Page 906 - Clinical Immunology_ Principles and Practice ( PDFDrive )

876 Part SEVEN Organ-Specific Inflammatory Disease

high levels of tumor necrosis factor (TNF)-α and the enzyme of T cells shows that these are mainly activated memory T cells
inducible nitric oxide synthase (iNOS) and can be considered expressing HLA-DR, CD25, CD27, and cutaneous lymphocyte
the human equivalent of TIP-DC (TNF-α and iNOS-producing antigen (CLA). Although there is differential T-cell receptor usage
DCs), which have been shown in mice to have effector functions in T cells from psoriatic skin, the causative antigens responsible
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in clearing some bacterial infections. The proinflammatory for T-cell activation in psoriasis remain unknown. Exposure of
nature of TNF-α in psoriasis and other inflammatory diseases altered autoantigens from keratinocytes could be responsible
is well established, and the receptors TNFR1 and TNFRII are for the activation and expansion of distinct T-cell subpopulations
expressed on a wide range of cells in psoriatic skin, including in psoriatic skin. These autoantigens may include keratin 17
keratinocytes and endothelial cells. TNF-α induces expression of (patients with active psoriasis have an increased frequency of
ICAM-1 on keratinocytes, facilitating the adhesion of circulating circulating Th1 cells reacting to peptides from keratin 17) and
leukocytes. Moreover, TNF-α can stimulate keratinocytes and corneodesmosin, an attractive candidate for psoriasis susceptibility
dermal fibroblasts to produce the potent neutrophil chemoat- based on its putative biological function in keratinocyte adhe-
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tractant CXCL8, as well as the proinflammatory cytokines IL-6 sion. Keratinocytes could also be responsible for the activation
and IL-1, which help generate and maintain Th17 cells (Chapters of pathogenetic T cells by viral or bacterial products. For example,
10 and 16). The role of TNF-α in psoriasis is underlined by the human papillomavirus 5 (HPV-5) DNA and antibodies to HPV-5
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therapeutic success of anti–TNF-α therapies in psoriasis. In virus-like particles have been found in psoriasis. Streptococcal
addition, polymorphisms of the TNF-α promoter region have infections are also frequently associated with psoriasis, and
been associated with psoriasis. However, iNOS production by streptococcal superantigens could be presented to T cells by
inflammatory DCs leads to nitric oxide (NO) release, inducing binding to MHC class II molecules expressed by lesional kera-
vasodilation, inflammation, and antimicrobial effects in psori- tinocytes. Putative psoriatic antigens are assumed to be kerati-
atic skin. Interestingly, NO inhibitors (e.g., statins) can have a nocyte proteins that might share structural homology with
beneficial effect on psoriasis, although this has not been studied streptococcal proteins and might thereby induce cross-reactive
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in a randomized prospective manner. Inflammatory DCs also T-cell responses against skin components. Recently, it has been
produce other cytokines (Chapter 9) (e.g., IL-23 and -12), which found that two-thirds of patients with moderate-to-severe plaque
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are linked to psoriasis. IL-12 mainly induces IFN-γ production, psoriasis harbor CD4 and/or CD8 T cells specific for LL-37.
whereas IL-23 also stimulates IL-17 and IL-22 release by T cells, LL37-specific T cells produce IFN-γ, and CD4 T cells also produce
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as shown in mice. Other evidence for a role of IL-23 in psoriasis Th17 cytokines. LL37-specific T cells can infiltrate lesional skin
includes the clinical efficacy of an anti-p40 monoclonal antibody and can be tracked in patients’ blood. The presence of circulating
(mAb) against psoriasis and the association of a single nucleotide LL37-specific T cells correlates significantly with disease activity,
polymorphism in the IL-23R gene in psoriasis patients. mDCs of suggesting a contribution to disease pathogenesis.
psoriatic lesions also release the proinflammatory cytokine IL-15, T-cell migration from the dermis into the epidermis is a key
which induces T-cell proliferation and monocyte activation, as well event in psoriasis. It is controlled by the interaction of α 1 β 1
as skin hyperplasia by protecting keratinocytes from apoptosis. integrin (very late antigen 1) on T cells with collagen IV in the
Another population of inflammatory mDCs, defined by the basement membrane of the epidermis. Blockade of this interaction
selective expression of the 6-sulfo LacNAc residue on the P-selectin inhibits the development of psoriasis in clinically relevant models.
glycoprotein ligand 1 membrane molecule, has been identified Based on the analysis of infiltrating cell types, their secreted
+
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in psoriatic skin. 6-Sulfo LacNAc DCs (slanDCs) have a well- products, and genetic signatures present in lesional skin, psoriasis
−
+
−
+
defined phenotype (CD1c , CD11c , CD16 , CD14 ) that clearly has been considered for many years as a type-1 (i.e., Th1)–medi-
+
+
+
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distinguishes them from classic CD1c blood DC (CD1c , CD11c ) ated reaction, with IFN-γ playing a prominent role. Consistent
or pDC (BDCA-2, BDCA-4). SlanDCs produce more TNF-α, with a Th1 pattern of response, CCR10 is preferentially expressed
+
IL-23, IL-12, IL-1β, and IL-6 and can thus induce Th1/Th17 by skin homing CLA memory T cells, which secrete TNF-α and
cells. SlanDCs also reinforce innate immunity in psoriasis by IFN-γ, but minimal amounts of IL-10 and IL-4, upon activation.
interacting with and potentiating the activity of neutrophils and However, other cytokines and T-cell subsets have also been
NK cells. 17 identified during inflammatory responses in psoriasis. These
The function of another DC subset, the Langerhans cell, is include Th17 and Th22 cells, which produce large amounts of
still controversial. Langerhans cells are only found in the epidermal IL-17 and IL-22, cytokines that have relevant effects on epithelial
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compartment where they are similar in number and phenotype cells. Keratinocytes are strongly influenced by IL-17 and
in lesional and nonlesional skin, but they fail to migrate in upregulate chemokines and immunomodulatory molecules in
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response to proinflammatory stimuli (Chapter 19). These response to this cytokine. A functional role of Th17 cells, and
findings and data from Langerhans cell ablation models suggest also Tc17 cells, in psoriasis is suggested by their reduction during
that Langerhans cells may help sustain immune tolerance in successful anti–TNF-α treatment or via blockade with neutralizing
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psoriasis. In psoriatic skin, the epidermis contains an additional mAb in a clinically relevant xenotransplantation mouse model.
DC subset, known as inflammatory dendritic epidermal cells and IL-22 also acts pathogenetically in psoriatic skin by inducing
are distinguishable from Langerhans cells by the expression of proliferation and de-differentiation of keratinocytes, as well as
the macrophage mannose receptor CD206. promoting their production of antimicrobial peptides and
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chemokines, including CXCL8 and CXCL1. Binding of IL-22
Activation of T Lymphocytes and Establishment of the to its receptor, whose expression in the skin is confined to
Cytokine Milieu Influencing Keratinocyte Proliferation keratinocytes, mediates epidermal acanthosis through the activa-
tion of STAT3. These observations may explain the increased
and Immune Functions STAT3 expression in the epidermal compartment and the
Psoriasis lesional skin shows many inflammatory T cells in both pathogenicity of STAT3 overexpression in the epidermis of
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the papillary dermis and the epidermis. Immunophenotyping transgenic mice (see below). The demonstration that T cells