Page 645 - Clinical Immunology_ Principles and Practice ( PDFDrive )

620 Part five Allergic Diseases

indicated that Th2 cells also participate in the development of abrade or irritate skin. After exposure to skin irritants, perturba-
contact hypersensitivity. 41 tion of the skin barrier and disorganization of the lipid bilayers
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Recently, both murine models and human studies have sug- with lamellar body lipid extrusion in the epidermis is seen,
gested the potential role of Th17 cells in the immunopathogenesis with an associated increase in TEWL.
of ACD. Increased levels of cytokines favoring a Th17 response Irritants cause direct activation of the innate immune system
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(i.e., IL-6) and allergen-specific IL-17–producing T cells were through hyperproduction of cytokines and chemokines, such
found in sensitized mice. In addition, IL-17–deficient mice showed as IL-1α, IL-1β, IL-6, IL-8, and TNF-α, which further induce a
decreased secretion of cytokines and chemokines, diminished cytokine cascade and inflammatory reaction with infiltration of
hapten-specific CD4 T-cell responses, and reduced ear swelling. inflammatory cells. Epidermal keratinocytes have been identified
In patients with ACD, Th17-associated mediators, such as IL-17A, as key effector cells in the initiation and propagation of contact
IL-17F, IL-22, IL-23, chemokine receptor 6 (CCR6), IL-22 receptor, irritancy. Keratinocytes can release both preformed and newly
and the Th17 transcription factor retinoic acid–related orphan synthesized cytokines, and can upregulate MHC class II molecules
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receptor γ, were shown to be produced by nickel-specific T cells and induce adhesion molecules in response to irritants. These
and were upregulated in ACD lesional skin and positive patch mediators can cause direct tissue damage, activating LCs, dermal
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test biopsy specimens. Nickel exposure was reported to induce DCs, and endothelial cells, which contribute to further cellular
production of IL-23 by keratinocytes, promoting a Th17-mediated recruitment, including neutrophils, lymphocytes, macrophages,
response, as detected by the presence of IL-17–producing T cells and mast cells, which also contribute to the inflammatory cascade.
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in peripheral blood from patients with nickel allergy. The The “final” cellular damage results from inflammatory mediators
role of IL-17 in ACD lesions includes induction of keratinocyte released by activated nonsensitized T cells.
release of cytokines and chemokines (i.e., IL-8 and IL-6) and Application of sodium lauryl sulfate (SLS) exerts direct toxic
promotion of T cell–induced apoptosis of keratinocytes. The effects on keratinocytes (an experimental model of ICD) and has
significance of IL-17 in ACD is emphasized by the correlation been demonstrated to induce LC mobilization and consequent
between the increase in IL-17–producing cells with the clinical migration to the draining lymph nodes. Other irritants have
manifestations of ACD, as well as by their significant percentage been shown to cause direct activation of the innate immune
(20%) among skin-infiltrating CD4 and CD8 T cells in contrast system through a set of membranous and intercellular receptors
to their minor representation (only 1.5%) in the regional lymph called Toll-like receptor 7 (TLR-7) and nucleotide-binding oligo-
nodes of allergen-primed mice. 43 merization domain (NOD)–like receptors (NLRs) that activate
A particular role for IL-22 (produced by Th22 and Th17 T the inflammasome and nuclear factor-κB (NF-κB) pathways,
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cells) has been suggested in ACD. Significantly higher levels of inducing release of many cytokines and chemokines.
IL-22 were detected in the serum of patients with ACD to nickel Although few immunohistopathological differences have been
compared with those seen in control subjects. IL-22 cytokine noted between ICD and ACD, ICD does not require prior
levels have also been shown to be upregulated in inflamed skin sensitization, and immunological memory is not involved. The
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of patients challenged with nickel allergy, although its specific cellular infiltrate includes CD4 T cells with a Th1-type profile.
contribution to ACD reactions is not yet known. Irritant reactions predispose to allergic reactions, making patients
The skin of patients with AD is at increased risk for the with ICD more susceptible to the development of ACD. Animal
development of ACD, and this may be attributed to multiple models in which skin was preirritated with 5% SLS showed an
factors. First, AD skin is exposed to chemicals used to treat AD, increase in skin sensitization rate to paraphenylenediamine from
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including moisturizers, topical corticosteroids, and TCIs. Second, 38% to 78% and enhanced T-cell proliferative responses to
the disturbed barrier system allows increased permeation of 2,4-dinitrochlorobenzene (DNCB). The DNCB-primed ICD
allergens. Third, AD skin has a heightened immunological status reaction conditioned the development and severity of the ACD
with existing activation of innate immunity, increased access of response. Similarly, in human studies, when patch test sites were
surface antigens to LCs, and selective upregulation of the Th2 pretreated with SLS, the threshold elicitation concentrations of
adaptive immune response. In patients with AD, cutaneous contact contact allergens, such as cobalt, nickel, and colophony, were
with irritants and allergens leads to amplification of innate significantly decreased, indicating that the activation of innate
immunity and enhanced adaptive immune responses, including immunity by irritants likely reduces the threshold for the develop-
Th2 and Th17 in patients with acute AD and Th22 and Th1 in ment of ACD.
patients with chronic disease. Just as innate immune activation In summary, although ACD, ICD, and AD are independently
stimulated by an irritant permits a lower threshold of ACD defined diseases, they interact and frequently occur in combina-
elicitation, the amplified adaptive responses in lesional and tion. In patients with AD, if the activation of an innate immune
nonlesional skin promote increased expression of ACD and ICD response is preceded by exposure to irritants and allergens, there
in patients with AD. is altered permeation of contact allergens, which are introduced
into an already activated innate immune system, resulting in
PATHOGENESIS OF IRRITANT CONTACT DERMATITIS amplification of innate immunity and enhanced adaptive immune
responses. The amplified adaptive responses in AD promote
ICD accounts for 80% of cases of CD. The clinical presentation increased ACD and ICD. Conversely, the innate immune activation
of ICD is usually restricted to skin that is directly in contact with stimulated by an irritant permits a lower threshold of ACD
the offending agent, with little or no extension beyond the site of elicitation (Fig. 44.2).
contact. The inflammatory response is dose- and time-dependent.
Any impairment to the epidermal barrier layer (e.g., fissuring, CLINICAL MANIFESTATIONS OF
overhydration) renders skin more susceptible to an irritant effect. CONTACT DERMATITIS
Contact with agents, such as detergents, solvents, alcohol, creams,
lotions, ointments and powders, and environmental factors, such The clinical and histological findings of ACD are characteristic,
as wetting, drying, perspiration, and temperature extremes, can but not diagnostic. ACD should be suspected in patients with