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International Journal of Molecular... Jul 2021We studied CD34+ stromal cells/telocytes (CD34+SCs/TCs) in pathologic skin, after briefly examining them in normal conditions. We confirm previous studies by other... (Review)
Review
We studied CD34+ stromal cells/telocytes (CD34+SCs/TCs) in pathologic skin, after briefly examining them in normal conditions. We confirm previous studies by other authors in the normal dermis regarding CD34+SC/TC characteristics and distribution around vessels, nerves and cutaneous annexes, highlighting their practical absence in the papillary dermis and presence in the bulge region of perifollicular groups of very small CD34+ stromal cells. In non-tumoral skin pathology, we studied examples of the principal histologic patterns in which CD34+SCs/TCs have (1) a fundamental pathophysiological role, including (a) fibrosing/sclerosing diseases, such as systemic sclerosis, with loss of CD34+SCs/TCs and presence of stromal cells co-expressing CD34 and αSMA, and (b) metabolic degenerative processes, including basophilic degeneration of collagen, with stromal cells/telocytes in close association with degenerative fibrils, and cutaneous myxoid cysts with spindle-shaped, stellate and bulky vacuolated CD34+ stromal cells, and (2) a secondary reactive role, encompassing dermatitis-e.g., interface (erythema multiforme), acantholytic (pemphigus, Hailey-Hailey disease), lichenoid (lichen planus), subepidermal vesicular (bullous pemphigoid), psoriasiform (psoriasis), granulomatous (granuloma annulare)-vasculitis (leukocytoclastic and lymphocytic vasculitis), folliculitis, perifolliculitis and inflammation of the sweat and sebaceous glands (perifolliculitis and rosacea) and infectious dermatitis (verruca vulgaris). In skin tumor and tumor-like conditions, we studied examples of those in which CD34+ stromal cells are (1) the neoplastic component (dermatofibrosarcoma protuberans, sclerotic fibroma and solitary fibrous tumor), (2) a neoplastic component with varying presentation (fibroepithelial polyp and superficial myxofibrosarcoma) and (3) a reactive component in other tumor/tumor-like cell lines, such as those deriving from vessel periendothelial cells (myopericytoma), epithelial cells (trichoepithelioma, nevus sebaceous of Jadassohn and seborrheic keratosis), Merkel cells (Merkel cell carcinoma), melanocytes (dermal melanocytic nevi) and Schwann cells (neurofibroma and granular cell tumor).
Topics: Animals; Antigens, CD34; Dermatitis; Dermis; Humans; Neoplasm Proteins; Skin Neoplasms; Telocytes
PubMed: 34298962
DOI: 10.3390/ijms22147342 -
Clinical and Experimental Dermatology Jan 2021While the majority of children with a chronic itchy rash suffer from atopic dermatitis (AD) and other forms of dermatitis, psoriasis is in the differential diagnosis....
BACKGROUND
While the majority of children with a chronic itchy rash suffer from atopic dermatitis (AD) and other forms of dermatitis, psoriasis is in the differential diagnosis. Certain patterns such as guttate and napkin psoriasis are accepted as classic paediatric psoriasis (PP); however, there are many patients who do not fit these classic forms of PP nor fulfil the accepted criteria for AD. 'Psoriasiform dermatitis' (PD) is a term that has been used for these patients; however, it has not been formally defined. Identification of this group of patients, who although not having the typical clinical features of psoriasis, respond well to psoriasis-specific treatment, may assist treatment decisions for these patients.
AIM
To describe PD and compare it with typical PP.
METHODS
Patients with classic PP (n = 109) were compared with a control group with AD (n = 449) and assessed for 21 clinical features associated with PP. Multivariate nonlinear regression analyses determined which features best separated the groups. Patients with dermatitis who demonstrated any of these 21 features (n = 43), which were used to diagnose PD, were then compared with the PP and AD groups. They were managed with psoriasis-specific treatment and Psoriasis Area and Severity Index (PASI) was recorded.
RESULTS
Of the 21 clinical features, 12 were found to clearly separate the classic PP and AD groups. Using the eight most significant (P < 0.0001) features, we found these two groups clearly separated at a score of 3 out of 8. Children with PD with ≥ 4 of these features responded well to treatment for psoriasis with a mean reduction of PASI by 85% at 6 weeks.
CONCLUSIONS
We found that patients with dermatitis who have ≥ 4 psoriasis-associated features may have a condition that has been previously alluded to but not defined in the literature, 'psoriasiform dermatitis'. Treatments usually reserved for patients with psoriasis appear to be effective in these patients.
Topics: Case-Control Studies; Child; Dermatitis; Dermatitis, Atopic; Diagnosis, Differential; Humans; Psoriasis
PubMed: 32735691
DOI: 10.1111/ced.14373 -
The American Journal of Surgical... Dec 2020Rash is one of the most common adverse events observed with mogamulizumab, an anti-C-C chemokine receptor 4 monoclonal antibody approved for previously treated mycosis...
Rash is one of the most common adverse events observed with mogamulizumab, an anti-C-C chemokine receptor 4 monoclonal antibody approved for previously treated mycosis fungoides (MF) and Sezary syndrome (SS). Given the nonspecific clinical presentations of this rash, histopathologic distinction from MF/SS is critical for informing clinical management. We performed a comprehensive characterization of the histopathologic findings in mogamulizumab-associated rash (MAR) with the integration of high-throughput sequencing of T-cell receptor (TCR) genes. Fifty-two biopsy specimens from 19 patients were evaluated retrospectively. Three major histologic reaction patterns were identified: spongiotic/psoriasiform dermatitis (33/52), interface dermatitis (11/52), and granulomatous dermatitis (8/52). Almost half of the specimens (21/52) showed at least 2 of these reaction patterns concurrently. Dermal eosinophils were not a consistent feature, being present in only half (27/52) of specimens and prominent in only 3. Features mimicking MF/SS, including lymphocyte exocytosis, lamellar fibroplasia, and adnexal involvement, were commonly seen but tended to be focal and mild. In 38/43 specimens with available immunohistochemistry, intraepidermal lymphocytes demonstrated a CD4:CD8 ratio ≤1 : 1. Low background levels of the patient's previously identified MF/SS-associated TCR sequence(s) were demonstrated in 20/46 specimens analyzed by high-throughput sequencing of TCR. We conclude that MAR may demonstrate diverse histologic features. Findings that may distinguish MAR from MF/SS include the inverted or normalized CD4:CD8 ratio within intraepidermal lymphocytes and demonstration of absent or nondominant levels of disease-associated TCR sequences. Correlation with the clinical findings and immunohistochemical and molecular characterization of the patient's MF/SS before mogamulizumab, when possible, may facilitate recognition of MAR.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents; CD4-CD8 Ratio; Drug Eruptions; Exanthema; Female; Genes, T-Cell Receptor; High-Throughput Nucleotide Sequencing; Humans; Male; Skin; T-Lymphocytes
PubMed: 32976123
DOI: 10.1097/PAS.0000000000001587 -
The Australasian Journal of Dermatology Aug 2022
Topics: Antibodies, Monoclonal, Humanized; Dermatitis, Atopic; Eczema; Exanthema; Humans; Psoriasis
PubMed: 35460570
DOI: 10.1111/ajd.13846 -
Clinical Cancer Research : An Official... Jul 2024Immune-related cutaneous adverse events (ircAE) occur in ≥50% of patients treated with checkpoint inhibitors, but the underlying mechanisms for ircAEs are poorly...
PURPOSE
Immune-related cutaneous adverse events (ircAE) occur in ≥50% of patients treated with checkpoint inhibitors, but the underlying mechanisms for ircAEs are poorly understood.
EXPERIMENTAL DESIGN
Phenotyping/biomarker analyses were conducted in 200 patients on checkpoint inhibitors [139 with ircAEs and 61 without (control group)] to characterize their clinical presentation and immunologic endotypes. Cytokines were evaluated in skin biopsies, skin tape strip extracts, and plasma using real-time PCR and Meso Scale Discovery multiplex cytokine assays.
RESULTS
Eight ircAE phenotypes were identified: pruritus (26%), maculopapular rash (MPR; 21%), eczema (19%), lichenoid (11%), urticaria (8%), psoriasiform (6%), vitiligo (5%), and bullous dermatitis (4%). All phenotypes showed skin lymphocyte and eosinophil infiltrates. Skin biopsy PCR revealed the highest increase in IFNγ mRNA in patients with lichenoid (P < 0.0001) and psoriasiform dermatitis (P < 0.01) as compared with patients without ircAEs, whereas the highest IL13 mRNA levels were detected in patients with eczema (P < 0.0001, compared with control). IL17A mRNA was selectively increased in psoriasiform (P < 0.001), lichenoid (P < 0.0001), bullous dermatitis (P < 0.05), and MPR (P < 0.001) compared with control. Distinct cytokine profiles were confirmed in skin tape strip and plasma. Analysis determined increased skin/plasma IL4 cytokine in pruritus, skin IL13 in eczema, plasma IL5 and IL31 in eczema and urticaria, and mixed-cytokine pathways in MPR. Broad inhibition via corticosteroids or type 2 cytokine-targeted inhibition resulted in clinical benefit in these ircAEs. In contrast, significant skin upregulation of type 1/type 17 pathways was found in psoriasiform, lichenoid, bullous dermatitis, and type 1 activation in vitiligo.
CONCLUSIONS
Distinct immunologic ircAE endotypes suggest actionable targets for precision medicine-based interventions.
Topics: Humans; Male; Female; Immune Checkpoint Inhibitors; Middle Aged; Aged; Cytokines; Skin; Adult; Drug Eruptions; Pruritus; Neoplasms; Skin Diseases; Exanthema; Aged, 80 and over; Psoriasis; Eczema
PubMed: 38652814
DOI: 10.1158/1078-0432.CCR-23-3431 -
The Journal of Investigative Dermatology Mar 2023Psoriasis is driven by the interplay between hyperproliferative keratinocytes and infiltrating inflammatory cells. GDF15, a member of the TGF-β superfamily, has been...
Psoriasis is driven by the interplay between hyperproliferative keratinocytes and infiltrating inflammatory cells. GDF15, a member of the TGF-β superfamily, has been implicated in cachexia, metabolic control, and cancer invasion. However, the expression and immunomodulatory role of GDF15 in inflammatory diseases has not been clarified. In this study, we report that GDF15 is decreased in the epidermis of patients with psoriasis and in an imiquimod-induced psoriasis-like mouse model. TNF-α suppresses GDF15 expression in keratinocytes by inhibiting the protein level of the transcription factor GATA2. GDF15 deficiency aggravates the development of psoriatic lesions, as evidenced by more severe skin inflammation in imiquimod-treated Gdf15-knockout (Gdf15) mice compared with that in wild-type mice. Importantly, GDF15 limited the synthesis of a panel of keratinocyte cytokines and chemokines by inhibiting TAK1/NF-κB activation and directly inhibited neutrophil adhesion and migration by inhibiting the activation of the small GTPase Rap1. Epidermal hyperplasia, infiltration of neutrophils, and transcripts of psoriasis-related markers in imiquimod-induced psoriasiform dermatitis were significantly alleviated by a topical supplement of recombinant murine GDF15. In summary, our study revealed an unexpected role of GDF15 in keratinocyte and neutrophil function in the skin of psoriasis, implying its therapeutic potential in treating psoriasis.
Topics: Mice; Animals; Imiquimod; Neutrophil Infiltration; Psoriasis; Skin; Dermatitis; Keratinocytes; Disease Models, Animal; Mice, Inbred BALB C
PubMed: 36049542
DOI: 10.1016/j.jid.2022.07.026 -
Seminars in Immunology Dec 2021The IL-23/IL-17 cytokine axis is related to spondyloarthropathy (SpA) pattern diseases that target the skin, eye, gut and joints. These share overlapping target tissues... (Review)
Review
The IL-23/IL-17 cytokine axis is related to spondyloarthropathy (SpA) pattern diseases that target the skin, eye, gut and joints. These share overlapping target tissues with Th2 type or allergic diseases, including the skin, eye and gut but SpA diseases exhibit distinct microanatomical topography, molecular characteristics, and clinical features including uveitis, psoriasis, apical pulmonary involvement, lower gastrointestinal involvement with colitis, and related arthritides including psoriatic arthritis and ankylosing spondylitis. Inflammatory arthritis is conspicuously absent from the Th2 diseases which are characterised IL-4/IL-13 dependent pathway activation including allergic rhino-conjunctivitis, atopic eczema, allergic asthma and food allergies. This traditional understanding of non-overlap of musculoskeletal territory between that atopic diseases and the IL-17 -mediated SpA diseases is undergoing a critical reappraisal with the recent demonstration of IL-4/IL-13 blockade, may be associated with the development of SpA pattern arthritis, psoriasiform skin disease and occasional anterior uveitis. Given the known plasticity within Th paradigm pathways, these findings suggest dynamic Th2 cytokine and Th17 cytokine counter regulation in vivo in humans. Unexpected, this is the case in peripheral enthesis and when the IL-4/13 immunological brake on IL-23/17 cytokines is removed, a SpA phenotype may emerge. We discuss hitherto unexpected observations in SpA, showing counter regulation between the Th17 and Th2 pathways at sites including the entheses that collectively indicate that the emergent reverse translational therapeutic data is more than coincidental and offers new insights into the "Th paradigms" in atopy and SpA.
Topics: Humans; Interleukin-17; Cytokines; Interleukin-13; Interleukin-4; Psoriasis; Interleukin-23; Arthritis
PubMed: 34799224
DOI: 10.1016/j.smim.2021.101520 -
Journal of Drugs in Dermatology : JDD Oct 2020Tumor necrosis factor-α inhibitors (TNFIs) have significantly improved the quality of life for patients with psoriasis and psoriatic arthritis. Despite their beneficial...
Tumor necrosis factor-α inhibitors (TNFIs) have significantly improved the quality of life for patients with psoriasis and psoriatic arthritis. Despite their beneficial effects, TNFIs have been reported to cause paradoxical ‘psoriasiform’ eruptions.1 Although this nomenclature has become pervasive in the dermatology lexicon, there is a growing body of literature highlighting the protean clinical presentation of this eruption (Figure 1), which could ultimately lead to a delayed diagnosis.2-5 The diversity of the morphology highlights the importance of identifying key histopathologic characteristics, which to date have not been well-characterized.2
Topics: Drug Eruptions; Humans; Psoriasis; Tumor Necrosis Factor Inhibitors
PubMed: 33026774
DOI: No ID Found -
PeerJ 2023Psoriasis is an autoimmune skin disease characterized by immunocyte activation, excessive proliferation, and abnormal differentiation of keratinocytes. Signal...
BACKGROUND
Psoriasis is an autoimmune skin disease characterized by immunocyte activation, excessive proliferation, and abnormal differentiation of keratinocytes. Signal transducers and activators of transcription 3 (STAT3) play a crucial role in linking activated keratinocytes and immunocytes during psoriasis development. T helper (Th) 17 cells and secreted interleukin (IL)-17A contribute to its pathogenesis. IL-17A treated STAT3 overexpressing mouse model might serve as an animal model for psoriasis.
METHODS
In this study, we established a mouse model of psoriasiform dermatitis by intradermal IL-17A injection in STAT3 overexpressing mice. Transcriptome analyses were performed on the skin of wild type (WT), STAT3, and IL-17A treated STAT3 mice. Bioinformatics-based functional enrichment analysis was conducted to predict biological pathways. Meanwhile, the morphological and pathological features of skin lesions were observed, and the DEGs were verified by qPCR.
RESULTS
IL-17A treated STAT3 mice skin lesions displayed the pathological features of hyperkeratosis and parakeratosis. The DEGs between IL-17A treated STAT3 mice and WT mice were highly consistent with those observed in psoriasis patients, including S100A8, S100A9, Sprr2, and LCE. Gene ontology (GO) analysis of the core DEGs revealed a robust immune response, chemotaxis, and cornified envelope, et al. The major KEGG enrichment pathways included IL-17 and Toll-like receptor signaling pathways.
CONCLUSION
IL-17A exacerbates psoriasis dermatitis in a STAT3 overexpressing mouse.
Topics: Mice; Animals; Interleukin-17; Imiquimod; Psoriasis; Skin; Disease Models, Animal; Dermatitis
PubMed: 37465147
DOI: 10.7717/peerj.15727 -
Antioxidants & Redox Signaling Oct 2021Neutrophil infiltration and increased oxidative stress are involved in the pathogenesis and severity of psoriasis. Although the therapy of psoriasis remains elusive,...
Neutrophil infiltration and increased oxidative stress are involved in the pathogenesis and severity of psoriasis. Although the therapy of psoriasis remains elusive, targeting treatment to reduce oxidative stress is considered a potential option. Our study demonstrates the anti-inflammatory effects of a natural furocoumarin, imperatorin, on activated human neutrophils and psoriasiform dermatitis in mice. Imperatorin inhibited superoxide anion generation, neutrophil adhesion, and migration in -formyl-l-methionyl-l-leucyl-l-phenylalanine (fMLF)-stimulated human neutrophils. Further studies showed that imperatorin induced a decrease in cAMP-specific phosphodiesterase (PDE) activity, and increased intracellular cAMP levels and protein kinase A (PKA) activity in human neutrophils. The enzyme activities of PDE4 subtypes, but not PDE3 and PDE7, were inhibited by imperatorin. Furthermore, imperatorin inhibited the phosphorylation of protein kinase B (Akt), extracellular regulated kinase (ERK), and c-Jun -terminal kinase (JNK), as well as Ca mobilization in fMLF-stimulated neutrophils. These suppressive effects of imperatorin on cell responses and signaling were reversed by PKA inhibitor, suggesting that cAMP/PKA is involved in the anti-inflammatory effects of imperatorin. studies of imiquimod- and interleukin-23-induced mouse psoriasiform dermatitis demonstrated that imperatorin alleviated skin desquamation, epidermal thickening, keratinocyte hyperproliferation, and neutrophil infiltration. Our results demonstrate that imperatorin inhibits human neutrophil respiratory burst, adhesion, and migration through the elevation of cAMP/PKA to inhibit Akt, ERK, JNK, and Ca mobilization. Imperatorin is a natural inhibitor of PDE4A/B/C and may serve as a lead for developing new therapeutics to treat neutrophilic psoriasis. 35, 885-903.
Topics: Adult; Animals; Cell Adhesion; Chemotaxis; Dermatitis; Female; Furocoumarins; Humans; Imiquimod; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neutrophils; Phosphodiesterase 4 Inhibitors; Respiratory Burst; Young Adult
PubMed: 33107318
DOI: 10.1089/ars.2019.7835