Page 638 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPter 44 Atopic and Contact Dermatitis 613

and severe bacterial infections. Hyper-IgE syndrome (HIES) with immunity, interleukin-1 (IL-1) family signaling, Tregs, the vitamin
mutations in the signal transducer and activator of transcription D pathway, and the nerve growth factor pathway in the pathogenesis
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3 gene (STAT3) is an autosomal dominant multisystem disorder of AD. Thus a combination of varied genetic factors may influence
characterized by recurrent deep-seated bacterial infections, a wide range of phenotypes of AD among individuals.
including cutaneous cold abscesses and pneumonias caused by
S. aureus. Patients with mutations in the gene encoding dedicator Immune Abnormalities in Atopic Dermatitis
of cytokinesis 8 protein (DOCK8) have an immunodeficiency Immunohistology
with eczema, recurrent viral infections, including some with On the basis of clinical appearance and duration of illness, AD
CNS involvement, and many have associated food allergies. skin can be characterized as nonlesional AD, acute AD lesions
Patients with tyrosine kinase 2 (TYK2) deficiency can also present (≤3 days after onset), and chronic skin lesions. Nonlesional AD
with an eczematous rash with high serum IgE and recurrent skin is not normal and is characterized by a sparse perivascular
cutaneous staphylococcal infections. Other diseases to consider T-cell infiltrate, suggesting the presence of minimal inflammation
in the differential diagnosis of AD include cutaneous T-cell at baseline. Langerhans cells (LCs) also exhibit surface-bound
lymphoma, especially in adults with no history of childhood IgE molecules, which have enhanced capacity to present allergen
eczema and without other atopic features, human immunode- to T cells. In acute lesions, there is epidermal spongiosis with
ficiency virus (HIV) infection, and CD (see section on ACD). an increased infiltration of activated memory T cells bearing
Contact allergy can also complicate AD, especially in patients the skin-homing cutaneous lymphocyte-associated antigen
+
whose AD does not respond to or worsens with therapy. (CLA ). Eosinophils, basophils, and neutrophils are rare. Mast
cells are seen in various stages of degranulation.
PATHOGENESIS OF ATOPIC DERMATITIS Chronic lichenified AD lesions are characterized by epidermal
hyperplasia, prominent hyperkeratosis, and an increased number
Genetics of dendritic cells (DCs) bearing surface IgE. Macrophages domi-
The genetics of AD are complex with key roles played by skin nate the dermal mononuclear cell infiltrate, but lymphocytes
barrier or epidermal differentiation genes and immune response remain prominent. Although intact eosinophils are rarely seen,
or host defense genes. eosinophil product deposition can be readily identified, suggesting
they contribute to allergic skin inflammation.
KeY CONCePtS Immune Pathways in Atopic Dermatitis
Pathogenesis of Atopic Dermatitis (AD) AD is associated with a combination of defective innate responses
to microbes and altered adaptive responses to environmental
• Patients with AD have abnormalities of skin barrier and immune allergens (reviewed in references 1,2,10 ). A key difference between
dysregulation. epidermal keratinocytes found in AD skin, compared with normal
• Some patients with AD have decreased filaggrin in the skin based on skin, is the presence of thymic stromal lymphopoietin (TSLP)
mutations in the gene encoding filaggrin (FLG), copy number variation
of FLG, or secondary to type 2–mediated cytokine (e.g., IL-4, IL-13) and IL-33 in the AD epidermis. TSLP and IL-33 are key cytokines
suppression of FLG. secreted by epithelial cells that induce DCs to drive T-helper 0
• FLG mutations are associated with early-onset, severe, persistent AD (Th0) cells into the Th2-cell differentiation pathway. Nonlesional
with increased risk for asthma and allergic sensitization. AD and acute AD skin lesions are predominantly associated with
• Normal-appearing skin in patients with AD is associated with immune expression of IL-4, IL-5, IL-13, IL-25, and IL-33. These type 2
activation and epidermal terminal differentiation abnormalities. cytokines are present in all stages of AD and can be secreted by
• Patients with AD are predisposed to Staphylococcus aureus colonization
or infection, and a small subset are prone to eczema herpeticum. multiple cell types, including innate lymphoid type 2 cells (ILCs),
• Patients with an “Asian phenotype” of AD have features of psoriasis mast cells, and basophils, which are present in AD skin lesions
with increased T-helper 17 (Th17) and Th22 along with increased Th2 and contribute to substantial redundancy in allergic inflammation.
skewing. As such, cytokine targeting, as opposed to cell targeting, is
considered a more effective approach in the treatment of AD.
It is noteworthy that experimental studies demonstrate pretreat-
Loss-of-function mutations of FLG are a major predisposing ment with IL-4 and IL-13 dampens responses to IFNs and IL-17,
factor for AD. Patients with FLG gene mutations have early-onset, suggesting that once the early AD lesion is exposed to IL-4 and
severe, and persistent AD and are at increased risk for developing IL-13, there is a long-lasting persistent effect.
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asthma, as well as food and inhalant allergies. Other skin barrier Besides Th2, other cytokine pathways are also activated during
proteins implicated in AD include loricrin and involucrin, which the evolution of AD. The IL-22–IL-17 pathway is of particular
are both significantly decreased in lesional and nonlesional skin interest, since it, along with IL-4 and IL-13, can inhibit terminal
of patients with AD. Candidate gene approaches have also keratinocyte differentiation, including filaggrin expression. Since
implicated variants in the SPINK5 gene, and haplotype tagging DC-derived IL-23 enhances IL-22/IL-17 cell differentiation, all
of SNPs for the claudin-1 gene (CLDN1) has revealed associations of these cytokines are being closely examined for their potential
with AD. These observations have established a key role for role in AD. It is interesting that IL-4 and Il-13 can enhance IL-23
impaired skin barrier function in the pathogenesis of AD that production by DCs. Furthermore, blockade of the IL-4 and IL-13
allows increased transepidermal water loss and penetration of pathway, leading to improvement in AD, is also associated with
allergens, antigens, and chemicals from the environment, resulting reduced IL-23 and IL-17 expression in AD skin. When acute AD
in cutaneous inflammation. Additional genome-wide significant skin lesions become chronic, there is an increase in Th1 cytokines,
susceptibility loci identified through the genome-wide association such as IFN-γ, which potentiates AD skin inflammation. A recent
study (GWAS) and immunochip analysis continue to be reported birth cohort study, however, demonstrated that TSLP could be
and suggest a role for epidermal barrier function, innate-adaptive detected in at-risk infants before onset of AD, suggesting that