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282 ParT TwO Host Defense Mechanisms and Inflammation

differentiation factors IL-12 and IL-23, which are critical for the is less certain, Igs play key roles in the pathogenesis of
development of Th1 and Th17 cells, respectively. 32 several different dermatological diseases. IgE-dependent skin
Chemokines facilitate leukocyte migration and thus skin diseases include urticaria and angioedema and bullous pemphi-
inflammation and antigen-specific responses (see Table 19.2). 9,33 goid. Hyper-IgE syndrome (HIES) is an autosomal dominant
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Secondary lymphoid chemokine (SLC, CCL21) attracts CCR7 disease that develops cutaneous manifestations of severe der-
DCs and T cells to lymph nodes, and stromal cell-derived factor matitis, recurrent infections of staphylococcal abscesses, and, to
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1 (SDF1; CXCL12) facilitates DC migration out of skin. CCL17 a lower extent, cutaneous candidiasis. Dominant negative
and CCL27, produced by keratinocytes and dermal cells, facilitate mutations in the signal transducer and activator of transcription
transmigration of circulating skin-homing T cells (expressing 3 (STAT3) gene are associated with this disease. Deficient
the chemokine receptors CCR4 and CCR10). Human skin–resident STAT3 signaling leads to impaired β-defensin expression,
T cells are retained through interaction of their chemokine which may explain some of the clinical manifestations of
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receptor CCR8 and its ligand CCL1 bound to the dermal matrix, HIES. Pathogenic IgG causes blistering disorders, including
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which is produced by cutaneous cells. During inflammation, pemphigus, bullous pemphigoid, epidermolysis bullosa acquisita,
CXCL1 and CXCL8/IL-8 expedite infiltration of granulocytes and paraneoplastic pemphigus, as well as leukocytoclastic vas-
and monocytes into skin. culitis. IgA is key to the pathogenesis of dermatitis herpetiformis,
Cutaneous T-cell lymphoma (Chapter 79) is a disease in which linear IgA bullous dermatosis, and IgA-mediated cutaneous
a malignant population of skin-homing T cells accumulate in vasculitis.
skin. Clinical manifestations include erythematous, pruritic
patches, plaques, and skin tumors. The malignant T cells express
CCR4 chemokine receptor. Clinical trials of humanized mAbs ULTRAVIOLET RADIATION AND
directed against the CCR4 receptor on T-cells (mogamulizumab) CUTANEOUS IMMUNITY
have shown promise.
Sunlight is the major environmental agent to which skin is
MAST CELLS AND SKIN exposed. Although the presence of sunlight is essential for life,
injudicious exposure to wavelengths in the ultraviolet (UV)
22
Skin is a rich source of mast cells (Chapter 23). These cells are spectrum can lead to sunburn, aging of skin, skin cancers, and
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derived from CD34 progenitors in bone marrow and migrate a variety of photosensitivity diseases, many of which have an
into many different tissues in the body, especially those at immunological pathogenesis. Although much of the investigation
environmental interfaces. In skin, they are found in the dermis into the immunological effects of UVR has been conducted in
2
at a density of up to 20 000/mm . They are typically concentrated animal models, many of the observations have been corroborated
around the dermal microvasculature, appendages, and nerves. in humans.
Metachromatic stains, such as toluidine blue and Giemsa, stain In mice, as in humans, chronic exposure to UVR results in
mast-cell granules purple, a distinguishing feature. Their cyto- the development of highly antigenic skin cancers that are capable
plasmic granules contain a plethora of preformed mediators of stimulating a vigorous antitumor response in untreated mice.
that include histamine and heparin; the proteases tryptase, Despite their antigenic nature, these tumors grow progressively
chymase, carboxypeptidase, arylsulfatase A, β-hexosaminodase, in their original host. This apparent paradox was resolved in
and β-glucuronidase; and the cytokines TNF-α, GM-CSF, IL-3, studies that showed that in addition to producing mutant
IL-4, IL-5, IL-6, IL-8, and IL-13. neoplastic cells, UVR also impairs cell-mediated immune surveil-
Mast cells express the high affinity surface receptor for the Fc lance that normally eliminate mutant cells before they develop
portion of the IgE molecule (FcεRI), which bind and retain IgE into clinically apparent tumors. Thus mutant cells develop tumors
for long periods. Antigen-induced cross-linking of IgE bound to only in an environment of immune suppression. In fact, organ
FcεRI initiates a sequence of calcium- and energy-dependent transplant recipients who are treated with immunosuppressive
events that culminate in the fusion of granules to the plasma medications have a greatly increased risk of developing UV-
membrane and the release of granule contents. Degranulation induced skin cancers, and those tumors tend to behave more
releases potent prostanoids, histamines, and inflammatory aggressively. 35
cytokines that rapidly recruit inflammatory cells. Nonantigenic Studies have shown that UVR mediates its effects, in part, by
stimuli, such as opiates, C5a, anaphylatoxin, stem cell factor, and perturbing the function of skin APCs. UV-irradiated APCs are
substance P, can activate degranulation through FcR-independent poor stimulators of Th1 cells but are able to activate Tregs, which
opioid, adenosine, and β-adrenergic receptors. The products and promote antigen-specific immunological tolerance. The immu-
contents of mast-cell granules are causative agents of acute nosuppressive effect is mediated, at least in part, through UV-
vasodilatation, edema, pruritus, and rapid influx of leukocytes induced enhanced production of the suppressive cytokine IL-10
and eosinophils into skin. Eosinophils are especially important and reduction of the Th1 activation cytokine IL-12. It may seem
for fighting parasitic infections (Chapter 24). Mast-cell activation surprising that an environmental carcinogen, such as UVR,
is implicated in the pathogenesis of bullous pemphigoid, leuko- suppresses immunological function in skin. One proposed
cytoclastic vasculitis, atopic dermatitis, allergic contact dermatitis, explanation is that altered epithelial proteins are constantly
and mastocytosis (urticaria pigmentosa) and plays a prominent generated by UVR exposure, necessitating chronic induction of
role in the pathogenesis of urticaria and angioedema. immune tolerance to UV-damaged proteins to preserve the
integrity of the skin barrier.
ANTIBODIES AND SKIN The immunosuppressive effect of UVR has been exploited
for therapeutic purposes. UVR phototherapy is used to manage
Less is known regarding B cells in skin. Although the role pathogenic immune responses that cause certain skin diseases,
of IgG, IgA, and IgE antibodies in normal skin homeostasis such as psoriasis and atopic dermatitis. 36