Page 644 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 44 Atopic and Contact Dermatitis 619

vast majority of cases of contact-induced skin reactions are The immune response of ACD requires completion of both an
attributable to CD. However, there are other less-well-defined afferent (sensitization) and an efferent (elicitation) phase.
contact reactions, including contact urticaria, contact urticaria In the afferent limb, the hapten enters the epidermis and
syndrome, and protein contact dermatitis. ACD affects approxi- activates keratinocytes to release inflammatory cytokines and che-
mately 7% of the general population, 13.3–24.5% of pediatric mokines, including tumor necrosis factor (TNF)-α, granulocyte
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patients, and 33–64% of the elderly population. CD was macrophage–colony-stimulating factor (GM-CSF), IL-1α, IL-1β,
associated with more than 10.6 million physician office visits, IL-8, IL-10, IL18, and macrophage inflammatory protein-2 (MIP-
with annual direct costs estimated at $1.6 billion and indirect 2). The activation of LCs, other DCs, and endothelial cells can lead
costs at $566 million as a result of loss of work time, school to recruitment of even more DCs at the site of antigen contact.
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time, and productivity. Numerous studies have reported an The release of IL-1β by epidermal LCs promotes their egress
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increased frequency of ACD in patients with AD, likely as a from the epidermis. LCs process the antigen while migrating to
result of the increased exposure to products and chemicals used regional lymph nodes, where they present it to naïve T cells. This
to treat AD, the barrier defect, and immunological changes in phase is influenced by multiple factors. Defects in the integrity
AD, which predispose a patient to both ICD and ACD. 37 of the stratum corneum allow greater penetration of allergen
and increase the chances of activating antigen-presenting cells
PATHOGENESIS OF ALLERGIC (APCs) in skin. The availability and viability of APCs in skin,
CONTACT DERMATITIS as well as the presence or absence of cytokines produced by
keratinocytes, can promote or hinder APC–T-cell engagement.
The Genes In the draining lymph nodes, LCs present the peptides to T cells
ACD is a multifactorial condition in which genetic background and activate CD4 and CD8 antigen-specific T cells. An important
plays an important part, as shown by twin and family studies. property of LCs and DCs is their ability to present exogenous
An association has been demonstrated between loss of function antigens on both major histocompatibility complex (MHC) class
mutations R501x and 2282del4 in the filaggrin (FLG) gene and I and class II molecules. This cross-priming leads to the activation
contact sensitization against nickel II-sulfate, combined with of both CD4 and CD8 hapten-specific T cells. Although classic
an intolerance to fashion jewelry but not with other contact delayed-type hypersensitivity reactions are mediated primarily
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allergens. FLG mutations have further been shown to lower by CD4 cells, CD to haptens is mediated primarily by CD8 cells
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the age of onset of nickel sensitization. Thus FLG defects may with a Th1-type cytokine profile. LCs activate hapten-specific
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be a risk factor for contact sensitization to allergens. T cells, which include Th1, Th2, Th17, and Treg subsets. This
preexisting mix of T-cell subtypes specific for the antigen influence
The Allergens the outcome of this process. The higher the frequency of cells
Most contact allergens are haptens, that is, simple chemicals that of an effector subtype, the higher the likelihood that dermatitis
bind to carrier proteins present in skin to form a complete antigen will result, whereas a higher frequency of cells of a regulatory
(Chapter 6). To be allergenic, the chemical must be able to subtype may limit or prevent the development of dermatitis.
penetrate the principal barrier in skin (stratum corneum) and The efferent phase of ACD occurs on subsequent contact of
reach the living cells of the epidermis. Only molecules with skin with the hapten. Antigen-specific memory T cells and other
molecular mass of <500 daltons (Da) are capable of penetrating inflammatory cells leave vessels and enter skin through sequential
the stratum corneum. Lipid solubility promotes transit through activation of a number of adhesion molecules by cytokines.
the stratum corneum. Thus most contact allergens are small, Memory T cells constitutively express CLA. E-selectin, the ligand
lipophilic molecules. Once in the epidermis, the nature of the for CLA, is induced on vascular endothelium by inflammatory
protein carrier for the hapten is very important because if the mediators, such as IL-1 and TNF-α. This interaction causes
contact sensitizer is complexed to nonimmunogenic carriers, memory T cells to slow down and roll along the endothelial surface
this may induce tolerance rather than sensitization. 38 as a prelude to migration to sites of inflammation. Firm adhesion
and migration of leukocytes to the endothelium are mediated by
The Immune Response T-cell very late antigen-4 (VLA-4)/leukocyte function–associated
antigen-1 (LFA-1) and endothelial cell vascular cell adhesion mol-
KeY CONCePtS ecule-1 (VCAM-1)/intercellular adhesion molecule 1 (ICAM-1),
Pathogenesis of Contact Dermatitis respectively (Chapter 11). Subsequently, LFA-1β T cells migrate
toward ICAM-1β epidermal cells.
• Allergic contact dermatitis (ACD) is a delayed-type, T cell–mediated Mast cells can also participate in the elicitation phase. In mice,
response with an afferent limb or sensitization phase and an efferent mast cells can be activated by a T-cell–derived antigen-binding
or elicitation phase. factor that induces release of serotonin, producing swelling 2
• Irritant contact dermatitis (ICD) is caused by irritants exerting toxic hours after challenge. In addition, mast cells contain preformed
effects on keratinocytes, causing a direct activation of the innate TNF-α, which may regulate the adhesion molecules involved
immune system through hyperproduction of cytokines and chemokines in the early recruitment of Th cells. The net result is an influx
and inducing an inflammatory skin reaction.
• Patients with ICD are more susceptible to the development of ACD, of sensitized T cells homing to the hapten-provoked skin site,
indicating that the activation of innate immunity by irritants likely releasing their inflammatory mediators, IL-2 and IFN-γ, and this
reduces the threshold for development of ACD. results in an enhanced immune response through activation and
• There is an increased frequency of ACD in patients with AD likely recruitment of more inflammatory cells, producing spongiosis
because of the disturbed skin barrier allowing increased allergen and the inflammatory dermal infiltrate characteristic of ACD.
penetration on an already amplified adaptive response in AD. Although Th1 cells have been classically considered the primary
• Although ACD, ICD, and AD are independently defined diseases, they
frequently interact and coexist. effector cells of ACD (responses to haptens, such as nickel, were
dominated by IFN-γ–producing cells), recent studies have