Dermal Vessels Research Articles

Pathological and immunohistochemical evaluation of skin and teat papillomas in cattle

Bovine skin and teat papillomas were examined for immunohistochemical expression of bovine papillomavirus (BPV), proliferating antigens (PCNA, Ki-67), CD3+ T lymphocytes, and some of the type III intermediate filaments. Papillomas showed epidermal hyperplasia, koilocytes, and hyperkeratosis with prominent dermal connective tissue. Immunohistochemistry found the presence of BPV antigens in the nuclei of granulosa cells. PCNA and Ki-67 revealed positive nuclear staining in the dermis and epidermis. Perivascular cuffing in the dermis predominantly consisted of CD3+ T cells. Immunoreaction to vimentin was strong in the connective tissue of the dermis. $\alpha$SMA positivity was mainly in the media of vessels. Smooth muscle cells of the dermal blood vessels showed an immunopositive reaction for desmin. Dermal connective tissue and squamous epithelia were negative for S-100 protein. This work revealed that BPV proliferates predominantly in the stratum granulosum cells and that in the regression of warts cell-mediated immune response has a key role. Vimentin was a very useful marker to show the contribution of fibrotic response to viral replication.

Porphyria Cutanea Tarda is a Biochemical and Not Histological Diagnosis

Porphyria cutanea tarda is the most common porphyria, due to acquired deficiency of hepatic uroporphyrinogen decarboxylase (UROD) enzyme, presenting with photosensitivity and blistering skin lesions. Factors making an individual susceptible to PCT include alcohol consumption, smoking, hepatitis C, HIV, estrogen use, and UROD mutation. Diagnosis of PCT is made with typical porphyrin profile of elevated plasma porphyrins (maximum fluorescence at 620 nm) and urine porphyrins (predominant hexa-, penta-, hepta- carboxyporphyrins). Skin biopsy may show features consistent with PCT, however by themselves may not be diagnostic. PCT is readily treatable with either phlebotomy schedule or low dose hydroxychloroquine regimen. We present two cases referred to our centre, all of them diagnosed with PCT based on a skin biopsy. An 81 year old man presented with blistering skin lesions and photosensitivity on dorsal hands and scalp. Skin biopsy from dorsal hand performed by his dermatologist showed dilated blood vessels in dermis with collagen deposition, consistent with PCT. He had no susceptibility factors for PCT. The porphyrin profile was normal with plasma porphyrins of 0.1 mcg/dl (normal <0.9) and urine porphyrins of 35 nmol/L (normal <300). A 28 year old female was diagnosed with PCT based on skin biopsy. She had 4 year history of photosensitivity and plaque like lesions on dorsal hands, which were progressive in spite of being treated with hydroxychloroquine. Except history of smoking, she had no other susceptibility factors of PCT. Biochemical porphyrin profile was normal. She is being treated for pseudoporphyria secondary to doxycycline and is doing well. Conclusions: Biochemical porphyrin profile and not skin histology is the confirmatory test for the diagnosis of PCT

Structural Alteration in Dermal Vessels and Collagen Bundles following Exposure of Skin Wound to Zeolite-Bentonite Compound.

Background. This study examines the impact of one-time direct application of haemostatic agent zeolite–bentonite powder to wounded skin on the healing process in rats. Materials and Methods. 24 male Sprague-Dawley rats were randomly allocated into two groups (n = 12): (1) the rats whose wounds were washed only with sterile normal saline (NS-treated) and (2) those treated with zeolite–bentonite compound (ZEO-treated). The wound was circular, full-thickness, and 2 cm in diameter. At the end of the 12th day, six animals from each group were randomly selected and terminated. The remaining rats were terminated after 21 days. Just after scarification, skin samples were excised and sent for stereological evaluation. Results. The results showed a significant difference between the two groups regarding the length density of the blood vessels and diameter of the large and small vessels on the 12th day after the wound was inflicted. Besides, volume density of both the dermis and collagen bundles was reduced by 25% in the ZEO-treated rats in comparison to the NS-treated animals after 21 days. Conclusions. One-time topical usage of zeolite–bentonite haemostatic powder on an animal skin wound might negatively affect the healing process through vasoconstriction and inhibition of neoangiogenesis.

T-Cadherin Expression in the Epidermis and Adnexal Structures of Normal Skin

Background: T-cadherin is an atypical glycosylphosphatidylinositol-anchored member of the cadherin superfamily of adhesion molecules. The role of T-cadherin in biology of the skin is poorly understood. Expression of T-cadherin in basal keratinocytes and dermal blood vessels of the healthy epidermis has been demonstrated, but studies on expression in skin appendages are rare. Methods: We conducted an immunohistochemical analysis of T-cadherin expression in the epidermis and adnexal structures of normal skin. Results: T-cadherin expression is restricted to basal keratinocytes of the epidermis. The basal cell layer of sebaceous glands was T-cadherin positive, whereas sebocytes were negative. Within apocrine glands, only myoepithelial cells were T-cadherin positive. In contrast, both the secretory coils and excretory ducts of eccrine glands were T-cadherin positive. In terminal hair follicles, the outer root sheath layers strongly expressed T-cadherin throughout different regions of the follicle, with the strongest immunoreactivity at the bulge and suprabulbar regions. T-cadherin and CK15 stem cell marker similarly localized within the bulge and suprabulbar region. T-cadherin and CD34 stem cell marker similarly localized at the suprabulbar level. Conclusion: The specific patterns of T-cadherin expression in the epidermis and adnexal structures suggest an important guardian role in skin homeostasis.

La gangrène cutanée thrombotique : une manifestation extradigestive rare de la rectocolite hémorragique

Thrombotic cutaneous gangrene is a rare extra-intestinal manifestation of ulcerative colitis with a severe prognosis. A 35-year-old woman with a 7-year history of ulcerative colitis presented with extensive ecchymotic lesions that began a few hours earlier. On examination, she was febrile with multiple necrotic lesions. Skin biopsy showed multiple microthrombi in the dermal vessels. A diagnosis of thrombotic cutaneous gangrene was established. The patient was treated with heparin and systemic corticosteroids. The majority of cutaneous lesions showed improvement after 1month. Thrombophlebitis of the left lower limb occurred subsequently. Thrombotic cutaneous gangrene is attributed to microvascular thrombosis, which arises from the hypercoagulability observed in ulcerative colitis. Complete blood and coagulation tests must be performed and early anticoagulation with heparin must be considered in order to prevent the progression of cutaneous infarction.

Dermatology 101 for the Gastroenterologist: Drug Induced Vasculitis from Anti-TNF Treatment for Crohnʼs

Background: Biological agents, particularly TNF- alpha (TNF-α) inhibitors, continue to grow in use for the management of rheumatic and immunologic diseases. TNF- α inhibitors are also paradoxically associated with secondary autoimmune conditions. Anti-TNF-α therapy has been associated with cutaneous vasculitis, lupus-like syndrome, systemic lupus erythematosus, and interstitial lung disease. Monoclonal antibodies have become the most common agents associated with drug-induced vasculitis (DIV). This usually involves small vessels in leukocytoclastic vasculitis, small-vessel disease similar to an ANCA-related vasculitis, or mid-sized muscular arteries in a polyarteritis-like picture. The clinical presentation can be nonspecific with arthralgias, myalgias, and skin rash. Gastroenterologists who prescribe anti-TNF should be aware of these side effects. Case: A 22 year old man with past medical history of Crohn's disease of the ileum diagnosed at age 11 was initially treated with prednisone and 5-ASA on initial presentation and started on azathioprine. Adalimumab was added several years later after a flare-up of disease. Three years after initiation of therapy, patient developed a painful erythematous purpuric rash on his legs that initially resolved but recurred several months later. Patient was afebrile on presentation and physical exam was notable for multiple scattered bilaterally symmetric 1-3 mm red thin papules on bilateral lower extremities consistent with palpable purpura suggestive of DIV. The adalimumab was stopped and he was referred to Dermatology for suspicion of drug induced vasculitis. Biopsy revealed focal fibrinoid necrosis of the walls of the superficial dermal small vessels with associated karyorrhexis of neutrophils with extravasated red blood cells consistent with small vessel vasculitis/ leukocytoclastic vasculitis. Patient did well after discontinuation of TNF-α therapy. Discussion: By 2012, TNF inhibitors have become the leading group of reported cases of DIV. There are over 200 cases reported worldwide. Given increasing use of these agents for treatment of inflammatory bowel disease, a high index of suspicion on the part of the clinician is obligatory.Figure 1

Myeloid Fli1 deficiency induces tissue fibrosis, vasculopathy, and immune abnormalities recapitulating systemic sclerosis

Systemic sclerosis (SSc) is a multisystem chronic disease characterized by immune abnormalities, vasculopathy, and tissue fibrosis. In SSc lesional skin, transcription factor Friend leukemia virus integration 1 (Fli1) is constitutively down-regulated in various cell types, especially by an epigenetic mechanism in dermal fibroblasts, and Fli1 deficiency in dermal fibroblasts and endothelial cells induces an SSc-like phenotype in each cell type. However, it has still remained to be elucidated whether Fli1 deficiency in immune cells has an impact on the pathogenesis of SSc. As a part of studies to address this issue, we focused our interests on myeloid cells in this study. We generated myeloid cell-specific Fli1 deficient (Fli1 Mye-KO) mice (LysM-Cre+/−Fli1flox/flox) and examined the phenotypic changes in these mice. Fli1 Mye-KO mice showed increased dermal thickness and collagen production through activation of dermal fibroblasts. As for vasculopathy, Fli1 Mye-KO mice showed stenosis, dilatation, and regression of dermal blood vessels as visualized by FITC-conjugated dextran injection. Increased permeability of dermal blood vessels was also confirmed by leakage of Evans blue dye into interstitial spaces in Fli1 Mye-KO mice. Histopathological analysis of the skin of Fli1 Mye-KO mice showed decreased pericyte coverage in dermal blood vessels, leading to endothelial hyperplasia, vascular dilatation, and decreased stability of blood vessels. Regarding immune dysfunction, Fli1 Mye-KO mice showed production of anti-nuclear antibodies. Thus, Fli1 deficiency in myeloid cells may contribute to the induction of three cardinal pathological features of SSc, including dermal fibrosis, vascular injury, and immune abnormalities.

EXPRESSION AND SIGNIFICANCE OF PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR γ IN KELOID

To investigate the expression and significance of peroxisome proliferator activated receptor γ(PPAR-γ) in human keloid. Twenty-three keloid samples were harvested from the patients undergoing keloid and auto-skin grafting operation as the experimental group (keloid group), and the residual normal skin after auto-skin grafting operation was collected as the control group. The expression of PPAR-γ protein was examined by immunohistochemistry staining in both keloid and normal skin. Referring to Shimizu immunohistochemical standard, the result was graded; the positive rate of samples and the rate of positive cells were calculated. Immunohistochemistry staining showed that PPAR-γ protein was expressed in both keloid and normal skin. In keloid, it located in the pricle cell layer, and granular layer of epidermis, and the dermal vessel; the degree of dyeing was very light. However, in normal skin, it located in the base layer of epidermis, dermal vessel walls, sweat glands and sebaceous glands; the dyeing degree was deeper. Immunohistochemical staining score in the keloid group (2.65±0.78) was significantly lower than that in the control group (3.65±1.19) (t=5.030, P=0.000). The positive rate of samples in the keloid group (52.17%, 12/23) was significantly lower than that in the control group (82.61%, 19/23) (χ2=4.847, P=0.028). The rate of positive cells was 46.04%±8.61% in the keloid group, which was significantly lower than that in the control group (59.39%±11.26%) (t=5.974, P=0.000). Compared with normal skin, the expression of PPAR-γ protein in keloid is down-regulated in in human keloid, indicating that PPAR-γ may be related to the formation of keloid.

A potential contribution of antimicrobial peptide LL-37 to tissue fibrosis and vasculopathy in systemic sclerosis.

LL-37 is an antimicrobial peptide with pleiotropic effects on the immune system, angiogenesis and tissue remodelling. These are cardinal pathological events in systemic sclerosis (SSc). To elucidate the potential role of LL-37 in SSc. The expression of target molecules was evaluated by immunostaining and quantitative reverse-transcription real-time polymerase chain reaction in human and murine skin. The mechanisms regulating LL-37 expression in endothelial cells were examined by gene silencing and chromatin immunoprecipitation. Serum LL-37 levels were determined by enzyme-linked immunosorbent assay. In SSc lesional skin, LL-37 expression was increased in dermal fibroblasts, perivascular inflammatory cells, keratinocytes and, particularly, dermal small vessels. Expression positively correlated with interferon-α expression, possibly reflecting LL-37-dependent induction of interferon-α. In SSc animal models, bleomycin-treated skin exhibited the expression pattern of CRAMP, a murine homologue of LL-37, similar to that of LL-37 in SSc lesional skin. Furthermore, Fli1+/- mice showed upregulated expression of CRAMP in dermal small vessels. Fli1 binding to the CAMP (LL-37 gene) promoter and Fli1 deficiency-dependent induction of LL-37 were also confirmed in human dermal microvascular endothelial cells. In the analysis of sera, patients with SSc had serum LL-37 levels significantly higher than in healthy controls. Furthermore, serum LL-37 levels positively correlated with skin score and the activity of alveolitis and were significantly elevated in patients with digital ulcers compared with those without. LL-37 upregulation, induced by Fli1 deficiency at least in endothelial cells, potentially contributes to the development of skin sclerosis, interstitial lung disease and digital ulcers in SSc.

Possible association of elevated serum collagen type IV level with skin sclerosis in systemic sclerosis.

Collagen type IV is the primary collagen in the basement membranes around blood vessels and in the dermoepidermal junction in the skin. Perivascular collagen type IV is synthesized by endothelial cells and pericytes, and contributes to the homeostasis and remodeling of blood vessels. It has been well recognized that elevated serum collagen type IV levels are associated with the liver fibrosis. The objective was to examine serum collagen type IV levels and their clinical associations in patients with systemic sclerosis (SSc), and to examine the expression of collagen type IV in the fibrotic skin in SSc. Serum collagen type IV levels in SSc patients and diffuse cutaneous type SSc patients were significantly higher than those in healthy individuals. Serum collagen type IV levels were positively correlated with modified Rodnan total skin score. Serum collagen type IV levels in early stage (disease duration ≤3 years) diffuse cutaneous SSc patients were significantly elevated. Serum collagen type IV levels in SSc patients with digital ulcers (DU) were significantly elevated. In immunohistochemical staining, the expression of collagen type IV around dermal small vessels in the affected skin was reduced compared with those of normal individuals. These results suggest that elevated serum collagen type IV levels may be associated with the skin sclerosis in the early stage of SSc. The measurement of serum collagen type IV levels in SSc patients may be useful as a disease activity marker in skin sclerosis and DU.

Lymphatic vessels regulate immune microenvironments in human and murine melanoma.

Lymphatic remodeling in tumor microenvironments correlates with progression and metastasis, and local lymphatic vessels play complex and poorly understood roles in tumor immunity. Tumor lymphangiogenesis is associated with increased immune suppression, yet lymphatic vessels are required for fluid drainage and immune cell trafficking to lymph nodes, where adaptive immune responses are mounted. Here, we examined the contribution of lymphatic drainage to tumor inflammation and immunity using a mouse model that lacks dermal lymphatic vessels (K14-VEGFR3-Ig mice). Melanomas implanted in these mice grew robustly, but exhibited drastically reduced cytokine expression and leukocyte infiltration compared with those implanted in control animals. In the absence of local immune suppression, transferred cytotoxic T cells more effectively controlled tumors in K14-VEGFR3-Ig mice than in control mice. Furthermore, gene expression analysis of human melanoma samples revealed that patient immune parameters are markedly stratified by levels of lymphatic markers. This work suggests that the establishment of tumor-associated inflammation and immunity critically depends on lymphatic vessel remodeling and drainage. Moreover, these results have implications for immunotherapies, the efficacies of which are regulated by the tumor immune microenvironment.

Evaluation of Peripheral Blood Circulation Disorder in Scleroderma Patients Using an Optical Sensor with a Pressurization Mechanism.

Blood circulation function of peripheral blood vessels in skin dermis was evaluated employing an optical sensor with a pressurization mechanism using the blood outflow and reflow characteristics. The device contains a light source and an optical sensor. When applied to the skin surface, it first exerts the primary pressure (higher than the systolic blood pressure), causing an outflow of blood from the dermal peripheral blood vessels. After two heartbeats, the pressure is lowered (secondary pressure) and blood reflows into the peripheral blood vessels. Hemoglobin concentration, which changes during blood outflow and reflow, is derived from the received light intensity using the Beer–Lambert law. This method was evaluated in 26 healthy female volunteers and 26 female scleroderma patients. In order to evaluate the blood circulation function of the peripheral blood vessels of scleroderma patients, pressurization sequence which consists of primary pressure followed by secondary pressure was adopted. Blood reflow during the first heartbeat period after applying the secondary pressure of 40mmHg was (mean±SD) 0.059±0.05%mm for scleroderma patients and 0.173±0.104%mm for healthy volunteers. Blood reflow was significantly lower in scleroderma patients than in healthy volunteers (p<0.05). This result indicates that the information necessary for assessing blood circulation disorder of peripheral blood vessels in scleroderma patients is objectively obtained by the proposed method.

Non-motor involvement in amyotrophic lateral sclerosis: new insight from nerve and vessel analysis in skin biopsy.

To assess cutaneous sensory and autonomic nerves and the vascular bed in amyotrophic lateral sclerosis (ALS). We enrolled 41 patients (M = 20, aged 63.5 ± 11.8 years), and 41 age- and gender-matched healthy volunteers (M = 20, aged 63.5 ± 11.8 years). Disease severity and sensory and autonomic symptoms were scored using dedicated rating scales. Skin biopsies obtained from thigh, leg and fingertip were processed using indirect immunofluorescence. Intraepidermal nerve fibres, Meissner corpuscles (MCs), intrapapillary myelinated endings, cholinergic and noradrenergic pilomotor nerves and dermal vessels were quantified on confocal images. Intraepidermal nerve fibres, pilomotor nerves and vessels were also assessed on distal leg skin samples of 10 spinal cord injury patients to compare our findings with those of a chronic hypomobility condition. Compared to healthy controls skin biopsies showed: (i) non-length-dependent loss of intraepidermal nerve fibres (P < 0.01) and loss of MCs (P < 0.01); (ii) reduced (P < 0.01) density of pilomotor nerves involving cholinergic and noradrenergic fibres and (iii) a reduced (P < 0.01) vascular bed. Autonomic nerve and dermal vessel densities were higher in patients with higher disease progression rate (P < 0.01). Moreover, we observed signs of nerve regeneration coexisting with nerve degeneration and increased complexity of the dermal vessels. In patients with posttraumatic spinal cord injury, the density of intraepidermal nerve fibres, pilomotor nerves and of the vascular bed did not differ from controls (P > 0.05). We demonstrated a cutaneous sensory and autonomic denervation in ALS and a previously undescribed relationship between autonomic and vascular involvement that appeared to be linked to the disease progression rate.

Acquired vulvar lymphangioma: Report of two cases

Vulvar lymphangioma is a rare case and often being misdiagnosed as genital wart. This acquired disorder manifests as dilatation of superficial lymph vessel due to obstruction. It is caused by urogenital infection and most often occurs following surgery and radiotherapy of cervical cancer. The diagnosis is established based on clinical and histopathological features. Treatment aimed to eliminate the cause of obstruction. This article reports two cases of vulvar lymphangioma found in our Hospital. First case was a 43-year-old female with a history of surgery and radiation for cervical cancer 10 years ago presented with vesicular skin lesion in genital area, oozing copious clear fluid since 4 years ago. There are multiple lenticular vesicles containing clear fluid in vulvar area accompanied with bilateral lymphedema of lower extremities. Histopathological features demonstrated dilated superficial lymph vessels. Second case was a 44-year-old female with enlargement of lower abdomen with vesicular lesion containing clear fluid in genital area since 3 years ago. Abdominal USG showed enlarged inguinal lymph node. Histopathological features demonstrated dilated superficial lymph vessels. The treatment for both cases were gradual electrosurgery. In both cases, vulvar dermis’ superficial lymph node dilatation caused the skin lesions. Obstruction of lymph vessel due to radiation and surgery for cervical cancer in the first case and of inguinal lymph node in the second case lead to increased lymphatic pressure in the dermis and later on the dilatations. The treatment in both cases using electrical excision produced good responses; however, we should be attentive on recurrent case. Keywords: acquired vulvar lymphangioma, dilatation of dermal lymph vessels, electrosurgery

A miniature shock wave driven micro-jet injector for needle-free vaccine/drug delivery.

This article presents a miniature shock wave driven micro-jet generator to deliver liquid drugs into human skin, to a controlled depth, with minimal invasion. The device can release the vaccine/drug to the depth of dermal blood vessels, without breaching much of the microcirculation system of dermis. The drug delivery technique is needle-free, which can reduce pain, trauma, and contamination besides minimal dosage and systemic exposure. The device can also be used to deliver liquid or colloidal drugs into soft tissues in human. The mechanical analyses of the device were carried out by analyzing the strength of the impulse of the shock wave, measuring the velocity of the generated jet and capturing the pressure exerted by the jet on the target. The penetrating ability of the jet was investigated by delivering it into sample of human skin and gelatin slabs. Theoretical analyses were carried out on the physics of the delivery and the predicted results had a close agreement with the experimental observations. The development can offer an important cost-effective solution to needle-free health care worldwide. Biotechnol. Bioeng. 2016;113: 2507-2512. © 2016 Wiley Periodicals, Inc.

015 Norepinephrine (NE) biases Langerhans cell (LC) antigen presentation to T cells toward a Th17 response via actions on endothelial cells

We now report that exposure of primary dermal microvascular endothelial cells (pDMECs) to NE induces them to bias LC antigen presentation to CD4+ T cells toward generation of Th17 cells. BALB/c pDMECs (1x104/well) were plated in 96-well round bottom plates in medium containing 10-8 M to 10-5 M NE. After 3 h, plates were washed 4 times and 1x104 BALB/c LCs and 2x105 CD4+ T cells from DO11.10 mice (BALB/c background) were added per well followed by addition of a fragment of chicken ovalbumin (cOVA323-339) to 10 μM in 200 μl of medium. DO11.10 mice express transgenes in their T cell receptors that recognize cOVA323-339. After 48 h, supernatants were assayed for cytokine content by ELISA. Addition of NE-exposed pDMECs significantly enhanced IL-6 and IL-17A production while inhibiting interferon-γ (IFNγ) and IL-22 release compared to wells containing non-treated pDMECs. When T cells were harvested from these cultures and analyzed by FACS for intracellular cytokines, increased numbers of cells containing IL-17A were observed along with a decrease in cells containing IFNγ. RNA was extracted from T cells from these cultures. By quantitative RT-PCR the presence of NE-treated pDMECs led to a significant increase in mRNA for IL-17A and RORγT while IFNγ, IL-22 and T-bet mRNA were decreased. Similar experiments in which Transwell inserts were used to separate pDMECs from LCs and responding T cells showed that the effect on cytokine release did not depend on cell-cell contact. Thus, NE can influence the outcome of antigen presentation toward a Th17-type immune response through actions on ECs that induce release of a soluble mediator(s) mediating the effects. As dermal blood vessels and lymph nodes are associated with sympathetic nerves, we hypothesize that, when the sympathetic nervous system is activated by stress, NE release biases antigen presentation towards the Th17 pole via actions on ECs. This may exacerbate psoriasis and, perhaps, other inflammatory skin disorders involving Th17 cells. This pathway may prove to be a therapeutic target.

ACKR4 on Stromal Cells Scavenges CCL19 To Enable CCR7-Dependent Trafficking of APCs from Inflamed Skin to Lymph Nodes.

Dermal dendritic cells and epidermal Langerhans cells are APCs that migrate from skin to draining lymph nodes (LN) to drive peripheral tolerance and adaptive immunity. Their migration requires the chemokine receptor CCR7, which directs egress from the skin via dermal lymphatic vessels and extravasation into the LN parenchyma from lymph in the subcapsular sinus. CCR7 is activated by two chemokines: CCL19 and CCL21. CCL21 alone is sufficient for the migration of APCs from skin to LN. CCL19 and CCL21 also bind atypical chemokine receptor (ACKR) 4. ACKR4-mediated CCL21 scavenging by lymphatic endothelial cells lining the subcapsular sinus ceiling stabilizes interfollicular CCL21 gradients that direct lymph-borne CCR7(+)APCs into the parenchyma of mouse LN. In this study, we show that ACKR4 also aids APC egress from mouse skin under steady-state and inflammatory conditions. ACKR4 plays a particularly prominent role during cutaneous inflammation when it facilitates Langerhans cell egress from skin and enables the accumulation of dermal dendritic cells in skin-draining LN. Stromal cells in mouse skin, predominantly keratinocytes and a subset of dermal lymphatic endothelial cells, express ACKR4 and are capable of ACKR4-dependent chemokine scavenging in situ. ACKR4-mediated scavenging of dermal-derived CCL19, rather than CCL21, is critical during inflammation, because the aberrant trafficking of skin-derived APCs inAckr4-deficient mice is completely rescued by genetic deletion ofCcl19 Thus, ACKR4 on stromal cells aids the egress of APCs from mouse skin, and, during inflammation, facilitates CCR7-dependent cell trafficking by scavenging CCL19.

A potential contribution of altered cathepsin L expression to the development of dermal fibrosis and vasculopathy in systemic sclerosis.

Cathepsin L (CTSL) is a lysosomal proteolytic enzyme involved in inflammation and vascular and extracellular matrix remodelling, which are the three cardinal pathological events associated with systemic sclerosis (SSc). To elucidate the potential role of CTSL in the development of SSc, we here investigated CTSL expression in the lesional skin of patients with SSc and SSc animal models and the clinical correlation of serum CTSL levels. CTSL expression was elevated in dermal small vessels of SSc patients compared with those of healthy controls. Consistently, CTSL mRNA levels were increased in SSc lesional skin samples, but not in cultivated SSc dermal fibroblasts, compared with corresponding control samples from healthy individuals. Serum CTSL levels were significantly higher in SSc patients than in healthy controls and inversely correlated with skin score. Furthermore, the elevation of serum CTSL levels was linked to SSc vasculopathy. Supporting these results, Ctsl mRNA levels were decreased in the skin of bleomycin-treated mice, an SSc animal model recapitulating its fibrotic aspect, and CTSL expression was enhanced in dermal small vessels of endothelial cell-specific Fli1 knockout mice, reminiscent of SSc vasculopathy. Importantly, gene silencing of FLI1 induced CTSL mRNA expression and Fli1 occupied the CTSL promoter in human dermal microvascular endothelial cells. Collectively, these results suggest that endothelial CTSL up-regulation partially due to Fli1 deficiency may contribute to the development of vasculopathy, while the decrease in dermal CTSL expression is likely associated with dermal fibrosis in SSc.

Sarcoïdose cutanée à type de livédo

The cutaneous signs of sarcoidosis are extremely polymorphous and may be classified under several different headings. Herein, we report the case of a 51-year-old female patient presenting bilateral livedo of the knees accompanied by systemic signs with polyarthralgia, impaired general state of health, weight loss, and a sensation of dyspnoea. Skin biopsy revealed giant-cell granuloma around the dermal vessels, with no caseous necrosis. Histopathological examination of the patient's blood vessels revealed no abnormalities. Laboratory tests showed high levels of angiotensin converting enzyme (1.5×ULN), bilateral mediastinal adenomegaly and incipient pulmonary fibrosis. Systemic sarcoidosis was diagnosed on the basis of the overall clinical and laboratory picture. The patient subsequently presented hepatic involvement and hypercalcaemia associated with the sarcoidosis; systemic corticosteroid therapy (prednisone) was initiated, with slow dose-reduction. The outcome was favourable with a return to normal laboratory values, regression of the adenomegaly and subsidence of the livedo. The literature contains reports of a number of cases of livedo heralding sarcoidosis. The majority of such cases involved young or middle-aged female patients of Asian origin presenting systemic sarcoidosis, with a high frequency of ocular and neural involvement. Livedo could be accounted for by the specific disposition of granulomas around the arterioles, resulting in disturbance of local blood flow, which was probably associated with the mechanical compression of vessels and with the micro-thrombi noted at histology. Livedo may be considered a clinical sign of cutaneous sarcoidosis. Laboratory tests to screen for sarcoidosis may be proposed in the exploration of atypical livedo.

Calcitonin Gene-Related Peptide-Exposed Endothelial Cells Bias Antigen Presentation to CD4+ T Cells toward a Th17 Response.

Calcitonin gene-related peptide (CGRP) is a neuropeptide with well-established immunomodulatory functions. CGRP-containing nerves innervate dermal blood vessels and lymph nodes. We examined whether CGRP regulates the outcome of Ag presentation by Langerhans cells (LCs) to T cells through actions on microvascular endothelial cells (ECs). Exposure of primary murine dermal microvascular ECs (pDMECs) to CGRP followed by coculture with LCs, responsive CD4(+) T cells and Ag resulted in increased production of IL-6 and IL-17A accompanied by inhibition of IFN-γ, IL-4, and IL-22 compared with wells containing pDMECs treated with medium alone. Physical contact between ECs and LCs or T cells was not required for this effect and, except for IL-4, we demonstrated that IL-6 production by CGRP-treated pDMECs was involved in these effects. CD4(+) cells expressing cytoplasmic IL-17A were increased, whereas cells expressing cytoplasmic IFN-γ or IL-4 were decreased by the presence of CGRP-treated pDMECs. In addition, the level of retinoic acid receptor-related orphan receptor γt mRNA was significantly increased, whereas T-bet and GATA3 expression was inhibited. Immunization at the site of intradermally administered CGRP led to a similar bias in CD4(+) T cells from draining lymph node cells toward IL-17A and away from IFN-γ. Actions of nerve-derived CGRP on ECs may have important regulatory effects on the outcome of Ag presentation with consequences for the expression of inflammatory skin disorders involving Th17 cells.