanism against microbes that survive within phagocytes or infect nonphagocytic cells. CMI functions to enhance antimicrobial actions of phagocytes to eliminate microbes. This T-cell–mediated activation of phagocytes depends on interferon gamma (IFN-γ), a major cytokine produced by CD4+ helper T cells, subtype 1 (Th1). However, anti-IFN-g neutralizing antibodies (Abs) do not completely abrogate delayed-type hypersensitivity responses. IFN-γ or IFN-γR knock out (KO) mice do reveal attenuated delayed-type hypersensitivity responses. These results indicate that delayed-type hypersensitivity action cannot be solely attributed to IFN-γ.
The identification of Th17 cells shed a light on the previously observed delayed-type hypersensitivity responses in the absence of IFN-γ actions. Interleukin (IL)-17 KO mice did display attenuated delayed-type hypersensitivity against bovine serum albumin and bacille Calmette-Guérin (BCG).1 The role of Th17 and Th1 cells in delayed-type hypersensitivity may vary depending on stimulants.2
Phagocytic cell activation and inflammation induced by CMI can cause tissue injury called delayed-type hypersensitivity (DTH). In experimental animal models, delayed-type hypersensitivity reactions are characterized by a granulomatous response consisting of macrophages, monocytes, and T lymphocytes.
Delayed-type hypersensitivity reactions in the skin have been used to assess CMI in vivo. An antigen is introduced intradermally (ID), and induration and erythema at 48-72 hours postinjection indicate a positive reaction. Positive responses require the subject's exposure to the antigen 4-6 weeks prior to skin testing. The lack of a delayed-type hypersensitivity response to a recall antigen is termed anergy. In the absence of underlying disease, anergy may indicate a possible T-cell immunodeficiency. The prototype recall antigen is Mycobacterium tuberculosis; other commonly used antigens in humans include tetanus, Candida and Trichophyton species, and mumps. Delayed-type hypersensitivity antigens for several fungi and streptococci are no longer available or recommended for clinical use.
Delayed-type hypersensitivity reaction in the skin can also occur in contact hypersensitivity (CH) to certain chemicals, including nickel, dinitrochlorobenzene (DNCB), and picryl chloride. Delayed-type hypersensitivity reaction can also occur with various medications, including sulfonamides, phenytoin, and carbamazepine. These small chemicals are believed to act as haptens.
Originally, CH was thought to be skin delayed-type hypersensitivity reaction. However, recent studies indicate that CH may be caused by different immune mechanisms. That is, in delayed-type hypersensitivity, CD4+ T cells are major effector cells, with CD8+ cell playing a regulatory role. In rodents, chemically induced CH was reported by attenuated by recombinant IFN-γ.2 In contrast, chemically induced CH was enhanced by IL-17A, which induces production of IL-6, IL-8, granulocyte macrophage colony-stimulating factor (GM-CSF), and upregulated expression of intercellular adhesion molecule (ICAM)-1 in human keratinocytes, and IL-4 KO mice revealed attenuated CH responses.1,3 Cytotoxic CD8+ T cells that produce IL-17A (Tc17 cells) are also implicated in induction of CH in rodentmodels.4 Thus, at least in rodent models, induction of CH appears to be mediated by Th17 and Th2 cytokines; Th17 cells produce IL-17A, and Th2 cells are a major source of IL-4.
Pathophysiology
A delayed-type hypersensitivity reaction in the skin is initiated when certain antigens are presented by antigen-presenting cells (APCs) in the skin (ie, Langerhans cells) to sensitized memory T cells. The antigen presentation and subsequent T-cell activation elicit an influx of macrophages, monocytes, and lymphocytes at the site of antigen exposure. These cells then produce inflammatory cytokines including tumor necrosis factor–α (TNF-α), IL-17A, and IFN-γ. At the onset of the reaction, vasopermeability is increased by serotonin and histamine release, and adhesion molecules are up-regulated in the vascular endothelium so that additional cellular components migrate into the local site of antigen presentation.The APCs present antigens complexed in the groove of major histocompatibility complex (MHC) molecules expressed on the cell surface of the APCs. For most protein antigens or haptens associated with skin delayed-type hypersensitivity, CD4+ T cells are presented with antigens bound to MHC class II alleles, human leukocyte antigen (HLA)-DR, HLA-DP, and HLA-DQ. Specific MHC class II alleles are recognized to produce excessive immune activation to antigens.
T cells recognize antigens through T-cell receptors (TCRs), which are composed of heterodimers containing constant and variable regions analogous to the constant and variable regions of immunoglobulin (TCR ab or TCR gd). Most delayed-type hypersensitivity responses are elicited through TCR ab. TCR gd is more commonly expressed on T cells in the epithelium boundaries with limited diversities. The function of TCR gdT cells is not well elucidated.
TCRs on the cell surface form a complex with CD3 composed of g, d, and e proteins and cytoplasmic z chain. To activate T cells through TCR, additional signaling through CD4 (helper) or CD8 (cytotoxic) molecules is required; these molecules are physically closely associated with CD3/TCR complex. Other signals for T-cell activation include costimulatory molecules expressed on APC and T cells. Costimulatory molecules are not physically associated with CD3/TCR complex but provide antigen-independent signals. Activation of naïve T cells usually requires expression of B7.1 (CD80) and B7.2 (CD86) on the APC, which interact with CD28 on T cells.
For memory or effector T-cell activation, expression of inducible costimulator (ICOS)–L on APC that interacts with ICOS expressed on T cells is required. Th1 cells produce Th1 cytokines, including IFN-γ. Th17 cells produce IL-17A, IL-21, IL-22, and other cytokines. These cytokines further activate T cells and phagocytes. Activation of T cells is also counter-regulated by expression of inhibitory costimulatory molecules expressed on T cells, including CTLA-4 (CD152) and programmed death-1 (PD-1). These inhibitory costimulatory molecules are not expressed at the initial stage of delayed-type hypersensitivity responses but become up-regulated when inflammatory responses progress to abrogate excessive inflammatory responses.
delayed-type hypersensitivity responses to some organisms seem to be more predominantly mediated through CD8 T cells, and effector stage Th1 cells augment CD8 T-cell activation. CD8+ T cells activate macrophages by contact-mediated signals through CD40L-CD40 interactions and IFN-γ production. The differences in T-cell immune responses to intracellular microbes may determine disease outcomes in certain diseases. For example, ineffective T-cell–mediated immunity is seen in patients with lepromatous leprosy with high Mycobacteria leprae load in macrophages and destructive skin lesions. In contrast, in tuberculoid leprosy, strong CMI induces granulomas with less M leprae but sensory nerve defects.
IFN-γ is the key cytokine that plays the dominant role in delayed-type hypersensitivity and is a major activator of macrophage-monocyte lineage cells, augmenting its phagocytic function and production of reactive oxygen intermediates (ROIs). IFN-γ is produced by both natural killer (NK) cells and Th1 cells. Its function is to up-regulate T-cell activation markers, including CD69, CD71, the IL-2 receptor a (CD25), and HLA-DR; promote differentiation of Th1 cells; and suppress Th2 differentiation partly through down-regulating production of Th2 cytokines, including IL-4 and IL-5. IFN-γ acts on B cells to promote isotype switching of antibodies that facilitate phagocytic cell–mediated immune responses and also to up-regulate MHC molecules on APCs.
IFN-γ exerts regulatory actions on CD4+ Th cells.5 IFN-γ affects activation-induced cell death of Th cells, contributing to lymphocyte homeostasis. In addition, IFN-γ was implicated with conversion of CD4+ CD25- T cells to inducible CD4+ CD25+ regulatory T (Treg) cells by augmenting expression of Foxp3. Such actions of IFN-γ may be associated with beneficial effects of IFN-γ observed in the late phase of certain autoimmune diseases.
TNF-α has been shown to be essential for an effective delayed-type hypersensitivity response. Major cellular sources of TNF-α include macrophages and Th1 cells, but TNF-α is also produced by many other lineage cells. TNF-α induces chemokine production from macrophages and endothelial cells and also up-regulates adhesion molecules on vascular endothelial cells, resulting in cellular influx of further inflammatory cells. TNF-α also induces other inflammatory cytokines, such as IL-1. In delayed-type hypersensitivity responses to poison ivy and nickel, mast cells may be a major source of TNF-α, in addition to production of other inflammatory mediators including histamine.
Another key cytokine associated with delayed-type hypersensitivity response is IL-12. IL-12 is mainly produced by APCs augments IFN-γ production by NK cells and T cells, and promotes Th1 cell differentiation. It also enhances cytolytic functions of NK and CD8+ T cells. IL-18 was recently shown to also augment IFN-γ production in the presence of IL-12.
A defect in delayed-type hypersensitivity reaction is best illustrated in the gene mutation in IFN-g receptor 1 (IFNGR1). IFNGR1 deficiency is characterized by ineffective granuloma formation with disseminated infection of atypical Mycobacterium species, BCG, and Salmonella species. This mutation resides on band 6q23-24. The gene consists of 50 kilobases (kb), composing 7 exons. It is highly polymorphic and encodes a 90-kilodalton transmembrane protein, which binds IFN-γ with high affinity. IFNGR1 is expressed on T cells, monocytes, macrophages, and polymorphonuclear neutrophils (PMN).
Mutations identified thus far include frameshift deletions or insertions, a splice mutation, and missense mutations at the upstream end of the gene. These mutations usually lead to absent surface expression of IFNGR1 or nonfunctional binding sites for IFN-γ, although leaky proteins are predicted in missense mutations. In the absence of IFN-γR expression, IFN-γ fails to activate monocytes to secrete TNF-α and produce ROIs. The gene mutation of IFNGR2 also induces similar clinical features. Mutations in IFNGR1 at a downstream hotspot disrupt the intracytoplasmic domain and result in a dominantly expressed disorder with milder clinical features.6
Murine models of IFNGR1 deficiency are susceptible to infection with a wider range of organisms than reported for humans with IFNGR1 mutations. The former develop infections with Listeria monocytogenes, Legionella pneumophila, Toxoplasma gondii, and Leishmania species, as well as with lymphocytic choriomeningitis virus, mouse hepatitis virus, and herpes simplex virus (HSV).
Down-regulation of CMI in the immunocompetent host is an active process and important for minimizing tissue injury associated with delayed-type hypersensitivity. Cytokine such as IL-10 down-regulate production of Th1 cytokines or counteract actions of Th1 cytokines. Recent studies also indicate importance of naturally occurring and inducible Treg cells that suppress effector cell proliferation directly or indirectly by producing cytokines such as IL-10 and transforming growth factor–β (TGF-β). Drugs that block components of delayed-type hypersensitivity include the histamine-2 (H2)–receptor antagonist cimetidine and the prostaglandin antagonist indomethacin. Interestingly, as indicated above, IFN-γ can augment induction of inducible Treg cells that produce IL-10 and TGF-β in the late stage of inflammation.5
As indicated above, Th17 and Tc17 cells are implicated in delayed-type hypersensitivity and CH responses in rodent models. This appears to also be true in humans. For example, nickel-specific Th clones established from patients with contact dermatitis against nickel were shown to produce IL-17A.7
Frequency
United States
Seventy-five percent of healthy children aged 12-36 months mount positive delayed-type hypersensitivity skin test reactivity to a Candida antigen. Evaluating CMI with in vitro lymphocyte proliferative responses to the specific antigen is necessary in the absence of a skin delayed-type hypersensitivity response.
Anergy is observed in patients who are malnourished, have severe atopic dermatitis, and those with severe infections caused by M tuberculosis, measles, mumps, HIV, influenza, mononucleosis, lepromatous leprosy, and certain fungi. Anergy is also observed in patients who have recently received the measles, mumps, and rubella (MMR) vaccine, patients with sarcoidosis, or patients with parasitic infestations. In addition, immunosuppressive drugs, such as cytotoxic medications and corticosteroids, lead to anergy. Malignancy, especially malignant lymphomas, also induces anergy.
Interestingly, delayed-type hypersensitivity reactions in patients with impaired IFN-γ and IL-12/IL-23 pathways tend to reveal excessive delayed-type hypersensitivity reactions. In contrast, in patients with autosomal dominant hyper immunoglobulin E (IgE) syndrome with STAT3 mutations, decreased delayed-type hypersensitivity responses against Candida may be observed due to Th17 cell deficiency.8
International
The presence of delayed-type hypersensitivity reactivity to tuberculin follows BCG vaccination. BCG is the most commonly administered vaccine throughout the world; however, it is not commonly used in the United States.
Mortality/Morbidity
Delayed-type hypersensitivity skin testing is almost never associated with mortality or morbidity. The major error is associated with failure of differentiating anergy from negative delayed-type hypersensitivity reactivity. Anergy may result from overwhelming infection or immunodeficiency. Secondary immunodeficiency is commonly due to therapy with corticosteroids, chemotherapy, calcineurin inhibitors (eg, cyclosporine, tacrolimus), and various monoclonal antibodies directed against the immune system.Patients with T-cell immunodeficiency diseases such as severe combined immunodeficiency (SCID) are anergic.
Patients with mutations in IL12P40 or in IL12RB1 may show a positive, often excessive, delayed-type hypersensitivity reactivity through activation of other components of delayed-type hypersensitivity responses such as IL-17 and perhaps due to lack of regulatory effects of IFN-γ.
Mutations in IFNGR2, STAT-1, IL12P40, and IL12RB1 are autosomal recessive. Mutations found in complete IFN-γ R deficiency are also autosomal recessive. Mutations in IFNGR1 that affect the downstream intracytoplasmic domain are autosomal dominant and are clinically manifested as partial IFN-γ R deficiency. Patients with complete IFN-γ R deficiency often succumb to death from overwhelming infection caused by nontuberculosis mycobacteria (NTM) BCG at young age. Severe cytomegalovirus (CMV) infection is also described in these patients.
Mutations partially impairing IFN-γ signaling pathway may be manifested with milder mycobacterial infection, nontyphus Salmonella infection, Legionella infection, and listeriosis.
Race
Some individuals from the Mediterranean area have mutations leading to insufficient IFN-g function. Specifically, a family from Tunisia, several families from Malta, and 1 family from Italy have been reported. Genetic defects involving the IFN-g/IL-12 axis are now increasingly reported in other races.
Sex
Anergy to BCG and of idiopathic disseminated BCG infection are equally distributed among males and females. As expected in autosomal recessive gene mutations, IFNGR1, IL12P40, and IL12RB1 mutations are found with equal frequency in males and females.
Age
Delayed-type hypersensitivity reactivity to Candida antigens can be detected in infants as young as 3-4 months, but reactivity depends on exposure to the antigen. Positive delayed-type hypersensitivity reactivity to tetanus toxoid requires completion of the primary immunization series of 3 injections administered 4-6 weeks apart; only one third of infants have a positive response to tetanus after the first dose of immunization. Patients with IFNGR1/IFNGR2 mutations that cause complete loss of IFN-receptor expression or IFN-γ– mediated signaling have presented as infants or in early childhood with disseminated BCG or NTM infections, respectively. This age-related infection seems to reflect the age of exposure to the causative organisms.
Clinical
History
Delayed-type hypersensitivity (DTH) skin testing is usually performed to detect exposure to tuberculosis and, occasionally, when unusually extensive Candida infection has occurred. In these settings, the patient often has no prior history of unusually severe or opportunistic infections. In developing countries, ruling out confounding clinical malnutrition and rubeola infection that negate delayed-type hypersensitivity skin test reactivity is crucial. HIV infections and malignancies, such as Hodgkin lymphoma, also negate delayed-type hypersensitivity responses.
The presence of any cause for immunosuppression modifies the interpretation of tuberculin delayed-type hypersensitivity skin tests; in an immunosuppressive condition, 5-mm induration is interpreted as a positive response.
Delayed-type hypersensitivity skin test reactions are absent in patients with lepromatous leprosy (M leprae), sarcoidosis, coccidioidomycosis, schistosomiasis, rheumatological diseases, severe viral infections (eg, influenza, mononucleosis, mumps), and those given the measles, mumps, rubella (MMR) vaccine recently (£ 3 wk). Systemic steroid therapy can cause anergy; however, inhaled steroids with high bioavailability could also decrease delayed-type hypersensitivity reactions and less frequently produce anergy when administered in large doses. Longer duration (>2 wk) and higher doses of steroids increase the risk for anergy, but no exact doses or duration predict induction of anergy in a given individual.
Other immunosuppressive agents that cause anergy include cancer chemotherapy agents, calcineurin inhibitors, and monoclonal antibodies against the immune system such as anti-TNF (infliximab) and anti-CD20 (rituximab).
Usually, a patient with anergy caused by a T-cell immunodeficiency can be identified before wasting sets in. A pattern of unusually frequent or severe common infections, extensive mucocutaneous candidiasis, or dermatitis together with lymphopenia raises the suspicion of severe combined immunodeficiency (SCID) or another severe T-cell immunodeficiency.
A patient with disseminated bacille Calmette-Guérin (BCG) or nontuberculosis mycobacteria (NTM) infection may have a history of consanguinity or familial infection indicating autosomal recessive genetic disorders. Evaluate these patients for IFNGR1, IFNGR2, STAT-1, IL12P40, and IL12RB1 mutations. Patients with BCG infection usually present in early infancy after administration of the BCG vaccine. NTM infection develops more typically in mid childhood when community exposure to these mycobacteria occurs. A patient with one of the above mutations responds poorly to appropriate antimycobacterial therapy and often has a fulminant fatal infection.
Nontyphus Salmonella infections are more frequently observed in patients with the above-described disorders. Asthma, atopy, and immune complex disease (eg, glomerulonephritis, vasculitis, positive rheumatoid factors) are sometimes present.
Repetitive delayed-type hypersensitivity skin testing does not change the parameters used to define a positive test result. The immediate hypersensitivity reaction of erythema may increase, which is what determines the delayed-type hypersensitivity response.
Delayed-type hypersensitivity antigens for coccidioidomycosis are no longer available. Diagnosis depends on identifying the organism or serology. Negative skin test reactivity to coccidioidin does correlate with a less favorable clinical outcome. However, the positive skin test result usually persists following an initial infection so that recurrence cannot be determined by the delayed-type hypersensitivity skin testing.
Delayed-type hypersensitivity skin test reactivities for histoplasmosis and blastomycosis cross-react. In addition, positive delayed-type hypersensitivity skin reactions in exposed but not infected individuals living in endemic areas confound interpretation. Both fungal infections have increased in incidence in HIV patients; these patients are frequently anergic. Diagnosis now requires culturing the organism, antigen detection, and/or serologic confirmation.
Physical
The delayed-type hypersensitivity skin test response is determined by the extent of induration. Erythema indicates an immediate hypersensitivity reaction and begins earlier than but often persists after induration has developed.
Delayed-type hypersensitivity skin test reactivity to most antigens is read as positive when induration is 5 mm or more at 48 hours and 72 hours following inoculation. For tuberculin, 15 mm is considered a positive response for persons aged 4 years or older without risk factors; 10 mm is considered a positive response for younger children and those in populations with increased exposure or in whom immunosuppression is likely. A tuberculin reaction of 5 mm is considered positive when clinical evidence of tuberculosis, HIV infection, or close contact with people with infectious tuberculosis is noted.
Disseminated BCG and NTM infection are characterized by fever, wasting, lymphadenopathy, and hepatosplenomegaly.
Causes
A positive delayed-type hypersensitivity response to the purified protein derivative (PPD) of M tuberculosis is elicited 4-6 weeks after exposure to tuberculosis. Populations at increased risk for tuberculosis include immigrants from countries with a high incidence of tuberculosis, such as African, Asian, and South American countries, and those with HIV infection. High-risk populations in the United States include those who are incarcerated, those who are homeless, migrant workers, and those who use illicit drugs. Individuals who are exposed to these populations are also at increased risk.
Anergy is discussed under History and Pathophysiology.
A single functional mature T cell can transfer delayed-type hypersensitivity DTH reactions; thus, a patient who received hematopoietic stem cell transplant from a donor with positive delayed-type hypersensitivity responses to the specific antigen could reveal positive delayed-type hypersensitivity responses to the same antigen.
Contact delayed-type hypersensitivity reactions occur in patients with poison ivy and nickel hypersensitivity
delayed-type hypersensitivity to sulfonamides, phenytoin, and carbamazepine has been described. Reactions to penicillin-type antibiotics may be cell-mediated, but immunoglobulin G (IgG)-mediated responses are much more common.
More on Delayed-type Hypersensitivity |
 Overview: Delayed-type Hypersensitivity |
| Differential Diagnoses & Workup: Delayed-type Hypersensitivity |
| Treatment & Medication: Delayed-type Hypersensitivity |
| Follow-up: Delayed-type Hypersensitivity |
| References |
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Further Reading
Keywords
delayed-type hypersensitivity, DTH, DTH reaction, DTH response, delayed-type hypersensitivity reaction, delayed type hypersensitivity, delayed hypersensitivity, hypersensitive response, hypersensitive reaction, cell mediated immunity, CMI, antigen-presenting cells, APCs, cell-mediated immunity to recall antigens, anergy, anergic reaction, T cell, T-cell receptor, Candida antigen, Candida infection, DTH skin test, T-cell disorder, T-cell defect, bone marrow transplantation, BMT
Mycobacterium tuberculosis, tetanus, Candida, Trichophyton, mumps, contact hypersensitivity, nickel, dinitrochlorobenzene, DNCB, picryl chloride, leprosy, poison ivy, Listeria monocytogenes, Legionella pneumophila, Toxoplasma gondii, Leishmania, lymphocytic choriomeningitis virus, mouse hepatitis virus, herpes simplex virus, HSV, malnutrition, atopic dermatitis, MMR vaccine, sarcoidosis, mononucleosis, HIV, influenza, malignant lymphomas, severe combined immunodeficiency, SCID, cytomegalovirus, CMV, Hodgkin lymphoma, asthma, atopy, glomerulonephritis, treatment, diagnosis
