Emma Guttman-Yassky

IL-22–producing “T22” T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17–producing TH17 T cells

BACKGROUNDnPsoriasis and atopic dermatitis (AD) are common inflammatory skin diseases. An upregulated TH17/IL-23 pathway was demonstrated in psoriasis. Although potential involvement of TH17 T cells in AD was suggested during acute disease, the role of these cells in chronic AD remains unclear.nnnOBJECTIVEnTo examine differences in IL-23/TH17 signal between these diseases and establish relative frequencies of T-cell subsets in AD.nnnMETHODSnSkin biopsies and peripheral blood were collected from patients with chronic AD (n = 12) and psoriasis (n = 13). Relative frequencies of CD4+ and CD8+ T-cell subsets within these 2 compartments were examined by intracellular cytokine staining and flow cytometry.nnnRESULTSnIn peripheral blood, no significant difference was found in percentages of different T-cell subsets between these diseases. In contrast, psoriatic skin had significantly increased frequencies of TH1 and TH17 T cells compared with AD, whereas TH2 T cells were significantly elevated in AD. Distinct IL-22-producing CD4+ and CD8+ T-cell populations were significantly increased in AD skin compared with psoriasis. IL-22+CD8+ T-cell frequency correlated with AD disease severity.nnnCONCLUSIONnOur data established that T cells could independently express IL-22 even with low expression levels of IL-17. This argues for a functional specialization of T cells such that T17 and T22 T-cells may drive different features of epidermal pathology in inflammatory skin diseases, including induction of antimicrobial peptides for T17 T cells and epidermal hyperplasia for T22 T-cells. Given the clinical correlation with disease severity, further characterization of T22 T cells is warranted, and may have future therapeutic implications.

Integrative Responses to IL-17 and TNF-α in Human Keratinocytes Account for Key Inflammatory Pathogenic Circuits in Psoriasis

Psoriasis is a complex inflammatory disease mediated by tumor necrosis factor (TNF)-α and cytokines secreted by specialized T-cell populations, e.g., IL-17, IL-22, and IFN-γ. The mechanisms by which innate and adaptive immune cytokines regulate inflammation in psoriasis are not completely understood. We sought to investigate the effects of TNF-α and IL-17 on keratinocyte (KC) gene profile, to identify genes that might be coregulated by these cytokines and determine how synergistically activated genes relate to the psoriasis transcriptome. Primary KCs were stimulated with IL-17 or TNF-α alone, or in combination. KC responses were assessed by gene array analysis, followed by reverse transcriptase-PCR confirmation for significant genes. We identified 160 genes that were synergistically upregulated by IL-17 and TNF-α, and 196 genes in which the two cytokines had at least an additive effect. Synergistically upregulated genes included some of the highest expressed genes in psoriatic skin with an impressive correlation between IL-17/TNF-α-induced genes and the psoriasis gene signature. KCs may be key drivers of pathogenic inflammation in psoriasis through integrating responses to TNF-α and IL-17. Our data predict that psoriasis therapy with either TNF or IL-17 antagonists will produce greater modulation of the synergistic/additive gene set, which consists of the most highly expressed genes in psoriasis skin lesions.

Contrasting pathogenesis of atopic dermatitis and psoriasis—Part I: Clinical and pathologic concepts

Atopic dermatitis and psoriasis are 2 of the most common inflammatory skin diseases. They are similar in that they are complex inherited diseases involving genes that encode immune components and structural proteins that regulate differentiation of epidermal cells. Each disease is characterized by proliferation of epidermal keratinocytes and abnormal cornification or terminal differentiation in the epidermis; skin lesions contain immune infiltrates of T cells, dendritic cells, and other types of leukocytes. We review similarities between the diseases and differences in epidermal barrier defects and immune cells. We also propose mechanisms of pathogenesis based on differences in the balance of immune cell subsets that could cause the phenotypes that distinguish these diseases. The first part of this 2-part review focuses on the clinical and pathologic features of the diseases; the second part discusses differences in immune cell subsets between atopic dermatitis and psoriasis and recentxa0therapeutic strategies.

Contrasting pathogenesis of atopic dermatitis and psoriasis—Part II: Immune cell subsets and therapeutic concepts

Atopic dermatitis (AD) and psoriasis are among the most common inflammatory skin diseases. In the first part of this 2-part review, we discussed the similarities and differences between AD and psoriasis with respect to clinical features and pathology. The diseases are characterized by infiltration of skin lesions by large numbers of inflammatory cells; the second part of this review focuses on immune cell subsets that distinguish each disease and the therapeutic strategies that might be used or developed based on this information. We discuss the interactions among different populations of immune cells that ultimately create the complex inflammatory phenotype of AD and compare these with psoriasis. Therapeutic strategies have been developed for psoriasis based on the cytokine network that promotes inflammation in this disease. Antibodies against IL-12 and IL-23p40 antibody and antagonists of TNF are used to treat patients with psoriasis, and studies are underway to test specific antagonists of IL-23, IL-17, IL-17 receptor, IL-20, and IL-22. We discuss how these therapeutic approaches might be applied to AD.

Nonlesional atopic dermatitis skin is characterized by broad terminal differentiation defects and variable immune abnormalities

BACKGROUNDnAtopic dermatitis (AD) is a common inflammatory skin disease with a T(H)2 and T22 immune polarity. Despite recent data showing a genetic predisposition to epidermal barrier defects in some patients, a fundamental debate still exists regarding the role of barrier abnormalities versus immune responses in initiating the disease. An extensive study of nonlesional AD (ANL) skin is necessary to explore whether there is an intrinsic predisposition to barrier abnormalities, background immune activation, or both in patients with AD.nnnOBJECTIVEnWe sought to characterize ANL skin by determining whether epidermal differentiation and immune abnormalities that characterize lesional AD (AL) skin are also reflected in ANL skin.nnnMETHODSnWe performed genomic and histologic profiling of both ANL and AL skin lesions (n = 12 each) compared with normal human skin (n = 10).nnnRESULTSnWe found that ANL skin is clearly distinct from normal skin with respect to terminal differentiation and some immune abnormalities and that it has a cutaneous expansion of T cells. We also showed that ANL skin has a variable immune phenotype, which is largely determined by disease extent and severity. Whereas broad terminal differentiation abnormalities were largely similar between involved and uninvolved AD skin, perhaps accounting for the background skin phenotype, increased expression of immune-related genes was among the most obvious differences between AL and ANL skin, potentially reflecting the clinical disease phenotype.nnnCONCLUSIONnOur study implies that systemic immune activation might play a role in alteration of the normal epidermal phenotype, as suggested by the high correlation in expression of immune genes in ANL skin with the disease severity index.

Broad defects in epidermal cornification in atopic dermatitis identified through genomic analysis

BACKGROUNDnPsoriasis and atopic dermatitis (AD) are common, complex inflammatory skin diseases. Both diseases display immune infiltrates in lesions and epidermal growth/differentiation alterations associated with a defective skin barrier. An incomplete understanding of differences between these diseases makes it difficult to compare human disease pathology to animal disease models.nnnOBJECTIVEnTo characterize differences between these diseases in expression of genes related to epidermal growth/differentiation and inflammatory circuits.nnnMETHODSnWe performed genomic profiling of mRNA in chronic psoriasis (n = 15) and AD (n = 18) skin lesions compared with normal human skin (n = 15).nnnRESULTSnAs expected, clear disease classifications could be constructed on the basis of expected immune polarity (T(H)1, T(H)2, T(H)17) differences. However, even more striking differences were identified in epidermal differentiation programs that could be used for precise disease classifications. Although both psoriasis and AD skin lesions displayed regenerative epidermal hyperplasia, which is a general alteration in epidermal growth, keratinocyte terminal differentiation was differentially polarized. In AD, we found selective defects in expression of multiple genes encoding the cornified envelope, with the largest alteration in loricrin (expressed at 2% of the level of normal skin). At the ultrastructural level, the cornified envelope in AD was broadly defective with highly decreased compaction of corneocytes and reduced intercellular lipids. Hence, the entire keratinocyte terminal differentiation program (cytoplasmic compaction, cornification, and lipid release) is defective in AD, potentially underlying the immune differences.nnnCONCLUSIONnOur study shows that although alterations in barrier responses exist in both diseases, epidermal differentiation is differentially polarized, with major implications for primary disease pathogenesis.

Reversal of atopic dermatitis with narrow-band UVB phototherapy and biomarkers for therapeutic response.

BACKGROUNDnAtopic dermatitis (AD) is a common inflammatory skin disease exhibiting a predominantly T(H)2/T22 immune activation and a defective epidermal barrier. Narrow-band UVB (NB-UVB) is considered an efficient treatment for moderate-to-severe AD. In patients with psoriasis, NB-UVB has been found to suppress T(H)1/T(H)17 polarization, with subsequent reversal of epidermal hyperplasia. The immunomodulatory effects of this treatment are largely unknown in patients with AD.nnnOBJECTIVEnWe sought to evaluate the effects of NB-UVB on immune and barrier abnormalities in patients with AD, aiming to establish reversibility of disease and biomarkers of therapeutic response.nnnMETHODSnTwelve patients with moderate-to-severe chronic AD received NB-UVB phototherapy 3 times weekly for up to 12 weeks. Lesional and nonlesional skin biopsy specimens were obtained before and after treatment and evaluated by using gene expression and immunohistochemistry studies.nnnRESULTSnAll patients had at least a 50% reduction in SCORAD index scores with NB-UVB phototherapy. The T(H)2, T22, and T(H)1 immune pathways were suppressed, and measures of epidermal hyperplasia and differentiation normalized. The reversal of disease activity was associated with elimination of inflammatory leukocytes and T(H)2/T22- associated cytokines and chemokines and normalized expression of barrier proteins.nnnCONCLUSIONSnOur study shows that resolution of clinical disease in patients with chronic AD is accompanied by reversal of both the epidermal defects and the underlying immune activation. We have defined a set of biomarkers of disease response that associate resolved T(H)2 and T22 inflammation in patients with chronic AD with reversal of barrier pathology. By showing reversal of the AD epidermal phenotype with a broad immune-targeted therapy, our data argue against a fixed genetic phenotype.

Characterisation of the cutaneous pathology in non-small cell lung cancer (NSCLC) patients treated with the EGFR tyrosine kinase inhibitor erlotinib

INTRODUCTIONnEGFR inhibitors (EGFRIs) have been shown to be clinically effective in various cancers. Unique skin toxicity is commonly observed with EGFRIs and a correlation between the clinical benefit of EGFRIs and this characteristic rash has been reported. Erlotinib is a potent EGFRI approved for treatment of non-small cell lung cancer (NSCLC) and pancreatic cancer.nnnMETHODSnThis is the first time in which patients were given increasing doses of an EGFRI to induce a mechanistic rash and study its associated pathology in skin. Biopsies were collected during treatment from both rash-affected and unaffected skin of 23 NSCLC patients and compared with pre-treatment biopsies.nnnRESULTSnAltered differentiation of appendegeal epithelium (hair follicles and sebaceous glands) was remarkable in both affected and unaffected skin, although epidermal growth was not significantly reduced. A predominantly mononuclear leucocyte infiltrate was detected in the interfollicular dermis or around skin appendages. This infiltrate included TRAIL-positive cells with a dendritic cell (DC) morphology, although T-cells, antigen-presenting DCs and macrophages were also evident. This is the first report showing the involvement of a dendritic cell subtype with EGFRI skin toxicity.nnnCONCLUSIONSnAltered differentiation of pilosebaceous epithelium is evident in both rash-affected and unaffected skin and constitutes the primary process of EGFRI in human skin. We propose that this eventually triggers inflammation and the EGFRI rash. TRAIL-positive inflammatory cells could link rash development and immune-triggered apoptosis of epithelial cells, including those of underlying carcinomas.

Psoriasis Treatments: A Review of the Current Research Pipeline

Psoriasis treatment is aimed at suppressing skin lesions and preventing relapses. Although in the last decade biological therapies have revolutionized the pharmacologic treatment armamentarium for psoriasis, many patients are still inadequately controlled with currently available therapeutics. An advanced understanding of the immunopathogensis of psoriasis has led to development of new drugs that refine existing treatments or target novel molecular and immunologic pathways. Here we review the most promising topical, oral, and injectable psoriasis treatments in the research pipeline, including agents that target cytokines interleukin (IL)-12/23, tumor necrosis factor-α, IL-20, IL-17, IL-22, inhibitors of calcineurin, phosphodiesterase type 4, protein kinase C, Janus kinase, p38 kinase, purine nucleotide phosphorylase, adenosine receptor agonists, and recombinant chaperonin protein. These targeted therapeutics offer the potential for greater clinical efficacy and less toxicity than traditional agents. As the number of treatment options continues to expand, clinicians will have more diverse opportunities to help patients achieve better psoriasis control.

Cytokine Targeted Therapeutics for Alopecia Areata: Lessons from Atopic Dermatitis and Other Inflammatory Skin Diseases

Alopecia areata is a T-cell-mediated disease that shares phenotypic similarities with other inflammatory diseases, particularly atopic dermatitis, and lacks safe, effective, mechanism-specific treatments. Increasing data suggests that alopecia areata harbors contributions of T helper type 1, T helper type 2, T helper type 17/IL-23, and phosphodiesterase pathways. Antagonism of these axes is undergoing evaluation, and might elucidate the underlying molecular circuitry of alopecia areata, advancing the translational revolution for this disease.