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CHaPTEr 19 Host Defenses in Skin 277

small numbers of resident dermal pDCs leads to abundant KEY CONCEPTS
production of type I interferons (IFN-α), inducible nitric oxide
synthase (iNOS), and arginase, which aid in the eradication of • Skin is the major interface between an individual and his or her
viral infection and other invading organisms. environment. Skin-resident and recirculating immunocompetent
Resolution. After the pathogen is eliminated, keratinocytes cells and immune mediators are used to defend against intrusion by
microorganisms, noxious exogenous chemicals, and mutant cells that
switch their cytokine production program in response to IL-6 arise within it.
and generate anti-inflammatory factors, such as IL-10 and IL-1 • When the immune system overperforms, it can give rise to autoimmune
receptor antagonist (IL-1RA). During this phase, recruited skin diseases. Pemphigus, for example, is a blistering disease in which
leukocytes can also produce IL-10. IL-10 is a potent inhibitor antibodies are directed at desmogleins-1 and -3.
of adaptive and inflammatory cellular responses, whereas IL-1RA • When the immune system underperforms, cutaneous immunodeficiency
effectively blocks the activity of IL-1β. Both activities function occurs. For example, patients taking immunosuppressive medications
to return skin to its normal resting state. In addition, macro- suffer an increased risk of developing squamous cell carcinomas
of skin.
phages and certain DC subsets can inhibit ongoing adaptive • Skin-specific immune system components provide targets for new
immune responses through their expression of indoleamine 2,3 therapies. For instance, T-helper type 17 (Th17) cells play a dominant
dioxygenase (IDO), an enzyme that alters tryptophan metabolism role in psoriasis, and neutralizing antibodies to IL-17 have recently
in T cells. been approved as a highly effective treatment for this disease.

Antimicrobial Peptides
Skin is a production site for antimicrobial peptides, which
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are important components of the innate immune response.
Over 20 antimicrobial peptides have been described. They func- ADAPTIVE IMMUNITY AND SKIN
tion at the earliest stages of infection by microorganisms
that breach the stratum corneum. These antimicrobial peptides Although the innate immune response forms the first line of
have the ability to disrupt bacterial and fungal membranes, as defense against microbial threats in an antigen-nonspecific
well as viral envelopes. These peptides have broad effects on manner, the host’s adaptive immune response provides antigen-
innate and adaptive immune responses. The two best character- specific protection against intracellular and extracellular
ized skin antimicrobial peptides are the cathelicidins and pathogens. In contrast to innate immunity, adaptive immunity
β-defensins. They are synthesized by keratinocytes, cells of the is able to distinguish self from nonself to eliminate microbial-
epidermal sebaceous and eccrine glands, and dermal mast cells. infected or mutated cancer cells without damaging normal cells.
Cathelicidins are secreted as precursor proteins (e.g., hCAP18), The adaptive immune response in skin is carried out primarily
which are then processed to an active form (e.g., IL-37). by T cells and by immunoglobulin E (IgE) antibodies that are
They are detected at low levels in unperturbed skin but are bound to mast cells. T cell–mediated immunity is dependent
strongly increased following infection or disruption of the on activation by antigen-presenting DCs.
epidermal barrier.
Cathelicidins interact with a variety of cell-surface receptors, Dendritic Cells
including TLR-like and endothelial growth factor (EGF) receptors. DCs are a heterogeneous group of leukocytes that typically exhibit
They enhance leukocyte migration, stimulate the secretion of a DC surface, providing a large surface area for interaction with
cytokines and chemokines, and promote angiogenesis. Interest- T cells (Fig. 19.2) (Chapters 5 and 6). LCs are specialized epidermal
ingly, vitamin D 3 , the synthesis of which is initiated in skin by DCs originally discovered by Paul Langerhans in 1868. Under
UVR, plays an important role in regulating cathelicidin production resting conditions, two different types of DCs are typically found
through epigenetic mechanisms. 12 in the dermis–myeloid derived conventional DCs (cDCs) and
Abnormalities in antimicrobial peptides have been implicated lymphoid plasmacytoid DCs (pDCs). cDCs are the most potent
in a variety of immunological and nonimmunological skin APC type. pDCs are less dendritic and less potent APCs but are
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diseases. Deficiencies in antimicrobial peptide levels have been still potent producers of IFN-α. In perturbed skin, inflammatory
found in atopic dermatitis (Chapter 44), which may explain why DCs (iDCs) accumulate to produce abundant levels of TNFα
patients with these deficiencies are at greater risk for viral (herpes and iNOS. They are derived from circulating monocytes that
simplex, HPV-induced warts, and poxvirus-induced molluscum differentiate into DCs upon transendothelial migration into
contagiosum) and bacterial (Staphylococcus aureus) skin infections. inflamed dermis.
Rosacea manifests as an acneiform eruption with erythema, To perform APC function, LCs and DCs express a wide array
telangiectasias, and flushing of the face. In rosacea, excessive of antigen capture receptors that internalize bound microbes
amounts of cathelicidins are associated with characteristic and antigens into processing endosomes, where antigens are
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inflammation and angiogenesis. In psoriasis (Chapter 64), cleaved and trimmed into short peptides and then loaded into
cathelicidins are postulated to combine with self DNA the peptide-binding groove of MHC (or human leukocyte antigen
from damaged keratinocytes. This stimulates type I IFN produc- [HLA]) molecules (Chapters 5 and 6). Peptide–MHC molecular
tion by pDCs, which is a key to the development of pathogenic complexes are presented at the surface of DCs for recognition
Th17 cells. 14 by antigen-specific T-cell receptors (TCRs) (Chapter 4) on naïve
Nonimmune mechanisms that cause physical disruption of and/or memory T cells. Through integration of environmental
the skin barrier (e.g., shear forces, chemical, thermal, or UV signals, LCs and DCs are able to program naive T cells to dif-
damage) stimulate “sterile” inflammatory responses that produce ferentiate into appropriate, functionally distinct subsets of
similar proinflammatory mediators and antimicrobial peptides skin-homing effector cells that can eradicate a particular
to protect vulnerable sites during wound healing. pathogen.