Mast Cells In Skin Lesions Research Articles

CD4+CCR5+ T cells and CCL3+ mast cells are increased in the skin of patients with chronic spontaneous urticaria.

The proximity of activated T cells and mast cells in the lesional skin of patients with chronic spontaneous urticaria (CSU) is held to contribute to the development of wheals and angioedema. In a previous study, we demonstrated that increased IL-17 expression in T cells and mast cells in skin lesions of patients with CSU is associated with T/mast cell proximity, but the mechanisms that drive T cell/mast cell co-localization remain unknown. To assess if chemokines expressed in lesional CSU skin contribute to T cell/mast cell proximity. Biopsies from lesional CSU skin were compared to biopsies from healthy skin for expression of CCR5 and its ligand CCL3 by CD4+ T cells and mast cells, respectively. Numbers of CCR5-positive CD4+ T cells in lesional CSU skin were significantly increased as compared to healthy normal skin (p < 0.0001). The number of mast cells expressing CCL3 (ligand for CCR5) in CSU skin was also increased (p < 0.0002) and significant association with T-cell close proximity (p < 0.0001) is noticed. The close proximity of T cells and mast cells in the skin of severe CSU may be driven, at least in part by increased CCR5 and CCL3 expression. Therapies that target CCL3 interaction with CCR5 should be assessed for their effects in CSU.

Acupoint Autohemotherapy Attenuates DNCB-Induced Atopic Dermatitis and Activates Regulatory T Cells in BALB/c Mice.

Acupoint autohemotherapy (A-AHT) has been proposed as an alternative and complementary treatment for atopic dermatitis (AD), yet the exact role of its blood component in terms of therapeutic efficacy and mechanism of action is still largely unknown. This study aimed to evaluate the therapeutic efficacies and action mechanisms of intramuscular injections of autologous whole blood (AWB) and mouse immunoglobulin G (IgG) (autologous or heterologous) at acupoints on 2,4-dinitrochlorobenzene (DNCB)-induced AD mouse models. Serum levels of total immunoglobulin E (IgE), IgG, interleukin-10 (IL-10), and interferon-gamma (IFN-γ) were measured, as well as mRNA expression levels of Forkhead box P3 (FoxP3), IL-10 and IFN-γ in dorsal skin lesions, and IL-10+, IFN-γ+ and FoxP3+CD4+T cells in murine spleen. It showed that repeated acupoint injection of AWB, autologous total IgG (purified from autologous blood in AD mice) or heterologous total IgG (purified from healthy blood in normal mice) effectively reduced the severity of AD symptoms and decreased epidermal and dermal thickness as well as mast cells in skin lesions. Additionally, AWB acupoint injection was found to upregulate FoxP3+, IL-10+ and IFN-γ+ CD4+T cells in murine spleen, suppressing the production of IgE antibodies and increasing that of IgG antibodies in the serum. Furthermore, both AWB and autologous total IgG administrations significantly elevated FoxP3 expression, mRNA levels of IL-10 and IFN-γ in dorsal skin lesions. However, acupoint injection of heterologous total IgG had no effect on regulatory T (Treg) and Th1 cells modulation. These findings suggest that the therapeutic effects of A-AHT on AD are mediated by IgG-induced activation of Treg cells.

Glycyrrhizic acid suppresses atopic dermatitis-like symptoms by regulating the immune balance.

Glycyrrhiza is one of the most widely used traditional Chinese medicines in China. Its main bioactive ingredient glycyrrhizic acid (GA) has the potential to be used as a treatment for atopic dermatitis (AD) because it has similar actions to steroids, but with relatively few side effects. The objective of this study was to explore the potential mechanisms of GA on AD mice model. Calcipotriol, a vitamin D3 analogue (MC903) was applied topically to establish AD mouse model. Mice were intraperitoneally administrated with 2mg/kg dexamethasone (DEX), 25 or 50 mg/kg GA for 15 days. After mice were executed, skin tissues were collected and detected the expression levels of IL-4, IFN-γ, TNF-α and thymic stromal lymphopoietin (TSLP). The percentages of Th1, Th2, Th17, langerhans cells (LCs) in draining lymph nodes (dLNs) were measured by flow cytometry. Our data demonstrated that GA improved the symptoms of AD by exerting anti-inflammatory and anti-allergic functions in vivo. We found that GA treatment decreased the level of total IgE in serum, suppressed ear swelling, reduced the infiltration of mast cells in skin lesions and decreased expressions of IL-4, IFN-γ, TNF-α and TSLP in skin lesions. Furthermore, our experimental results demonstrated that GA suppressed the Th1/Th2/Th17-immune responses in the dLNs, inhibited the migration of LCs in dLNs. In conclusion, our findings suggested potential therapeutic effects of GA against MC903-induced AD-like skin lesions in mice.

The future of melasma therapy

AbstractMelasma is a chronic dermatologic condition defined by hyperpigmented macules and patches that appear in areas of sun exposure. Common areas of involvement include the forehead, cheeks, nose, and upper lip. Though melasma occurs in all genders and skin types, it is more commonly seen in females of Latin and African ancestry. Risk factors for the development of melasma include ultraviolet and visible light, high levels of estrogen, and family history. Histopathologic findings often include vacuolization at the basement membrane, increased melanin in the basal and suprabasilar layers of the epidermis with increased melanosomes and prominent dendrites; however, there is no increase in the total number of melanocytes. Newer findings reported also include an increase in vasculature and mast cells in lesional skin. Treatment of melasma includes an array of topical and oral medication in addition to various procedures. Medication treatment includes topical skin lightening agents that contain hydroquinone, azelaic acid, kojic acid, ascorbic acid, and newly released cysteamine. Tranexamic acid (TXA), both compounded in a topical form and given orally, has also been utilized with success. There is also a multitude of procedural treatments indicated for melasma, including micro‐needling and intradermal injections. Treatments, both topical and procedural, are often combined together for maximum benefit. Regardless of which option(s) you choose, it is of the utmost importance to adhere to strict sun protection to minimize the risk of continued recurrence, as UV and visible light exposure are often the culprits of melasma relapse.

Therapeutic effects of myricetin on atopic dermatitis in vivo and in vitro

BackgroundMyricetin (Myr) is a flavonoid compound that exist widely in many natural plants. Myr has been proven to have multiple biological functions, including immunomodulatory and anti-inflammatory effects. PurposeIn this study, we investigated the therapeutic effect of Myr on calcipotriol (MC903) induced atopic dermatitis (AD) mouse model and tumor necrosis factor (TNF)-α/interferon (IFN)-γ stimulated human immortal keratinocyte line (HaCaT) in vivo and in vitro. MethodsMC903 was applied topically to the left ears of mice to establish AD mouse model. After the AD model established successfully, the cream base, dexamethasone (DEX) cream or Myr cream were applied on the lesions of mice for 8 days. Through measuring ear thickness and scoring dermatitis severity, we evaluated the therapeutic effect of Myr, the draining lymph nodes (DLNs) and ears of the mice were collected for mechanistic study. In addition, TNF-α and IFN-γ-activated HaCaT cells were used to investigate the underlying mechanism. ResultsOur data demonstrated that Myr alleviated the symptoms of AD by exerting anti-inflammatory and anti-allergic functions in vivo. We found that Myr treatment suppressed ear swelling and IgE level in the serum, reduced the infiltration of mast cells in skin lesions, decreased expressions of thymus and activation regulated chemokine (TARC), IL-4, IFN-γ and thymic stromal lymphopoietin (TSLP) in ear lesions, increased the expressions of filaggrin (FLG). Furthermore, our experimental results demonstrated that Myr down-regulated the mRNA expressions of T-bet and GATA-3 in DLNs. In vitro, Myr treatment decreased MDC and TARC expressions in IFN-γ and TNF-α-induced HaCaT cells by blocking the NF-κB and STAT1 signal pathway. ConclusionThe present study is the first to investigate the anti-atopic effects of Myr. Our findings suggested the therapeutic effects of Myr against MC903-induced AD-like skin lesions in mice. Therefore, Myr may be a potential therapeutic agent for AD.

Effect of orally administered exopolysaccharides produced by Lactococcus lactis subsp. cremoris FC on a mouse model of dermatitis induced by repeated exposure to 2,4,6-trinitro-1-chlorobenzene

Lactococcus lactis subsp. cremoris (L. cremoris) FC is a lactic acid bacteria that produces exopolysaccharides (EPS). We studied the effects of EPS on the development of dermatitis in BALB/c mice induced by repeated exposure to 2,4,6-trinitro-1-chlorobenzene (TNCB) and on intestinal immunological activity in C3H/HeJ mice through Peyer’s patch cells. The EPS was shown to be composed of phosphopolysaccharides containing rhamnose, galactose, and glucose in a molar ratio of 1:1:3. Their weight average molecular weight (Mw) was 712,000. Oral administration of EPS suppressed skin thickening and infiltration of mast cells in skin lesions. EPS suppressed IL-4, IFN-γ, IL-6, and TNF-α overexpression caused by exposure to TNCB. Peyer’s patch cell medium cultured with EPS stimulated bone marrow cell proliferation. Together, these results suggest that EPS produced by L. cremoris FC may be an effective dietary component to prevent chronic skin inflammatory diseases.

Diospyros lotus leaf and grapefruit stem extract synergistically ameliorate atopic dermatitis-like skin lesion in mice by suppressing infiltration of mast cells in skin lesions.

Atopic dermatitis, a chronic relapsing and pruritic inflammation of the skin also thought to be involved in, or caused by immune system destruction is an upsetting health problem due to its continuously increasing incidence especially in developed countries. Mast cell infiltration in atopic dermatitis skin lesions and its IgE-mediated activation releases various cytokines and chemokines that have been implicated in the pathogenesis of atopic dermatitis. This study was aimed at investigating synergistic anti-inflammatory, anti-pruritic and anti-atopic dermatitis effects of Diospyros lotus leaf extract (DLE) and Muscat bailey A grapefruit stem extract (GFSE) in atopic dermatitis-like induced skin lesions in mice. Combinations of DLE and GFSE inhibited TNF-α and IL-6 production more than DLE or GFSE in PMA plus calcium ionophore A23187-activated HMC-1 cells. DLE and GFSE synergistically inhibited compound 48/80-induced dermal infiltration of mast cells and reduced scratching behavior than DLE or GFSE. Furthermore, DLE and GFSE synergistically showed a stronger ameliorative effect in skin lesions by reducing clinical scores; dermal infiltration of mast cells; ear and dorsal skin thickness; serum IgE and IL-4 production in atopic dermatitis-like mice. Collectively, these results suggest that DLE and GFSE synergistically exhibit anti-atopic dermatitis effects in atopic dermatitis-like skin lesions in mice.

Increasing Numbers of Mast Cells in Skin Lesions of Hyperpigmented Mycosis Fungoides with Large-Cell Transformation.

Dear Editor: Mycosis fungoides (MF) is a common type of cutaneous T-cell lymphoma. In recent years, several reports have been published on an uncommon and rare form of MF: hyperpigmented MF1,2,3,4. Herein, we report a case of hyperpigmented MF and discuss the mechanisms of hyperpigmentation. A 55-year-old Japanese man presented at the dermatological outpatient clinic of our hospital for widespread, pruritic, hyperpigmented plaques. The lesions, which first appeared nearly 15 years ago, gradually developed; they were diagnosed as MF, and were subsequently treated with topical corticosteroids and/or radiation with narrow-band ultraviolet B (UVB). However, no therapeutic response was observed and small nodular lesions developed. On physical examination of the patient, we observed hyperpigmented plaques with no atrophy on the face, trunk, and extremities (Fig. 1A). We found small nodules on the back. Blood cell count, urinalysis, and serum chemistry were within normal limits. Anti-human T-cell leukemia virus type I antibody was negative. Computed tomography scan from the neck to the pelvic area was normal. Histopathological analysis of skin specimens collected from a hyperpigmented plaque on the buttocks revealed slight acanthosis with atypical lymphocytic infiltration within the epidermis and upper dermis, containing some inflammatory cells and abundant melanophages (Fig. 1B). Rearrangement of the T-cell receptor (β chain) was detected using reverse transcriptase polymerase chain reaction method, but not Southern blot analysis. Immunohistochemically, most of the atypical lymphoid cells were CD4-positive (Fig. 1C and D). We diagnosed the lesions as MF, particularly, hyperpigmented MF. After X-ray irradiation to the nodules on the back, oral retinoid plus long-wave UVA therapy was started. Although CD30 (+) large-cell transformation was found during the therapeutic course, the patient's general health and skin improved over time. Fig. 1 (A) Clinical manifestation. Hyperpigmented plaques on the trunk. (B) Histology of the lesional skin of a hyperpigmented plaque. Slight acanthosis with atypical lymphocytic infiltration within the epidermis and upper dermis, containing abundant melanophages ... So far, the etiology of hyperpigmentation in certain MF cases is not clear. Pavlovsky et al.4 reported that hyperpigmented MF was characterized by a predominantly CD8-positive phenotype. Those authors speculated that CD8-positive tumor cells could have stronger cytotoxicity and affect neighboring cells such as melanocytes or basal keratinocytes, thereby causing interface changes and marked melanin incontinence, leading to the clinical appearance of hyperpigmentation4. However, in the present case, CD4-positive cells were dominant; therefore, hyperpigmentation cannot be attributed to this hypothesis. Yamamoto et al.1 reported the association of mast cell number with hyperpigmented MF. Melanocytes are strongly stimulated by stem cell factor (SCF), which also activates the mast cells. Increasing numbers of mast cells in the skin with lesions and an upregulation of SCF in sera of hyperpigmented MF cases were found1. Thus, we compared the numbers of mast cells in the skin with lesion with normal skin controls and non-pigmented MF cases. Mast cell counts were averaged from three random fields (cells/high-power field) in toluidine blue-stained skin specimens (Fig. 1E). As shown in Table 1, compared with normal and non-pigmented MF skin, the numbers of mast cells clearly increased in skin lesions of hyperpigmented MF. Unfortunately, we did not examine the serum levels of SCF. However, the increasing numbers of mast cells suggest the existence of similar underlying mechanisms as reported by Yamamoto et al.1 Table 1 Mast cell counts in skin

Elevated serum galectin-9 levels in patients with atopic dermatitis.

Galectin-9 is a member of the galectin family that has a wide spectrum of biological functions. Among them, galectin-9 has been known mainly as a potent chemoattractant for eosinophils. In addition, galectin-9 alters the T-cell balance by negatively regulating T-helper (Th)1 and Th17 cells, resulting in Th2 polarization. Atopic dermatitis (AD) is a skin allergic disease characterized by peripheral eosinophilia, mast cell activation and predominance of Th2 cells. To investigate possible roles of galectin-9 in AD, we measured serum galectin-9 levels in AD patients and investigated galectin-9 expression in lesional skin by immunohistochemistry. Serum galectin-9 levels in patients with AD were significantly higher than those in healthy controls and correlated with the Eczema Area and Severity Index. Serum galectin-9 levels were decreased after treatment, accompanied by improvement of skin lesions. Immunohistochemical study revealed that galectin-9 was expressed on epidermal keratinocytes and mast cells in lesional skin of AD. Our results suggest that elevated galectin-9 expression is associated with progression of AD and that galectin-9 could be a therapeutic target in AD.

Decrease in chymase activity is associated with increase in IL-6 expression in mast cells in atopic dermatitis.

Mast cell chymase and interleukin (IL)-6 can be involved in atopic dermatitis and chymase can degrade IL-6. Our aim was therefore to study the expression of mast cell chymase and IL-6 in atopic skin using enzyme- and immunohistochemistry and to analyse their interaction in vitro. Chymase activity was significantly reduced in mast cells in skin lesions whereas the percentage of IL-6(+) mast cells was increased. Low recombinant human (rh)-chymase concentration (10-100 ng/ml) stimulated and higher concentration (1,000 ng/ml) inhibited the proliferation of T cells and peripheral blood mononuclear cells. Rh-IL-6 inhibited T-cell proliferation, and even inhibited the proliferation induced by rh-chymase. Pretreatment of rh-IL-6 with a high rh-chymase concentration prevented the IL-6-induced inhibition in T-cell proliferation. The results suggest that reduction in chymase activity can give rise to increased cellular effects of mast cell IL-6 and that chymase and IL-6 can modify each other's effects.

Ameliorative effect of dietary milk-derived sphingomyelin concentrates on atopic-like dermatitis in NC/Nga mice

The effect of dietary milk-derived sphingomyelin concentrate (SPC) on atopic-like dermatitis was investigated. Atopic-like dermatitis was induced by sensitization to and repeated challenges with picryl chloride in male NC/Nga mice. Mice were fed an SPC-containing diet for 12 weeks, beginning 2 weeks before sensitization. The effect of SPC was assessed by monitoring clinical scores, serum immunoglobulin E levels, scratching behaviours, and in vitro cytokine productivities by splenocytes and mesenteric lymph node cells. Skin lesions were histologically investigated. Scratching behaviours were improved in the SPC group compared with the control group. The clinical score was ameliorated, and interleukin-6 productivity by splenocytes was significantly reduced in the SPC group. The numbers of infiltrated and degranulated mast cells in skin lesions were significantly lower in the SPC group than in the control group. These results indicate that dietary SPC significantly ameliorates atopic-like dermatitis in NC/Nga mice by suppressing systemic and peripheral inflammation.

Association of a Mutation in TRPV3 with Defective Hair Growth in Rodents

DS-Nh mice and WBN/Kob-Ht rats are spontaneous hairless mutant rodent strains. These animals develop spontaneous dermatitis under normal conditions. The non-hair Nh and Ht phenotypes are inherited in an autosomal dominant fashion, and the Nh mutation possesses a high potency for penetration. We previously reported that genes involved in dermatitis and hairlessness did not segregate from each other. Here, we carried out genetic analysis to identify the genes responsible for these hairless mutations. An amino-acid substitution at the same position in one gene was detected in DS-Nh mice and WBN/Kob-Ht rats: Gly573 to Ser (Nh mutation) or Gly573 to Cys (Ht mutation), located in the transient receptor potential (TRP) cation channel subfamily V member 3 (TRPV3) gene. Mutated TRPV3 was expressed in skin keratinocytes of DS-Nh mice. Histopathological analyses revealed that mast cells in skin lesions were increased in both rodents compared to their age-matched parent strains, and that this may partially be due to hairlessness and dermatitis. We concluded that TRPV3 was the gene responsible for Nh and Ht mutations, and that mutation in TRPV3 possibly correlated with increased mast cell numbers.

Early increase in TNF-alpha-containing mast cells in skin lesions

We have evaluated the numbers and immunohistochemical positivity for tumor necrosis factor (TNF) alpha of the mast cells in (a) 40 skin samples collected at autopsy from subjects who had survived for a few seconds to 1 h, (b) 10 samples of post-mortem skin lesions and (c) 10 surgical biopsies of healthy skin. Sections were treated with fluoresceinated avidin, to tag mast cell granules, followed by indirect immunohistochemistry for TNF-alpha with polyclonal primary and rhodaminated secondary antibodies. We could confirm a progressive increase in mast cell numbers, which became significant 1 h after trauma. More important, the fraction of mast cells positive for TNF-alpha increased progressively in the same time period and became significantly higher than controls in specimens collected more than 15 min after trauma. Samples from post-mortem lesions had significantly fewer mast cells and fewer TNF-alpha-positive cells than any other group of samples. The results suggest that mast cells are quickly recruited to an injured site in response to trauma and upregulate their TNF-alpha content, which can play an early role in directing tissue response to injury. The forensic pathologist can take advantage from this behavior of mast cells for the evaluation of the timing of early vital lesions.

Affinity cytochemistry analysis of mast cells in skin lesions: a possible tool to assess the timing of lesions after death

The histamine content in vital wounds is known to increase, with a zenith after 3 h, and then decrease until 24 h after wounding. We addressed whether this biochemical alteration has a morphological counterpart. Since the main source of skin histamine are mast cells, the distribution and number of these cells was assessed upon labeling with fluorescent avidin and with antibodies to the mast cell specific enzymes, chymase and tryptase. Analyses were performed on skin from 15 healthy controls (from surgical biopsies), from 15 post-mortem lesions and 75 vital lesions, obtained at autopsy from subjects who had survived from a few seconds to 24 h. The number of mast cells per unit area of section surface increased progressively with survival time, up to a maximum in subjects who survived 1-3 h ( p<0.01), and decreased thereafter becoming less than in the controls if lesions had occurred earlier than 6 h before death ( p<0.01). Samples from post-mortem lesions had significantly fewer mast cells than those of any other groups of samples ( p<0.01). We suggest that in association to other histological and circumstantial evidence the analysis of mast cells by affinity cytochemistry can help to discriminate vital from post-mortem lesions and to estimate survival time after lesions.

Medium- versus high-dose ultraviolet A1 therapy for urticaria pigmentosa: a pilot study

Background There is currently no definitive cure for urticaria pigmentosa (UP). Psoralen plus ultraviolet A therapy is efficacious in alleviating symptoms and reducing cutaneous lesions. Objective The purpose of this study was to assess the effect of ultraviolet A1 (UVA1) in adult patients with UP and to compare the effectiveness of high-dose (130 J/cm 2/day for 10 days) and medium-dose (60 J/cm 2/day for 15 days) UVA1 radiation. Methods Ten and 12 adult patients with UP were treated with high-dose or medium-dose UVA1, respectively. The number of skin lesions and dermal mast cells, the presence of Darier's sign, the intensity of pruritus, and quality of life measures were evaluated before, at the end of treatment, and 2 and 6 months later. Results Baseline characteristics were similar among the 2 groups of patients. In the majority of patients, the number of lesions was not significantly reduced. However, the number of mast cells in lesional skin decreased markedly in most patients by the end of treatment, and it remained low for the whole study period. Pruritus and quality of life improved considerably by the end of treatment, and the improvement was maintained during the 6-month follow up. No significant differences were observed between patients receiving high- or medium-dose UVA1. Conclusions UVA1 phototherapy ameliorates both objective and subjective symptoms of adult patients with UP and induces long-term remission in most cases. Medium-dose UVA1 appears at least as effective as high-dose UVA1.

Increased Interstitial Histamine Concentration in the Psoriatic Plaque

The psoriatic plaque contains an increased number of mast cells that are thought to have an important role in the initiation and maintenance of psoriatic lesions through the release of mediators such as histamine, proteoglycans, lipid mediators, and cytokines. It is not known, however, whether the interstitial concentration of histamine (and other mediators) is truly increased in the psoriatic plaque. The aim of the present study was to examine histamine concentration and histamine release from involved and uninvolved skin of psoriatic patients. Intracutaneous microdialysis was performed in lesional and nonlesional skin of 23 psoriatic subjects. The relative recovery of histamine was assessed after calibration in situ to approximately 76% in both lesional and nonlesional skin. The interstitial histamine concentration was 32 +/- 3 nmol per liter in lesional skin and 13 +/- 1 nmol per liter in nonlesional skin (mean +/- SEM) (p < 0.001). Dermal histamine release was estimated according to the Fick principle after measurements of the arterialized venous plasma histamine concentration (3 +/- 1 nmol per liter) and blood flow and was found to be 10-fold increased in lesional compared with nonlesional skin. The results are compatible with the hypothesis that mast cells in lesional skin secrete an increased amount of histamine that may contribute to the immunostimulation and inflammation in the psoriatic plaque.

Mitosis of mast cells in skin lesions of atopic dermatitis.

Mitoses of mast cells with cytoplasmic granules were observed in 6 out of 55 skin lesions of atopic dermatitis. It is thus likely that the local proliferation process of mast cells contributes to the increased number of mast cells in skin lesions of atopic dermatitis. Mitotic mast cells with cytoplasmic granules were also observed in 2 out of 8 dinitrochlorobenzene contact dermatitis lesions provoked in patients with atopic dermatitis. It is suggested that some mast cells in skin lesions of atopic dermatitis might be involved in the pathogenesis of type IV eczematous skin lesions of the disease.