Page 905 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 64 Immunology of Psoriasis 875

Plasmacytoid DCs as Inducers of Primary Immune suggests a fundamental role for LL-37 in alerting resident skin
Responses in Psoriasis pDCs of tissue damage associated with cell death and the release
pDCs are characterized by a plasma cell morphology and a of self-DNA. pDCs are typically absent in unperturbed skin and
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distinctive surface phenotype (CD4 , CD45RA , CD123 , peripheral tissues under homeostatic conditions but can enter
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BDCA-2 , BDCA-4 , CD62L , cutaneous lymphocyte-associated secondary lymphoid organs through the expression of CD62L
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antigen (CLA) , and CD11c ). They are considered as key effector and chemokine receptors (CXCR4, CXCR3, CCR5, and ChemR23).
cells in antiviral defense because of their ability to produce large pDCs can also infiltrate inflamed tissue of immune-mediated
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amounts of type I IFN. Upon viral stimulation, pDCs differentiate skin diseases, and, in particular, accumulate in the skin of patients
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into a unique type of mature DC and induce an IFN-α–dependent with psoriasis early during disease development. Many studies
activation of bystander mDCs with the ability to induce Th1- have shown an evident IFN-α signature (e.g., increased expression
responses (Chapter 16), thus providing a necessary link between of IRF7 and the presence of MxA, markers for IFN-α activity)
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innate and adaptive immunity. Several studies have demonstrated in primary psoriatic plaques in the absence of detectable levels
that pDCs infiltrate psoriatic skin, and that pDC-derived IFN-α of the IFN-α cytokine. Indeed, IFN-α expression was detected
initiates the expansion of autoimmune T cells, leading eventually early and transiently during the development of the psoriatic
to the skin lesions of psoriasis. 6,7,9,10 Blocking of type I IFN signal- phenotype, and its effect persisted until lesions became chronic.
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ing with neutralizing antibodies to IFN-α/β receptors inhibited Paralleling IFN-α expression, BDCA-2 pDCs were detected only
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the development of psoriasis in symptomless pre-psoriatic skin during the early developmental stages of psoriasis. In fact, pDC
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engrafted onto immunodeficient AGR129 mice. Moreover, infiltration in psoriatic skin correlates with the expression of
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inhibition of IFN-α release by pDCs through anti–BDCA-2 markers typical of early phases of psoriasis (CD15 neutrophils
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antibody prevented the activation and expansion of pathogenetic and c-kit mast cells localized in the mid- and papillary dermis,
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T cells and the development of a psoriatic phenotype. The detailed and few CD8 T lymphocytes or ICAM-1 keratinocytes), whereas
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mechanisms responsible for the IFN-α-induced expansion of T they are almost absent in long-lasting lesions. Importantly,
cells in psoriasis are currently unknown, but it appears that pDC recruitment in psoriatic skin is strictly associated with the
IFN-α favors cross-presentation of sequestered tissue-specific expression of the chemokine chemerin, which is temporally
autoantigens by mDCs. pDC-derived IFN-α may also enhance produced by dermal fibroblasts and active during psoriatic plaque
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the survival of autoreactive T cells through the induction of development. pDC migration toward fibroblast-derived chemerin
IL-15 or by promoting a Th1 cell bias through the induction of is completely dependent on the expression of ChemR23 receptor
T-bet and IL-12Rβ 2 expression. The pathogenetic role of IFN-α on pDC. Compared with other chemokines potentially active
is also suggested by the observations that its signaling signature on pDC (CXCL10 and CXCL12), chemerin is the main, if not
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is present in resident skin cells of psoriatic plaques and that the only, protein responsible for the pDC chemotactic activity
psoriasis is exacerbated if patients with psoriasis are treated with released by fibroblasts in psoriatic skin. 9
recombinant IFN-α for unrelated conditions (i.e., viral infections
or tumors), or with imiquimod, a Toll-like receptor (TLR) agonist DC Driving of T-Cell Responses in Psoriatic Skin
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that induces production of IFN-α by pDCs. In addition, excessive Although pDCs are responsible for triggering psoriasis, mDCs
activation of type I IFN signaling in mice deficient for IFN are the main amplifiers of local inflammation. Dermal mDCs are
regulatory factor (IRF)-2, a transcriptional repressor of IFN dramatically increased in psoriasis, and targeted immunotherapy
signaling, causes an inflammatory skin disease resembling reduces their quantity in patients with psoriasis, supporting the
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psoriasis. Recently, a genome-wide analysis conducted on paired concept that mDCs have a key pathogenetic role. Dermal mDCs
lesional and nonlesional psoriatic skin and on the skin of healthy are found at the dermal–epidermal junction as well as throughout
donors revealed a significant overexpression of many components the whole dermis. mDCs are able to capture extracellular antigens
of the IFN-α pathway in patients with psoriasis, including the for presentation to T cells and also intracellular antigens from
receptor subunits for type I IFN, IFN-AR1, and IFN-AR2, the adjacent cell types via cross-presentation (Chapter 6). In addi-
transcriptional activators of IFN-α-inducible genes, signal tion, mDCs within psoriatic lesions are intrinsically stronger
transducer and activator of transcription (STAT) 1, IRF1, and stimulators of T-cell proliferation compared with DCs derived
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IRF7. All of these molecules are master regulators of IFN-α- from peripheral blood or from the skin of healthy patients. mDCs
mediated immune responses. uniformly express CD11c, and they can be further subdivided on
The molecular mechanisms leading pDCs to produce type I the basis of expression of CD1c (BDCA-1). Steady-state skin has
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IFN involve the activation of TLR7 and TLR9, intracellular a predominance of CD11c CD1c resident DCs, whereas CD11c
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receptors that recognize viral/microbial nucleic acids within CD1c mDCs predominate in psoriatic inflammation. A small
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endosomal compartments. pDCs do not normally respond to fraction of CD11c CD1c DC bears “maturation” markers, such
self-DNA, but this restriction breaks down in some human as DC-LAMP, CD83, and endocytic receptor DEC-205/CD205,
autoimmune diseases. In psoriatic skin, pDCs can be activated suggesting that they could function as conventional DCs and
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to produce massive amounts of type I IFN in response to extracel- present antigens to T cells to trigger acquired immune responses.
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lular self-DNA fragments. However, this process requires the These rare, phenotypically mature cells, often aggregating in
coupling of self-DNA to the endogenous antimicrobial peptide dermal clusters, could be required for rapid antigen presentation
LL-37, known to be overexpressed in psoriatic skin. LL-37 breaks to local T cells or for ongoing “micro-” immune responses. During
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innate tolerance to self-DNA by forming aggregated and con- psoriasis development, dermal CD11c DC mature and acquire a
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densed structures that can trigger a robust IFN-α induction via CD1c HLA-DR CD45 CD14 DC-specific ICAM-3–grabbing
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TLR9 activation. LL-37 can also form complexes with RNA nonintegrin (DC-SIGN) phenotype. These inflammatory mDCs
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and activate pDCs through TLR7. In parallel, LL-37/RNA can are CCR7 and respond to the chemokine CCL19, suggesting
alert myeloid DCs through their TLR8, driving T-cell activation that they may migrate to draining lymph nodes for antigen
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and production of cytokines found in psoriasis. This finding presentation. CD11c CD1c inflammatory DC express very