Page 907 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPtEr 64 Immunology of Psoriasis 877

are the primary regulators of keratinocyte proliferation and response in the pathogenesis of psoriasis. Within psoriatic lesions,
differentiation in psoriasis came from studies showing that alterations are observed in the levels of expression of several
supernatants from lesional skin-derived T cells transformed growth factors, such as insulin-like growth factor, keratinocyte
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β-integrin keratin 1/keratin 10 PCNA stem cells of patients growth factor (KGF), transforming growth factor (TGF)-α, and
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with psoriasis, but not stem cells of healthy subjects, into PCNA amphiregulin, all of which stimulate basal cell proliferation in
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active cycling cells. T cell–derived supernatants contained high an autocrine fashion. Other cytokines aberrantly elevated in
levels of granulocyte macrophage–colony-stimulating factor psoriasis include members of the inhibitory TGF-β family, and
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(GM-CSF) and IFN-γ, and low levels of IL-3 and TNF-α. cytokines that stimulate keratinocyte proliferation and inflam-
However, among these cytokines, only IFN-γ affects the prolifera- mation, such as IL-19 and IL-20. 22,24 An important pathogenic
tion of psoriatic stem cells. In vivo, IFN-γ injection into prelesional role has also been uncovered for IL-36γ, a cytokine abundantly
psoriatic skin triggers keratinocyte proliferation and plaque induced by IL-17 in keratinocytes, whose overexpression in mouse
development. Considering that IFN-γ is an antiproliferative skin leads to a disease quite similar to human plaque psoriasis,
cytokine and an inducer of squamous differentiation, these latter whereas inhibition in human psoriatic skin ameliorates the
findings are paradoxical. This discrepancy may reflect an intrinsic inflammation. 29
defect in the response of psoriatic keratinocytes to IFN-γ, and/ Finally, two anti-inflammatory molecules, suppressors of
or altered localization and expression of the IFN-γ receptor cytokine signaling (SOCS)1 and SOCS3, are dysregulated in
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complex in the epidermis of psoriatic skin. psoriatic keratinocytes. These efficiently suppress the IFN-γ– and
Another T cell–derived cytokine that has been shown to TNF-α–dependent molecular cascades in keratinocytes, and it
regulate keratinocyte proliferation in psoriatic skin is IL-21, which has been hypothesized that strengthening of the action of SOCS1
is mainly released by CD4 T cells and natural killer T cells (NKT in keratinocytes could be a valid therapeutic approach for treat-
cells). IL-21 contributes to epidermal hyperplasia, and neutraliza- ment of IFN-γ- and TNF-α-dependent skin diseases, including
tion of IL-21 reduces both skin thickening and expression of psoriasis.
inflammatory molecules. Interestingly, IFN-γ is necessary for
IL-21–induced epidermal hyperplasia, while abrogation of IL-21 ON tHE HOrIZON
signals reduces IFN-γ expression in psoriatic T cells. 22,24
Finally, the importance of T regulatory (Treg) lymphocytes There have been significant advances in therapies for psoriasis during
the past 15 years that strongly reduce both symptoms and relapse
(Chapter 18) in psoriasis has been examined in the peripheral rates. New therapeutic approaches include the targeting of interleukin
blood and the inflamed skin of patients. The number of Treg (IL)-17A.
cells (defined by expression of the transcription factor FOXP3) Personalized therapies based on the employment of antagonists aligned
is increased in the peripheral blood of individuals with psoriasis, with elements of genetic risk of the patients will be likely more
and this increase is positively correlated with the disease activity successful.
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index. CD4 CD25 FOXP3 Treg cells are also present in psoriatic Newer strategies will also need to focus on treatments that do not
require continuous, long-term immune suppression (i.e., strategies to
lesions, with more in lesional skin biopsy specimens than those restore immune regulation or tolerance).
from control or uninvolved skin. However, these Treg cells may Future work to identify and clarify risk factors and antigenic triggers for
be less functional in that Treg cells from both the peripheral psoriasis may lead to strategies for preventing the disease.
blood and psoriatic skin lesions showed reduced ability to suppress
effector T cells. This impairment may be dependent on IL-6 as CONCLUSIONS
blockade of IL-6 reversed the impairment in suppression observed
in cocultures of Treg cells and effector T cells from patients with A complex interplay between environmental and genetic factors
psoriasis. triggers a cascade of events that leads to the expression of psoriasis.
Early upstream events occurring in the disease include activation
Intrinsic Defects of Keratinocytes Are Fundamental for of DCs and the generation of effector T cells that migrate into
the psoriatic skin lesions and expand there. Cross-talk between
the Amplification of Psoriatic Processes keratinocytes and immune cells amplifies inflammation and is
Endogenous defects in keratinocytes may be pathogenically responsible for chronicity. Recent research has implicated many
relevant for psoriasis, as shown in mice with engineered epidermal immunological mechanisms in psoriasis progression, and this
phenotypes. Transgenic animals that overexpress the transcription has led to the development of new, pathogenesis-based therapies.
factor STAT3 or that lack the inhibitor of NF-κB kinase-2 (IKK-2) Although this progress is remarkable, much remains unknown,
in their epidermis develop skin lesions that closely resemble especially regarding prevention of the condition and how to
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human psoriasis. Similarly, the abrogation of JunB in kerati- develop drugs with appropriate risk-benefit and long-term
nocytes triggers a skin phenotype with the histological features profiles. Future work must take into account these aspects to
of psoriasis, including marked hyperplasia of the epidermis and establish therapeutic and preventive approaches that lead to
dense dermal inflammatory cell infiltrates. The hyperplasia improved patient outcomes.
observed in these models may, in part, depend on overexpression
of S100A8 and S100A9, two antimicrobial peptides with che- Please check your eBook at https://expertconsult.inkling.com/
motactic activity and a recognized role in keratinocyte maturation for self-assessment questions. See inside cover for registration
and proliferation. The development of psoriatic lesions in mice details.
with an epidermal deletion of STAT3 depends on the presence
of activated T cells, whereas the inflammatory responses occurring REFERENCES
in the skin of IKK2-transgenic mice are mediated by TNF-α.
This implicates an intrinsically dysregulated interrelation between 1. Griffiths CE, Barker JN. Pathogenesis and clinical features of psoriasis.
keratinocytes and cells of both the innate and acquired immune Lancet 2007;370:263–71.