Page 295 - Clinical Immunology_ Principles and Practice ( PDFDrive )

276 ParT TwO Host Defense Mechanisms and Inflammation

9
patterns (PAMPs) and danger-associated molecular patterns immune response that is generated. They are also important in
(DAMPs) is principally undertaken by an array of PPRs. Membrane- driving nonimmunological processes, such as activating systemic
bound Toll-like receptors (TLRs) are present at the cell surface (TLRs responses to injury, wound healing, carcinogenesis, and pigmenta-
1, 2, 4–6) and intracellular endosomes (TLRs 3, 7–9). Also present tion. Production of these mediators in skin involve several different
are cytosolic nucleotide-binding domain, leucine-rich repeat contain- cell types and environmental stimuli.
6
ing receptors (NLRs) (formerly termed NOD-like receptors). TLR Keratinocytes produce a variety of immune mediators during
and NLR expression profiles are differentially expressed (often with different phases of immune reactions: proinflammatory cytokines
partial overlap) on epidermal and leukocyte cell subsets. IL-1, IL-6, IL-33, and tumor necrosis factor-α (TNF-α); immu-
Of the 10 TLRs that humans express, messenger RNA (mRNA) nosuppressive and antiinflammatory cytokines IL-10, TGF-αβ,
for all have been detected in keratinocytes. However, receptor proteins and IL-1 receptor antagonist (IL-1RA); colony-stimulating factors
6
and activities have been detected for only eight (TLR1-7 and 9). GM-CSF, G-CSF, and M-CSF; immunomodulatory cytokines
Human melanocytes constitutively express mRNA for TLRs 1–4, IL-7, IL-12, IL-15, IL-18, IL-19, IL-20, and IL-23; and chemokines
6, 7, and 9, and abundant functional protein is detected for TLRs CXCL8/IL-8, CCL2/MCP-1, CCL20/MIP3α, and CCL5/RANTES.
2–4, 7, and 9. Human and murine DC subsets also show differential LCs produce IL-1αβ, IL-12, and IL-23, CCL3/MIP1α, CCL4/
TLR expression profiles. For example, conventional DCs (DCs) MIP1αβ, and CCL5/RANTES. Melanocytes produce cytokines
express combinations of TLRs 1–5 and 8, whereas TLR expression IL-1β, IL-6, IL-8, TNF-αα, type I interferons (IFN-αα and IFN-β),
is restricted to virus-detecting endosomal TLRs 7 and 9 in plas- and chemokines CCL2, CCL3, and CCL5.
macytoid DCs (pDCs). The latter is consistent with their primary Although cytokines and chemokines produced in skin are
function as major interferon-α (IFN-α) producers. functionally identical to those secreted by nonskin cells, in skin
NLRs have over 20 members in humans and over 30 in mice, they can have unique effects. For example, IL-1 can remodel the
reflecting the broad spectrum of PAMPs and DAMPs they can dermis by inducing MMP production and augmenting collagen
recognize. Structurally, NLRs can be divided into four subfamilies: production. Mutant forms of cytokines can also cause cutaneous
(i) NOD, caspase recruitment domain (CARD)-containing NLRCs; diseases. For example, a deficiency of IL-1–receptor antagonist
(ii) NALP, pyrin domain (PYD)-containing NLRPs; (iii) NLRB, (DIRA) is associated with a mutation in the gene that encodes
NLR apoptosis inhibitory protein NAIP; and (iv) NLRA, the the IL-1–receptor antagonist. This mutation can cause severe
transcription factor CIITA. Primary human keratinocytes express pustulosis, ichthyosiform lesions, psoriasis-like changes, and nail
7
mRNA transcripts for 11 of 14 NALP family genes. NOD1 is abnormalities. 10
expressed in many tissues, including skin keratinocytes. NLRs
act independently, but in synergy with TLR signals, to trigger Phases of Active Cutaneous Cytokine Secretion
fast-acting potent innate immune responses against microbes. In response to immunological and inflammatory stimuli,
They can either promote nuclear factor-κB (NF-κB) activation keratinocytes produce different sets of immune mediators in three
or form inflammasomes that generate interleukin-1 (IL-1) family sequential phases: initiation, amplification, and resolution.
proinflammatory mediators. Initiation. The initial set of cytokines that are generated include
TLR ligands are derived from conserved microbial products, proinflammatory IL-1, IL-6, TNF-α, and many others. Keratin-
such as lipopolysaccharides (LPS) from gram-negative bacteria, ocytes constitutively produce a pool of inactive proinflammatory
lipoteichoic acid and peptidoglycans from gram-positive bacteria, precursors: pro–IL-1α, pro–IL-1β, and pro–IL-18. These molecules
mannans of yeast and fungi, and nucleic acids from viral and can be immediately processed into active mediators by inflam-
7
bacterial pathogens. Endogenous DNA derived from stressed masomes, which are rapidly formed in the presence of DAMPs.
host cells can be recognized by TLRs. DAMPs are recognized by IL-1β, a potent stimulator of endothelial cell activation, permits
NLRs. The set of TLRs and NLRs that are triggered determines rapid infiltration of inflammatory leukocytes and T cells from
what types of immunomodulatory or inflammatory responses blood into the dermis. TNF-α contributes to dermal microvascular
will be elaborated. Acting as adjuvants, they can also influence endothelial cell activation and augments expression of ICAM-1
the magnitude of the response. In the clinic, a drug known as a (CD54) on keratinocytes and endothelial cells. Infiltrating T
TLR7 agonist (imiquimod) is used as an effective topical agent cells express the β 2 integrin molecule leukocyte function–associated
for eliminating human papillomavirus (HPV)–induced genital antigen-1 (LFA-1), which binds to ICAM-1 expressed on affected
warts and nonmelanoma skin tumors. dermal and epidermal layers. IL-6 helps drive the development
Keratinocytes, DCs, and monocytes also express the PRR of IL-17–producing Th-17 cells. IL-6 can also perpetuate chronic
dectin-1. Dectin-1 is a membrane-associated glycoprotein that inflammation.
recognizes β-glucan, a polysaccharide component of several species Amplification. Activated keratinocytes respond to the first
of fungi. Dectin-1 activation results in the production of IL-1β, wave of proinflammatory mediators by generating of a second
IL-6, and IL-23 (Chapter 9), which promotes the development set of cytokines and chemokines (including GM-CSF, TNF-α,
of T-helper type 17 (Th17) cells—important antifungal effector and CXCL8/IL-8) with autocrine and paracrine effects. They
cells (Chapter 16). Patients lacking dectin-1 exhibit Th17-cell can activate unaffected neighboring keratinocytes to amplify
deficiency, which leads to recurrent vulvovaginal Candida albicans proinflammatory signals. These cytokines are key to triggering
5
infections and onychomycosis (Chapter 29). Mutations in Card9, adaptive immune responses by activating cutaneous LCs and
a mediator of dectin-1 signal transduction, also lead to a Th17 DCs to become mature potent antigen-presenting cells (APCs).
deficiency associated with chronic mucocutaneous candidiasis. 8 APC interaction with antigen-specific, skin-resident memory T
cells stimulates the proliferation and expansion of differentiated
Cutaneous Production of Cytokines and Chemokines effector T cells at the affected skin site. Keratinocyte-derived
Types of Cytokines and Chemokines IL-8 is a potent chemoattractant for neutrophils. The influx of
Skin is a rich source of cytokines (Chapter 9) and chemokines leukocytes further amplify local immune responses, inflammation,
(Chapter 10) that influence the magnitude and type of cutaneous and associated tissue damage. Stimulation of TLRs 7 and 9 within