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1.
Photodermatol Photoimmunol Photomed ; 34(2): 137-144, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29044786

ABSTRACT

BACKGROUND: Polymorphic light eruption (PLE) has been attributed to type IV, most likely delayed-type hypersensitivity response (adaptive immunity) but little is known on innate immunity, especially antimicrobial peptides (AMPs) in the disease. Abnormalities in AMP expression have been linked to pathological skin conditions such as atopic dermatitis (AD) and psoriasis. METHODS: Antimicrobial peptide profiling was carried out in PLE skin samples (n,12) compared with that of healthy (n,13), atopic (n,6), and psoriatic skin (n,6). RESULTS: Compared to healthy skin, we observed increased expression of psoriasin and RNAse7 (both mostly in stratum granulosum of the epidermis), HBD-2 (in the cellular infiltrate of the dermis), and LL37 (mostly in and around blood vessels and glands) in PLE lesional skin, a similar expression profile as present in psoriatic skin and different to that of AD (with little or no expression of psoriasin, RNAse7, HBD-2, and LL37). HBD-3 was downregulated in PLE compared to its high expression in the epidermis and dermis of healthy skin, AD, and psoriasis. CONCLUSION: The unique profile of differentially expressed AMPs in PLE implies a role in the pathophysiology of the disease, possibly directly or indirectly linked to the microbiome of the skin.


Subject(s)
Antimicrobial Cationic Peptides/biosynthesis , Dermatitis, Atopic/metabolism , Gene Expression Regulation , Psoriasis/metabolism , Skin/metabolism , Adolescent , Adult , Aged , Dermatitis, Atopic/pathology , Female , Humans , Male , Middle Aged , Psoriasis/pathology , Skin/pathology
3.
Exp Dermatol ; 24(7): 491-6, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25776520

ABSTRACT

Dermal mast cells protect the skin from inflammatory effects of ultraviolet (UV) radiation and are required for UV-induced immune suppression. We sought to determine a potential mechanistic role of mast cells in reducing the sensitivity to UV radiation (i.e. phototolerance induction) through photohardening. We administered single UV exposures as well as a chronic UV irradiation regime to mast cell-deficient Kit(W-Sh/W-Sh) mice and their controls. The chronic irradiation protocol was similar to that given for prophylaxis in certain photodermatoses in humans. Compared to controls, UV-exposed Kit(W-Sh/W-Sh) mice were more susceptible to epidermal hyperplasia and dermal oedema which was linked to blood vessel dilation. Unexpectedly, Kit(W-Sh/W-Sh) mice exhibited an excessive scratching behaviour following broadband UVB plus UVA or solar simulated UV irradiation at doses far below their minimal skin-swelling dose. Protection from this UV-induced scratching phenotype was dependent on mast cells, as engraftment of bone marrow-derived cultured mast cells abated it entirely. Kit(W-Sh/W-Sh) mice were entirely resistant to phototolerance induction by photohardening treatment. Compared to controls, these mice also showed reduced numbers of regulatory T cells and neutrophils in the skin 24 h after UV irradiation. While it is well known that mast cell-deficient mice are resistant to UV-induced immune suppression, we have discovered that they are prone to develop photo-itch and are more susceptible to UV-induced epidermal hyperplasia and skin oedema.


Subject(s)
Mast Cells/immunology , Mast Cells/radiation effects , Skin/immunology , Skin/radiation effects , Ultraviolet Rays/adverse effects , Animals , Edema/etiology , Edema/immunology , Hyperplasia , Immune Tolerance/radiation effects , Mast Cells/physiology , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neutrophils/immunology , Neutrophils/radiation effects , Proto-Oncogene Proteins c-kit/genetics , Proto-Oncogene Proteins c-kit/immunology , Pruritus/etiology , Pruritus/immunology , Pruritus/physiopathology , Skin/pathology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/radiation effects , Vasodilation/immunology , Vasodilation/radiation effects
4.
Exp Dermatol ; 23(6): 428-30, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24758562

ABSTRACT

The pathogenesis of polymorphic light eruption (PLE) has been linked to a lack of UV-induced immune suppression. To determine the role of Langerhans cells (LC), mast cells and regulatory T cells, biopsies from PLE patients were taken from exposed sites in spring before and after photohardening with 311 nm or PUVA as well as again in summer. Skin sections were assessed for the presence of Langerin/CD1a+ LC and CD3+, CD4+, CD25+ or FoxP3+ T cells and mast cells. Photohardening transiently decreased the density of epidermal LC and significantly increased a low baseline mast cell density in the papillary dermis of PLE patients. Baseline T cell numbers in the skin were low, and there was no difference in PLE patients among any time point. This suggests that LC suppression together with recruitment of mast cells into photohardened skin may be a key cellular event underlying the mechanism by which phototherapy protects from PLE.


Subject(s)
Dermis/pathology , Langerhans Cells/pathology , Mast Cells/pathology , Photosensitivity Disorders/pathology , Photosensitivity Disorders/therapy , Phototherapy , Skin Diseases, Genetic/pathology , Skin Diseases, Genetic/therapy , Ultraviolet Rays , Adult , Biopsy , Case-Control Studies , Cell Count , Dermis/radiation effects , Female , Humans , Langerhans Cells/radiation effects , Mast Cells/radiation effects , Middle Aged , PUVA Therapy , T-Lymphocytes, Regulatory/pathology , T-Lymphocytes, Regulatory/radiation effects , Treatment Outcome
6.
Photochem Photobiol Sci ; 12(1): 166-73, 2013 Jan.
Article in English | MEDLINE | ID: mdl-22949107

ABSTRACT

The etiopathogenesis of polymorphic light eruption (PLE) has been linked to impaired UV-immunosuppression, Langerhans cell (LC) retention, and an absence of neutrophil infiltration into UV-exposed PLE skin. We have previously shown that photohardening restores the impaired neutrophil responsiveness to the chemoattractants leucotriene B4 and formyl-methionyl-leucyl-phenylalanin in PLE patients. The aim of this study was to investigate whether photohardening modulates baseline chemokine and cytokine levels which would alter chemoresponsiveness and hence immune function in PLE patients. Sixteen PLE patients received photohardening therapy for 4-9 weeks by 311 nm UVB. Plasma samples were taken both before and within 48 h of the penultimate phototherapeutic exposure. Plasma from these 16 patients, 8 non-irradiated PLE patients, and 14 control subjects was analyzed for IL-1ß, CXCL8 (IL-8), IL-10, IL-17, TNF, CCL2 (MCP-1), CCL5 (RANTES), CCL11 (eotaxin), and CCL22 (MDC). These cytokines and chemokines were measured in early spring (March to April) and again in late spring (April to June). PLE patients had a significantly elevated level of CCL11 (p = 0.003) and IL-1ß (p = 0.002) in early spring (before phototherapy). In late spring, after phototherapy, PLE patients had significantly elevated CCL2 (p = 0.002) and TNF (p = 0.002) but a trend for lowered plasma levels of CXCL8 (p = 0.021). When comparing the cytokine shifts from early to late spring, while healthy controls and non-UV-irradiated PLE patients showed an increase, PLE patients undergoing photohardening exhibited a trend for decrease in IL-1ß (p = 0.012). Taken together, our results indicate that photohardening may alter the complex cytokine milieu in PLE, in particular via IL-1ß, helping to normalise the pathophysiologic response to subsequent UV exposure.


Subject(s)
Chemokines/blood , Cytokines/blood , Photosensitivity Disorders/metabolism , Adolescent , Adult , Chemokine CCL11/blood , Chemokine CCL2/blood , Female , Humans , Interleukin-1beta/blood , Interleukin-8/blood , Male , Middle Aged , Photosensitivity Disorders/pathology , Photosensitivity Disorders/therapy , Phototherapy , Tumor Necrosis Factor-alpha/blood , Ultraviolet Rays , Young Adult
7.
Am J Pathol ; 178(2): 699-708, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21281802

ABSTRACT

Platelet-activating factor (PAF), a potent biolipid mediator, is involved in a variety of cellular transduction pathways and plays a prominent role in inducing inflammation in different organs. We used K5.hTGF-ß1 transgenic mice, which exhibit an inflammatory skin disorder and molecular and cytokine abnormalities with strong similarities to human psoriasis, to study the pathogenic role of PAF. We found that injecting PAF into the skin of transgenic mice led to inflammation and accelerated manifestation of the psoriatic phenotype by a local effect. In contrast, injecting mice with PAF receptor antagonist PCA-4248 lowered the PAF level (most likely by depressing an autocrine loop) and neutrophil, CD68(+) cell (monocyte/macrophage), and CD3(+) T-cell accumulation in the skin and blocked progression of the psoriasis-like phenotype. This effect of PAF blockade was specific and similar to that of psoralen-UV-A and was paralleled by a decrease in abnormally elevated mRNA and/or protein levels of T-helper type 17 cell-related cytokines IL-17A, IL-17F, IL-23, IL-12A, and IL-6 and its transcription factor signal transducer and activator of transcription 3. In contrast, PCA-4248 treatment up-regulated mRNA levels of cyclooxygenase-2 and IL-10 in dorsal skin and release of IL-10 in serum and skin. Interfering with PAF may offer the opportunity to develop novel therapeutic strategies for inflammatory psoriasis and associated comorbidities, including metabolic syndrome and atherosclerosis, in which the IL-17 axis may be involved.


Subject(s)
Platelet Activating Factor/antagonists & inhibitors , Psoriasis/pathology , Signal Transduction , Th17 Cells/metabolism , Transforming Growth Factor beta1/genetics , Animals , Cytokines/genetics , Cytokines/metabolism , Dihydropyridines/administration & dosage , Dihydropyridines/pharmacology , Disease Progression , Down-Regulation/drug effects , Humans , Mice , Mice, Transgenic , PUVA Therapy , Phenotype , Platelet Activating Factor/metabolism , Platelet Membrane Glycoproteins/antagonists & inhibitors , Platelet Membrane Glycoproteins/metabolism , Psoriasis/drug therapy , Psoriasis/metabolism , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, G-Protein-Coupled/antagonists & inhibitors , Receptors, G-Protein-Coupled/metabolism , STAT3 Transcription Factor/metabolism , Signal Transduction/drug effects , Skin/drug effects , Skin/metabolism , Skin/pathology , Th17 Cells/drug effects , Th17 Cells/immunology , Transforming Growth Factor beta1/metabolism , Up-Regulation/drug effects
8.
J Immunol ; 184(12): 7257-67, 2010 Jun 15.
Article in English | MEDLINE | ID: mdl-20488788

ABSTRACT

To elucidate the molecular action of 8-methoxypsoralen plus UVA (PUVA), a standard dermatological therapy, we used K5.hTGF-beta1 transgenic mice exhibiting a skin phenotype and cytokine abnormalities with strong similarities to human psoriasis. We observed that impaired function of CD4+CD25+ regulatory T cells (Tregs) and increased cytokine levels of the IL-23/Th17 pathway were responsible for the psoriatic phenotype in this mouse model. Treatment of K5.hTGF-beta1 transgenic mice with PUVA suppressed the IL-23/Th17 pathway, Th1 milieu, as well as transcription factors STAT3 and orphan nuclear receptor RORgammat. PUVA induced the Th2 pathway and IL-10-producing CD4+CD25+Foxp3+Tregs with disease-suppressive activity that was abolished by anti-CTLA4 mAb treatment. These findings were paralleled by macroscopic and microscopic clearance of the diseased murine skin. Anti-IL-17 mAb treatment also diminished the psoriatic phenotype of the mice. This indicated that both induced Tregs involving CTLA4 signaling and inhibition of the IL-23/Th17 axis are central for the therapeutic action of PUVA.


Subject(s)
Interleukin-17/radiation effects , Interleukin-23/drug effects , Methoxsalen/administration & dosage , Photosensitizing Agents/administration & dosage , Psoriasis/therapy , T-Lymphocytes, Regulatory/drug effects , Animals , Antigens, CD/drug effects , Antigens, CD/immunology , Antigens, CD/radiation effects , CTLA-4 Antigen , Cell Separation , Disease Models, Animal , Enzyme-Linked Immunosorbent Assay , Flow Cytometry , Fluorescent Antibody Technique , Forkhead Transcription Factors/drug effects , Forkhead Transcription Factors/immunology , Forkhead Transcription Factors/radiation effects , Humans , Immunoassay , Immunohistochemistry , Interleukin-23/radiation effects , Mice , Mice, Transgenic , Phototherapy , Psoriasis/immunology , Reverse Transcriptase Polymerase Chain Reaction , Signal Transduction/drug effects , Signal Transduction/immunology , Signal Transduction/radiation effects , T-Lymphocyte Subsets/drug effects , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/radiation effects , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/radiation effects , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/immunology , Ultraviolet Rays
9.
J Am Acad Dermatol ; 47(3): 423-8, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12196754

ABSTRACT

BACKGROUND: The clinicopathologic spectrum of warty dyskeratoma (WD) is not well characterized and the pathogenesis of this unusual lesion is still unclear. OBJECTIVE: We reviewed the clinical and histopathologic spectrum of WD and investigated a possible involvement of human papillomavirus (HPV) infection in onset of this lesion. METHODS: A total of 46 cases of WD were analyzed clinically and histopathologically. Polymerase chain reaction (PCR) analysis for HPV-DNA was performed in 13 lesions of WD. RESULTS: A total of 46 lesions of WD from 45 patients (M/F ratio, 1:1.8; mean age 59.8 years, median 61 years, age range 3-88 years) presented as solitary papules or small nodules on the head and neck (32 cases), trunk (9 cases), lower extremities (4 cases), and upper extremities (1 case). One patient had 2 lesions. No patient had clinical signs of Darier's or Grover's disease. Histopathologically on scanning magnification, lesions showed mainly 3 architectural patterns, namely, cup-shaped (29 cases), cystic (6 cases), and nodular (2 cases). In 9 cases, a combination of two of these morphologic patterns was observed. Characteristically, the epithelial component in all WDs displayed foci of acantholytic dyskeratosis. Variable features suggestive of follicular differentiation toward the infundibular portion of a normal hair follicle were also observed, including a focal contiguity to pilosebaceous units in most cases (63%), and the presence of small infundibular cystic structures in a subset of lesions (46%). The majority of lesions (83%) also revealed a hyalinized or fibrous stroma with intrastromal clefts. PCR analysis for HPV-DNA performed in 13 cases inclusive of all representative architectural patterns was negative. CONCLUSION: We conclude that WD shows a wider spectrum of morphologic features than previously recognized. Despite some histopathologic similarities to viral warts, WD is not a manifestation of HPV infection. On the other hand, the majority of these lesions display overall histopathologic features consistent with a follicular adnexal neoplasm. On the basis of this finding, we propose the alternative term follicular dyskeratoma to better reflect the distinctive features of this peculiar lesion.


Subject(s)
Neoplasms, Adnexal and Skin Appendage/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Child , Child, Preschool , DNA, Viral/analysis , Darier Disease , Female , Hair Follicle/pathology , Humans , Male , Middle Aged , Papillomaviridae/genetics , Polymerase Chain Reaction , Terminology as Topic
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