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A disturbance in endothelial cell (EC) function maybe pathogenetic in the thrombotic tendency of patients with the lupus anticoagulant (LA). The ability of serum from normal subjects and patients with systemic lupus erythematosus (SLE), with and without the LA, to modulate the release of prostacyclin (PGI2) and the expression of procoagulant activity by cultured human EC was investigated. Only the 10% and 20% serum concentrations from patients with SLE-LA produced a significantly greater inhibition of 6-keto-prostaglandin F1α (6-keto-PGF1α) release (the stable metabolite of PGI2) than control serum. However, when patients with SLE-LA having Raynaud's phenomenon were excluded from this group, there was then no significant difference between the effect of the patient and control serum. Serum from patients with SLE ± LA caused a significant increase in EC procoagulant activity compared to healthy controls. The two-stage partial thromboplastin time expressed in seconds decreased from 66 (normal) to 34 (SLE - LA) and 31 (SLE + LA), but there was no significant difference between the patients with and without the LA. The significantly increased EC procoagulant activity induced by serum from patients with SLE ± LA may account for the observed increased incidence of thrombotic events in patients with SLE. Our data suggest that factors other than decreased prostacyclin release are responsible for the altered hemostasis observed in patients with SLE + LA. [ABSTRACT FROM AUTHOR]

Prostacyclin (PGI2) and PGE2, the predominant cyclooxygenase products of endothelial cells are potent vasodilators. An inability to produce appropriate concentrations of these prostanoids may be a factor in the pathogenesis of the digital vasospasm experienced by patients with Raynaud's phenomenon (RP). The effect of sera from normal subjects, patients with primary RP, and patients with RP in association with systemic sclerosis (SS) on the production of PGI2 and PGE2 by cultured human endothelial cells was investigated. All sera produced a dose-dependent inhibition of 6-keto-PGF1α, but both the 10% and 20% sera from patients with RP and SS produced a significantly greater inhibition than control sera. The mean production of 6-keto-PGF1α expressed in ng/104 cells was 2.278 (normal), 1.9311 (RP), and 2.1824 (SS) after incubation with 1% serum for 24 h. This decreased to 1.3647, 0.5927, and 0.4171, respectively following incubation with 20% sera for 24 h. This represented a 44% (normal), 76% (RP), and 83% (SS) inhibition of 6-keto-PGF1α production compared with serum free media. Similar results were obtained after 1 h incubation experiments. There was a nonsignificant decrease in mean PGE2 production following similar incubations with 1% and 20% sera for 24 h. These results suggest that factor(s) present in the sera of patients with RP may reduce the ability of endothelial cells to synthesize or release the vasodilator and antiaggregatory prostanoid PGI2. [ABSTRACT FROM AUTHOR]

The integrated behaviour of multiple senescent cell types within a single human tissue leading to the development of malignancy is unclear. Patients with Familial Melanoma Syndrome (FMS) have heterozygous germline defects in the CDKN2A gene coding for the cyclin inhibitor p16INK4a. Melanocytes within skin biopsies from FMS patients express significantly less p16INK4a but express higher levels of the DNA‐damage protein 훾H2AX a than fibroblastic cells. However, patient fibroblasts also exhibit defects since senescent cells do not increase in the skin during ageing and fibroblasts isolated from the skin of patients have increased replicative capacity compared to control fibroblasts in vitro, culminating in abnormal nuclear morphology. Patient derived fibroblasts also secreted less SASP than control cells. Predisposition of FMS patients to melanoma may therefore result from integrated dysregulation of senescence in multiple cell types in vivo. The inherently greater levels of DNA damage and the overdependence of melanocytes on p16 for cell cycle inhibition after DNA damage makes them exquisitely susceptible to malignant transformation. This may be accentuated by senescence‐related defects in fibroblasts, in particular reduced SASP secretion that hinders recruitment of T cells in the steady state and thus reduces cutaneous immunosurveillance in vivo. [ABSTRACT FROM AUTHOR]

Offers comments by a dermatologist on dermatomyositis. Diagnosis of dermatomyositis confirmed by muscle biopsy, electromyography and raised serum concentrations of creatine phosphokinase; Incidence of neoplasia in reported series; Nasopharyngeal carcinoma reported as the commonest underlying malignant disease in Chinese people; Statement that persons with a family history of cancer should be offered regular screening tests including chest radiography, mammography, pelvic ultrasonography and tests for tumor markers; Necessity of protection against the harmful rays of the sun.

Reactivation of the varicella zoster virus (VZV) increases during aging. Although the effects of VZV reactivation are observed in the skin (shingles), the number and functional capacity of cutaneous VZV-specific T cells have not been investigated. The numbers of circulating IFN-γ-secreting VZV-specific CD4+ T cells are significantly decreased in old subjects. However, other measures of VZV-specific CD4+ T cells, including proliferative capacity to VZV antigen stimulation and identification of VZV-specific CD4+ T cells with an major histocompatibility complex class II tetramer (epitope of IE-63 protein), were similar in both age groups. The majority of T cells in the skin of both age groups expressed CD69, a characteristic of skin-resident T cells. VZV-specific CD4+ T cells were significantly increased in the skin compared with the blood in young and old subjects, and their function was similar in both age groups. In contrast, the number of Foxp3+ regulatory T cells and expression of the inhibitory receptor programmed cell death -1 PD-1 on CD4+ T cells were significantly increased in the skin of older humans. Therefore, VZV-specific CD4+ T cells in the skin of older individuals are functionally competent. However, their activity may be restricted by multiple inhibitory influences in situ. [ABSTRACT FROM AUTHOR]

The cytokine IFN-α is secreted during viral infections and has been shown to inhibit telomerase activity and accelerate T cell differentiation in vivo. However, the mechanism for this inhibition is not clear. In this study, we show that IFN-α inhibits both the transcription and translation of human telomerase reverse transcriptase (hTERT), the catalytic component of telomerase, in activated CD8+ T cells. This was associated with increased activity of the repressor of hTERT transcription E2 transcription factor and decreased activation of NF-κB that promotes hTERT transcription. However IFN-α did not affect the translocation of hTERT from the cytoplasm to the nucleus. IFN-α also inhibits AKT kinase activation but increases p38 MAPK activity, and both of these events have been shown previously to inhibit telomerase activity. Addition of BIRB796, an inhibitor of p38 activity, to IFN-α-treated cells reversed, in part, the inhibition of telomerase by this cytokine. Therefore, IFN-α can inhibit the enzyme telomerase in CD8+ T cells by transcriptional and posttranslational mechanisms. Furthermore, the addition of IFN-α to CD8+CD27+CD28+ T cells accelerates the loss of both these costimulatory molecules. This suggests that persistent viral infections may contribute to the accumulation of highly differentiated/senescent CD8+CD27-CD28- T cells during aging by promoting IFN-α secretion during repeated episodes of viral reactivation. [ABSTRACT FROM AUTHOR]

We investigated the relationship between varicella zoster virus (VZV)-speciflc memory CD4+ T cells and CD4+Foxp3+ regulatory T cells (Tregs) that accumulate after intradermal challenge with a VZV skin test Ag. VZV-specific CD4+ T cells were identified with a MHC class II tetramer or by intracellular staining for either IFN-7 or IL-2 after Ag rechallenge in vitro. VZV-specific T cells, mainly of a central memory (CD45RA-CD27+) phenotype, accumulate at the site of skin challenge compared with the blood of the same individuals. This resulted in part from local proliferation because >50% of tetramer defined Ag-specific CD4+ T cells in the skin expressed the cell cycle marker Ki67. CD4+Foxp3+ T cells had the characteristic phenotype of Tregs, namely CD25hiCD127loCD39hi in both unchallenged and VZV challenged skin and did not secrete IFN-ɣ or IL-2 after antigenic restimulation. The CD4+Foxp3+ T cells from unchallenged skin had suppressive activity, because their removal led to an increase in cytokine secretion after activation. After VZVAg injection, Foxp3+CD25hiCD127loCD39hi T cells were also found within the VZV tetramer population. Their suppressive activity could not be directly assessed by CD25 depletion because activated T cells in the skin were also CD25+. Nevertheless, there was an inverse correlation between decreased VZV skin responses and proportion of CD4+Foxp3+ T cells present, indicating indirectly their inhibitory activity in vivo. These results suggest a linkage between the expansion of Ag-specific CD4+ T cells and CD4+ Tregs that may provide controlled responsiveness during Ag-specific stimulation in tissues. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 59-year-old man who experienced a nine episodes of erysipelas that affect his right cheek for almost six years. It states that several laboratory tests such as magnetic resonance imaging have confirmed that the patient has a homozygous mannose binding lectin (MBL) deficiency. It also discusses the homozygosity and heterozygosity, immunodeficiency state, and the lectin pathway of MBL.

Naturally occurring CD4(+)CD25(hi)Foxp3(+) Tregs (nTregs) are highly proliferative in blood. However, the kinetics of their accumulation and proliferation during a localized antigen-specific T cell response is currently unknown. To explore this, we used a human experimental system whereby tuberculin purified protein derivative (PPD) was injected into the skin and the local T cell response analyzed over time. The numbers of both CD4(+)Foxp3(-) (memory) and CD4(+)Foxp3(+) (putative nTreg) T cells increased in parallel, with the 2 populations proliferating at the same relative rate. In contrast to CD4(+)Foxp3(-) T cell populations, skin CD4(+)Foxp3(+) T cells expressed typical Treg markers (i.e., they were CD25(hi), CD127(lo), CD27(+), and CD39(+)) and did not synthesize IL-2 or IFN-gamma after restimulation in vitro, indicating that they were not recently activated effector cells. To determine whether CD4(+)Foxp3(+) T cells in skin could be induced from memory CD4(+) T cells, we expanded skin-derived memory CD4(+) T cells in vitro and anergized them. These cells expressed high levels of CD25 and Foxp3 and suppressed the proliferation of skin-derived responder T cells to PPD challenge. Our data therefore demonstrate that memory and CD4(+) Treg populations are regulated in tandem during a secondary antigenic response. Furthermore, it is possible to isolate effector CD4(+) T cell populations from inflamed tissues and manipulate them to generate Tregs with the potential to suppress inflammatory responses. [ABSTRACT FROM AUTHOR]

While memory T cells are maintained by continuous turnover, it is not clear how human regulatory CD4+CD45RO+CD25hi Foxp3+ T lymphocyte populations persist throughout life. We therefore used deuterium labeling of cycling cells in vivo to determine whether these cells could be replenished by proliferation. We found that CD4+CD45RO+Foxp3+CD25hi T lymphocytes were highly proliferative, with a doubling time of 8 days, compared with memory CD4+CD45RO+Foxp3-CD25- (24 days) or naive CD4+CD45RA+Foxp3-CD25- populations (199 days). However, the regulatory population was susceptible to apoptosis and had critically short telomeres and low telomerase activity. It was therefore unlikely to be self regenerating. These data are consistent with continuous production from another population source. We found extremely close TCR clonal homology between regulatory and memory CD4+ T cells. Furthermore, antigen-related expansions within certain TCR Vb families were associated with parallel numerical increases of CD4+CD45RO+CD25hiFoxp3+ Tregs with the same Vb usage. It is therefore unlikely that all human CD4+CD25+Foxp3+ Tregs are generated as a separate functional lineage in the thymus. Instead, our data suggest that a proportion of this regulatory population is generated from rapidly dividing, highly differentiated memory CD4+ T cells; this has considerable implications for the therapeutic manipulation of these cells in vivo. [ABSTRACT FROM AUTHOR]

We investigated the use of purinergic receptors as a new treatment modality for nonmelanoma skin cancers. Purinergic receptors, which bind adenosine 5′-tri-phosphate, are expressed on human cutaneous keratinocytes. Previous work in rat and human epidermis suggested functional roles for purinergic receptors in the regulation of proliferation, differentiation, and apoptosis. Immunohistochemical analysis of frozen sections in human basal cell carcinomas and squamous cell carcinomas for P2X5 , P2X7 , P2Y1 , P2Y2 , and P2Y4 receptors was performed, accompanied by detailed analysis of archive material of tumor subtypes in paraffin sections. Functional studies were performed using a human cutaneous squamous cell carcinoma cell line (A431), where purinergic receptor subtype agonists were applied to cells and changes in cell number were quantified via a colorimetric assay. Immunostaining in paraffin sections was essentially the same as that in frozen sections, although more detail of the subcellular composition was visible. P2X5 and P2Y2 receptors were heavily expressed in basal cell carcinomas and squamous cell carcinomas. P2X7 receptors were expressed in the necrotic center of nodular basal cell carcinomas and in apoptotic cells in superficial multifocal and infiltrative basal cell carcinomas, and squamous cell carcinomas. P2Y1 receptors were only expressed in the stroma surrounding tumors. P2Y4 receptors were found in basal cell carcinomas but not in squamous cell carcinomas. P2X5 receptors appear to be associated with differentiation. The P2X7 receptor agonist benzoylbenzoyl-adenosine 5′-triphosphate and high concentrations of adenosine 5′-triphosphate (1000–5000 μM) caused a significant reduction in A431 cell number (p<0.001), whereas the P2Y2 receptor agonist uridine... [ABSTRACT FROM AUTHOR]

OBJECTIVE Previous endocrine studies of women with acne have produced diverse results. This study was designed to seek evidence, from endocrine and genetic studies, for impaired steroid biosynthesis in patients with acne. DESIGN Adrenal stimulation tests with synthetic adrenocorticotrophic hormone (ACTH) were performed. MEASUREMENTS Steroid hormones were measured basally and 30 minutes after ACTH. The results were correlated with analysis of the steroid 21-hydroxylase gene (CYP21 ). PATIENTS Fifty-one consecutive female patients (mean age 27.1 years) referred with acne. RESULTS The median plasma 17-hydroxyprogesterone (17-OHP) before and 30 minutes after ACTH were 2.5 nmol/l (range 1.1–8.2) and 7.3 (2.1–17.8) nmol/l which were significantly above normal female controls (n = 11, mean age 25.6 years) at 1.5 (0.9–4.2) and 4.6 (2.6–8.4) nmol/l. Eighteen of 51 acne patients showed an abnormal 17-OHP response. The 21-hydroxylase gene (CYP21 ) was examined for major deletions and for three common point mutations in 31 of the patients (14 with exaggerated 17-OHP response). One patient had a deletion of CYP21 on one allele consistent with carrier status for the classical congenital adrenal hyperplasia (CAH). Five patients, one of whom had a normal 17-OHP response to Synacthen, were heterozygous for the val 281 leu mutation in exon 7 of the CYP21 and were therefore carriers for a mutation associated with late-onset CAH. One patient with a raised 17-OHP response was homozygous for the splice site mutation in intron 2 and one patient with a normal 17-OHP response was heterozygous for the mutation. None of the patients had the ile 172 asn mutation. Eight of the 31 acne patients who had CYP21 gene analysis were carriers for mutations in the 21-hydroxylase gene but only six would have been detected by an abnormal response of 17-OHP on stimulation. CONCLUSION Although alterations of the CYP21 gene were more common in acne than in controls there is a... [ABSTRACT FROM AUTHOR]

Basophils have been implicated as a source of histamine and pro-inflammatory eicosanoids in atopic dermatitis. However, mechanisms regulating basophil mediator release are not understood. An H3 receptor involved in the control of histamine synthesis and release has been identified in nervous tissue. In this study we have investigated 1) release of histamine, leukotriene C4, and prostaglandin D2 from anti - immunoglobulin E (IgE) - stimulated basophils of adults with atopic dermatitis and unaffected individuals and 2) specific H3 receptor-dependent basophil mediator release, using an H3 receptor agonist and antagonist. Basophil-rich leukocyte fractions were prepared by dextran sedimentation of venous blood from 19 patients with atopic dermatitis (five male, 14 female, mean age 30.6 years, range 19-59 years) and 15 unaffected individuals (five male, 10 female, mean age 27.6 years, range 19-50 years). Anti-IgE (0.78-78.0 μg/ml) stimulation of basophils induced a concentration-dependent release of histamine and leukotriene C4, but not prostaglandin D2. Histamine release was maximally induced by 7.8 μg/ml anti-IgE with no significant (Mann-Whitney U test) difference between atopic basophils (n = 17; 43.65 ± 4.16% mean ± SEM) and normal basophils (n = 13; 52.23 ± 4.39%). LTC4 release was maximal from atopic basophils incubated with 2.6 μg/ml anti-IgE (n = 5; 0.99 ± 0.29 pg/106 cells) and from normal basophils incubated with 0.78 μg/ml anti-IgE (n = 5; 25.38 ± 5.79 pg/106 cells). Anti-IgE-stimulated release of leukotriene C4 from atopic basophils was significantly less than from normal basophils at all concentrations (p <0.05). Basophils were co-incubated with anti-IgE (2.6 and 7.8 μg / ml) and either the H3 receptor agonist, (R) α-methylhistamine (10-8 and 10-7 M). Neither drug modulated anti-IgE-incuded release of histamine (atopics, n=10; normals, n=8). These results indicate 1) that basophils from adults with atopic dermatitis release the same amount of histamine as, but less leukotriene C4 than, basophils of unaffected adults and 2) that h3 receptors are not involved in anti-IgE release of histamine from basophils. These data do not support a role for increased basophil release of histamine as a mediator in the itch and erythema of atopic dermatitis in adults. [ABSTRACT FROM AUTHOR]

There is increasing evidence that exposure to organic allergens may induce or exacerbate lesional skin in patients with atopic dermatitis. In this study, patients with atopic dermatitis were patch tested to 11 common organic allergens and to control chambers containing 0.4% phenol and 50% glycerin in 0.9% saline. In biopsies from positive patch test reactions, patch test control skin, lesional eczematous and non-lesional skin from atopic individuals, and normal skin from non-atopic volunteers, the presence and distribution of macro- phages (RFD7+), dendritic cells (RFD1+), and Langerhans cells, and the expression of the low-affinity receptor for IgE (CD23) were investigated. In patch test reactions and lesional skin samples, inflammatory infiltrates of diffusely distributed macrophages (RFD7+), dendritic cells (RFD1+), T lymphocytes (RFTmix+), and Langerhans cells (CD1+) were seen, the latter being present in both the epidermis and the dermis. The numbers of Langerhans cells were reduced in the epidermis and increased in the dermis in patch test reactions and lesional skin compared to their controls. Double staining revealed a change in the distribution of CD23 antigen. In patch test control and non-lesional biopsies many macro- phages and only a few Langerhans cells within the dermal infiltrates expressed this antigen. In patch test reaction and lesional skin samples, however, the proportion of CD23+ dermal Langerhans cells had increased compared to macro- phages. Furthermore, in these latter samples an increased proportion of dermal CD1+ cells expressed the dendritic cell (RFD1+) marker. These results show that following antigen challenge there are marked similarities between the phenotype of the cellular infiltrate in patch test reaction and lesional skin biopsies, and also demonstrate a changing distribution of CD23 on antigen-presenting cells. [ABSTRACT FROM AUTHOR]

Background: The live attenuated vaccine Zostavax was developed to prevent varicella zoster virus (VZV) reactivation that causes herpes zoster (shingles) in older humans. However, the impact of vaccination on the cutaneous response to VZV is not known.Methods: We investigated the response to intradermal VZV antigen challenge before and after Zostavax vaccination in participants >70 years of age by immunohistological and transcriptomic analyses of skin biopsy specimens collected from the challenge site.Results: Vaccination increased the proportion of VZV-specific CD4+ T cells in the blood and promoted the accumulation of both CD4+ and CD8+ T cells in the skin after VZV antigen challenge. However, Zostavax did not alter the proportion of resident memory T cells (CD4+ and CD8+) or CD4+Foxp3+ regulatory T cells in unchallenged skin. After vaccination, there was increased cutaneous T-cell proliferation at the challenge site and also increased recruitment of T cells from the blood, as indicated by an elevated T-cell migratory gene signature. CD8+ T-cell-associated functional genes were also highly induced in the skin after vaccination.Conclusion: Zostavax vaccination does not alter the abundance of cutaneous resident memory T cells but instead increases the recruitment of VZV-specific T cells from the blood and enhances T-cell activation, particularly cells of the CD8+ subset, in the skin after VZV antigen challenge. [ABSTRACT FROM AUTHOR]