Page 300 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 19 Host Defenses in Skin 281

skin of a healthy adult contains nearly 20 billion T RM cells, about avoidance of autoimmune responses. This balance is achieved
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twice the number present in the entire blood volume. Among partly through the action of Tregs (Chapter 18). Natural Tregs
the best-characterized differentiated T-cell subsets are CD4 Th1, (nTregs) develop in the thymus in response to self antigens,
Th2, Th17, and Tregs, each of which produces a distinct profile whereas induced Tregs (iTregs) develop in the periphery in
of cytokines. The Th22 subset has recently been discovered and response to foreign antigens. Both are commonly characterized
+
+
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is implicated in human inflammatory skin diseases. CD8 T as CD4 /CD25 /Foxp3 , and both produce immunosuppressive
cells primarily function as cytotoxic effector cells, but they also cytokines (IL-10 and/or TGF-β). They can also express immu-
express cytokine profiles analogous to CD4 subsets, termed Tc1, noregulatory surface molecules, such as CTLA-4, PD-1,
Tc2, and Tc17. 22 glucocorticoid-induced TNFR family–related gene (GITR), and
Th1 responses. Th1 cells preferentially produce IFN-α and lymphocyte activation gene 3 (LAG-3). They can directly inhibit
IL-2 and are the principal regulators of type 1 immunity, the activation and function of T cells and suppress the activity
which eradicates intracellular pathogens and tumors. The major of antigen-presenting DCs. A defect in Treg function will result
effector cytokine produced by Th1 cells is IFN-α. Macrophages in autoimmune and inflammatory diseases. About 5–10% of
are stimulated by IFN-α to phagocytose and generate oxidative the T cells resident in normal human skin are Tregs. Tregs diminish
bursts that aid intracellular killing of microbes. IFN-α also immune responses in skin, an important function for dampening
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upregulates expression of class I and class II MHC molecules immune and inflammatory responses and limit tissue damage.
and ICAM-1 (CD54) on keratinocytes, dermal microvascular Conversely, increased Treg suppression can impair host immu-
endothelial cells and fibroblasts, and induces them to secrete nosurveillance against tumors. UVR-induced immunosuppression
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proinflammatory cytokines and chemokines. In animal models, is considered a critical mechanism for development of UVR-
deficiencies in IFN-α render them more susceptible to cutaneous induced tumors, and this is, to a great extent, mediated by
microbial infections and tumors. Th1 cells develop cutaneous UVR-induced Tregs. 27
delayed-type hypersensitivity responses, such as the tuberculosis CD8 T-cell immunity. CD8 T cells differentiate into cytotoxic
skin test reaction, and allergic contact dermatitis to haptens. T lymphocytes (CTLs), which are essential for the elimination
Haptens are small compounds that penetrate skin and bind to of viral infections and cancerous cells (Chapter 17). The CD8
epidermal proteins, generating “modified self” proteins as T-cell subsets Tc1, Tc2, and Tc17 also express cytokines analogous
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immunogenic antigens. Examples include urushiol in poison to CD4 helper subsets. Tc1 cells express the killer molecules
ivy and nickel. Fas-L, perforin, and granzyme B, as well as large amounts of
Th2 responses. Th2 cells are involved in type 2 immune IFN-α, all of which act to eradicate virally infected and neoplastic
responses, which are important for eradication of extracellular cells. Since CD8 T cells are important effectors of immune
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parasites and bacterial infection. They produce IL-4, IL-5, IL-10, surveillance, their presence in tumor tissues is a good prognostic
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and IL-13, which are important for the induction and develop- factor for certain types of cancer. Diminished CD8 T-cell
ment of humoral immune responses. IL-4 and IL-13 activate function increases the susceptibility to squamous cell and basal
B-cell proliferation, Ig class-switching, and antibody production. cell carcinomas in the skin of humans and animal models. Tc1
Th2 cell-mediated inflammation is characterized by the presence and Tc17 cells, producing IFN-α and IL-17 respectively, are key
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of eosinophils and basophils, as well as extensive mast cell mediators in allergic contact dermatitis (Chapter 44). Tissue
degranulation—a process dependent on cross-linking surface- damage by cytotoxic CD8 T cells also contributes to the pathology
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bound IgE. IL-5 is a potent hematopoietic cytokine, which of allergic contact dermatitis.
stimulates bone marrow production of eosinophils as well as γδ T cells. Dendritic epidermal T cells (DETCs) bridge innate
activation and chemotaxis of eosinophils and basophils to affected first line of defense and acquired immune mechanisms. In place
tissue. In mice, Th2-cell deficiency profoundly increases suscep- of conventional αβ chain TCRs, they express a more restricted
tibility to Leishmania infection in skin. In humans, Th2 cells repertoire of γ and δ chain TCRs and reside in epithelial tissues
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appear to play a critical role in the pathogenesis of atopic der- of skin, the gut, lungs, and the reproductive tract. In humans,
matitis (Chapter 44). A recent clinical trial with dupilumab, a γδ T cells account for at least 10% of the T cells in the epithelium.
fully human mAb that targets the IL-4 receptor-αα and blocks Epithelium-resident γδ T cells differ from circulating γδ T cells
IL-4 and IL-13 signaling, improved atopic symptoms . with respect to their development, selection, TCR diversity, and
Th17 responses. Th17 cells produce IL-17A, IL-17F, IL-21, effector functions. Epithelial γδ T-cell activation is not restricted
and IL-22. (IL-17A is commonly called IL-17.) Th17 cells have by MHC class I or class II molecules. Instead they recognize
protective effects against extracellular bacterial and fungal infec- PAMP and DAMP molecules presented by nonclassic MHC
tions in skin. Both IL-17A and IL-17F enhance protective immune molecules, such as CD1. They use alternate sets of costimulatory
responses by inducing the production of CXC chemokines, G-CSF, molecules, such as the junctional adhesion molecule–like protein
and antimicrobial peptides by keratinocytes and epithelial cells (JAML) and its ligand, the coxsackievirus and adenovirus receptor
of other organ systems. Mice deficient in IL-17A are highly (CAR). They are thought to be partially activated under static
susceptible to Staphylococcus aureus infections in skin. IL-17 and conditions. This enables them to rapidly mount responses to
IL-22 are important mediators of psoriasis and have been pathogenic stimuli. DETCs are involved in epidermal wound
implicated in other autoimmune skin disorders. In clinical trials repair, can influence DC activation, and can directly present
testing anti-human IL-17A antibodies (secukinumab and antigens.
ixekizumab), three-quarters of patients with psoriasis exhibited
reduced symptoms. Brodalumab, an IL-17 receptor antagonist, Cytokines and Chemokines and the Adaptive Immune
has shown efficacy in psoriasis. IL-17 may also promote tumor Response in Skin
development and UVR-induced immune suppression in skin. 25 A number of proinflammatory mediators are intimately involved
Regulatory T cells. The principal aim of the immune system in adaptive immunity in skin. IL-1 activates LC and dermal DC
is to establish a balance between defense against pathogens and migration and maturation processes. Mature DCs produce T-cell