Biomedical subjects
Publications and source records attributed to Michael David.
Tefillin (phylacteries) are a religious article worn by observant Jewish men. Only two cases of allergic contact dermatitis from tefillin have been reported previously. We describe 7 new cases of tefillin contact dermatitis and review the literature on contact allergy caused by religious objects and practices. All our patients had contact allergy to potassium dichromate, which was the only allergen relevant to tefillin .
Delivery of DNA encoding therapeutic genes in vivo has great potential for treating malignancy as well as genetic diseases. Delivery of placebo DNA without a transgene is used as a control in gene therapy studies. It is tacitly assumed by most investigators that the protein expressed from the transfected DNA has phenotypic consequences, but that the consequences are not from the DNA itself. Here, we demonstrate that transfection of control plasmid DNA (that does not express a gene product) into tumor cell lines induces a dramatic (>10-fold) increase in the expression of the interferon (IFN)-regulated genes IRF7, STAT1, MIG (approved gene symbol CXCL9), MHCI (MICA), and CD11a (ITGAL) in tumor cell lines. Induction of these genes inhibits tumor development and tumor growth in immunocompetent mice that are immunized with apoptotic tumor cells. The antibody depletion study indicates that the underlying mechanism by which transfection of control DNA induces IFN-regulated genes is the induction of a secreting factor(s) such as IFN-beta. Three lines of evidence indicate that DNA transfection-mediated induction of IFN-regulatory genes is independent of TLR9. The three lines of evidence are: (1) TLR9 is not expressed in either SCCVII or 4T1 cell line, (2) activation of TLR9 downstream signaling molecules is not associated with the induction of gene expression, and (3) the secretion factor(s) obtained from the conditioned medium of DNA-transfected SCCVII tumor cells induces the same type of gene expression in the 4T1 tumor cell line, which is refractory to the gene induction by DNA transfection. Our finding indicates that the 4T1 tumor cell line, which is resistant to the DNA transfection-mediated induction of IFN-regulated genes, can be used to determine the real therapeutic gene function.
Cytokine production is under genetic control and certain allelic variants of cytokine genes are associated with lower or higher cytokine production in vitro and in vivo. The general concept is that a shift from a Th1 to a Th2 cytokine profile accompanies disease progression from patch-stage mycosis fungoides to tumour stage, although the results of the studies carried out have not been entirely conclusive. We aimed to investigate whether certain cytokine polymorphisms might represent a risk factor for developing patch-stage mycosis fungoides. Genotyping for IFN-gamma (Th1 cytokine), IL-6, IL-10 (Th2 cytokines), TNF-alpha and TGF-beta 1 was undertaken for 33 patients with patch-stage mycosis fungoides and the results were compared with those in a control group. Genotype distribution showed no significant differences between the patients and the controls for any of the five cytokines studied. Our study suggests that patch-stage mycosis fungoides is not determined by a specific genotype polymorphism. However, further studies on larger numbers of cases are needed before definite conclusions can be drawn.
BACKGROUND: Laser treatment of venous malformations is a major challenge because of the large variations in skin pigmentation, anatomic location, and vessel size and depth. OBJECTIVE: To determine the safety and effectiveness of electro-optical synergy, a new technology that combines the 900 nm diode laser with radiofrequency current for the treatment of facial venous malformation. METHODS: Fourteen patients with Fitzpatrick skin types II to IV were treated for facial venous malformations with simultaneous radiofrequency energy (60-80 J/cm3) and optical diode laser energy (fluence 80-100 J/cm2) in one to three sessions. All lesions measured less than 100 cm2. Lesion clearance was evaluated by three specialists on the basis of digital photographs taken before the first treatment and 1 and 2 months after the last treatment. RESULTS: Thirteen patients showed a complete response and one patient a partial response. The results were rated excellent in the 13 patients and good in one patient. Transient swelling, erythema, and pain were present in all patients, with permanent scarring in only one patient. CONCLUSION: The combination of laser light and radiofrequency energy is effective and safe for the treatment of facial venous malformations. It provides additional heating of the vessels without increasing laser intensity. The side effects are minimal.
Pemphigus is a fatal autoimmune disease in which autoimmunoglobulins PV-IgG (binding to desmoglein 3) and PF-IgG (binding to desmoglein 1) in pemphigus vulgaris and pemphigus foliaceus, respectively, cause intraepidermal blisters, cell-cell separation (acantholysis), and cell death. The mechanism of acantholytic lesion formation has not yet been elucidated. Recently, we have reported that an apoptotic mechanism might be operative in PV-IgG-induced acantholysis: (1) in patients' lesional and some perilesional skin portions, the FasR pathway is activated as its components were enriched; (2) in cultured keratinocytes, PV-IgG upregulates effectors of the FasR pathway (including the mitochondrial loop), as found by immunodetermination (cytochemistry, Western blot of pathway effectors) and determination of caspases 1, 3, and 8 activity/activation; (3) in organ cultures of skin incubated with PV-IgG, activated caspase 8 was found also in perilesional cells and coaggregated with bound PV-IgG; (4) caspase 8 activation in DISCs precedes caspase 3 activation in keratinocytes in cultures upon incubation with PV-IgG. Because caspase activation was shown to accompany lesion formation in cell and organ cultures incubated with PV-IgG, we used caspase activity to monitor the pathogenicity of PV-IgG in relation to PV-IgG binding to epithelia. A rough correlation was found between sera titers, determined by IIF and by immunoblot binding to desmoglein 3, and activation of caspase 3.
Pemphigus is a group of organ-specific, autoimmune, mucocutaneous blistering disorders with an established immunological basis. The goal of therapy in pemphigus is to eliminate or neutralize the pathogenic autoantibodies. As in other autoimmune diseases, early systemic therapy is important for control of the disease and for achieving sustained remissions. Because of the sparse number of controlled studies, the treatment of autoimmune bullous diseases remains controversial. In this article, we discuss the current therapeutical options in pemphigus with an emphasis on IVIg treatment and suggest guidelines for the use of IVIg in the treatment of pemphigus.
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Posttranslational modification of proteins within T cell receptor signaling cascades allows T lymphocytes to rapidly initiate an appropriate immune response. Here we report a role for arginine methylation in regulating cytokine gene transcription in the T helper lymphocyte. Inhibition of arginine methylation impaired the expression of several cytokine genes, including the signature type 1 and type 2 helper cytokines, interferon gamma, and interleukin-4. T cell receptor signaling increased expression of the protein arginine methyltransferase PRMT1, which in turn methylated the nuclear factor of activated T cells (NFAT) cofactor protein, NIP45. Arginine methylation of the amino terminus of NIP45 modulated its interaction with NFAT and resulted in augmented cytokine production, while T cells from mice lacking NIP45 had impaired expression of IFNgamma and IL-4. Covalent modification of NIP45 by arginine methylation is an important mechanism of regulating the expression of NFAT-dependent cytokine genes.
The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is an essential cascade for mediating normal functions of different cytokines in the development of the hematopoietic and immune systems. Chronic exposure to arsenic has been found to cause immunotoxicity and has been associated with the suppression of hematopoiesis (anemia and leukopenia). Here, we report the novel finding of arsenic-mediated inactivation of the JAK-STAT signaling pathway by its direct interaction with JAK tyrosine kinase. Pretreatment with sodium arsenite strongly inhibited IL-6-inducible STAT3 tyrosine phosphorylation in HepG2 cells and did not affect its serine phosphorylation. As a result, sodium arsenite completely abolished STAT activity-dependent expression of suppressors of cytokine signaling (SOCS). Both cellular and subcelluar experiments showed that the inhibition of JAK-STAT signaling resulted from JAK tyrosine kinase's direct interaction with arsenite, and that arsenic's suppression of JAK tyrosine kinase activity also occurred in the interferon gamma (IFNgamma) pathway. The ligand-independent inhibition by arsenic indicates that JAK was the direct target of arsenic action. Other inflammatory stimulants, stress agents, and metal cadmium failed to induce similar effects on the tyrosine phosphorylation of STAT3 as arsenic does. Our experiments also revealed that arsenic inactivation of the JAK-STAT pathway occurred independent of arsenic activation of MAP kinases. Taken together, our findings indicate that arsenic directly inhibits JAK tyrosine kinase activity and suggest that this direct interference in the JAK-STAT pathway may play a role in arsenic-associated pathogenesis.
RNA helicase A (RHA) undergoes nuclear translocation via a classical import mechanism utilizing karyopherin beta. The nuclear transport domain (NTD) of RHA is known to be necessary and sufficient for its bi-directional nuclear trafficking. We report here that arginine methylation is a novel requirement for NTD-mediated nuclear import. Nuclear translocation of glutathione S-transferase (GST)-NTD fusion proteins is abrogated by arginine-methylation inhibitors. However, in vitro arginine-methylation of GST-NTD prior to injection allows the fusion protein to localize to the nucleus in the presence of methylation inhibitors. Removal of the arginine-rich C-terminal region negates the effects of the methylation inhibitors on NTD import, suggesting that methylation of the NTD C terminus the relieves the cytoplasmic retention of RHA. The NTD physically interacts with PRMT1, the major protein arginine methyltransferase. These findings provide evidence for a novel arginine methylation-dependent regulatory pathway controlling the nuclear import of RHA.
IFN-regulatory factor 3 (IRF3) is known to participate in the transcriptional induction of chemokines and cytokines, including IFNs, as a result of viral or bacterial infection. In this study, we demonstrate that the LPS-mediated activation of IRF3 and subsequent induction of chemokine genes or IRF3-responsive reporter constructs are inhibited after exposure of human or murine macrophages to the Bacillus anthracis toxin lethal factor. The inhibitory effect is caused by interference with the activation of the stress-activated protein kinase, p38, due to a proteolytic cleavage of mitogen-activated protein kinase kinase 6, and can be overcome by the ectopic expression of a cleavage-resistant mutant of mitogen-activated protein kinase kinase 6 or a constitutively active IRF3. The lethal factor-mediated inhibition of IRF3 activation and subsequent cytokine production through bacterial membrane components offers Bacillus anthracis an efficient mechanism to evade the innate immune response.
BACKGROUND: An increased prevalence of benign solar damage (eg, facial wrinkles) but not neoplastic lesions was observed among patients with psoriasis who were exposed to Dead Sea climatotherapy compared with controls. OBJECTIVES: To compare the prevalence of actinic keratosis in psoriatic patients and controls and to assess whether known risk factors behave similarly in both groups. DESIGN: Multicenter cross-sectional study. SETTING: Dermatology clinics in 4 participating Israeli hospitals and at a Dead Sea clinic. PARTICIPANTS: Adult subjects (n = 460) with plaque-type psoriasis were recruited from the Israel Psoriasis Association (volunteer sample) and from dermatology clinics (convenience sample). The control group (n = 738) consisted of nonimmunosuppressed patients attending these clinics for benign conditions unrelated to sun exposure, such as atopic or contact dermatitis. MAIN OUTCOME MEASURES: Prevalence and distribution of actinic keratoses and odds ratios associated with skin, hair, and eye color and propensity or history of sunburn adjusted for age, ethnicity, and sun exposure. RESULTS: Actinic keratoses were observed in 200 controls (27%) and 51 subjects (11%) (P<.001). This increased prevalence occurred in both sexes, participants aged 35 years or older, all ethnic groups, smokers, and nonsmokers. The anatomical distribution of lesions did not substantially differ between subjects and controls. In multivariate analysis, psoriasis conferred a protective effect (odds ratio, <1), as did dark skin, dark eyes, and a history of severe sunburn in childhood. However, significant interactions were observed between psoriasis and hair color as well as psoriasis and propensity to sunburn, whereby a linear association was observed for controls but not for patients with psoriasis. CONCLUSIONS: Psoriasis confers protection against actinic keratosis. Hair color and propensity to sunburn exert differential effects among psoriatic patients and controls.
BACKGROUND: Acquired ichthyosis is a known paraneoplastic sign of lymphoproliferative malignancies, with histopathologic findings that are nonspecific, revealing no insinuation of the underlying neoplasm. Ichthyosiform eruption as a specific manifestation of mycosis fungoides (MF), ie, ichthyosiform MF, is, however, regarded as rare and to date has been reported in only a few cases. OBJECTIVE: We sought to study the clinical, histopathologic, immunohistochemical, and genotypic features of patients with ichthyosiform MF. METHODS: The files of patients with MF seen during the past 8 years in our department were reviewed to search for cases of ichthyosis-like MF. RESULTS: Seven patients, comprising 3.5% of the patients seen with MF, had an ichthyosiform eruption with histopathologic features characteristic of early MF. In 2 patients it was the sole manifestation of the disease and in 5 patients it appeared either in conjunction with conventional patches and/or plaques or with follicular lesions. Immunohistochemically, all showed a predominance of CD3+ CD4+, except for 1 patient in whom the epidermotropic T cells were predominantly CD8+. In 3 of the 7 patients clonality could be demonstrated by polymerase chain reaction. None had extracutaneous involvement. All had an indolent course of the disease and responded well to skin-targeted therapies. CONCLUSIONS: Ichthyosiform MF is yet another atypical clinical variant of cutaneous T-cell lymphoma that is not as rare as reflected in the literature. It may be the sole manifestation of the disease but also may appear in conjunction with conventional or follicular MF lesions.
BACKGROUND: Climatotherapy at the Dead Sea (CDS) is a well-established therapeutic modality for moderate to severe psoriasis vulgaris, resulting in sustained remissions. It has also been found to be effective for atopic dermatitis, another T-cell-mediated dermatosis. OBJECTIVE: We sought to prospectively evaluate the efficacy of CDS in patch-stage mycosis fungoides. METHODS: A total of 12 patients with patch-stage mycosis fungoides (6 with stage IA and 6 with stage IB) were treated with CDS as monotherapy for 28 consecutive days according to the protocol for psoriasis, ie, a gradual increase of sun exposure to a maximum of 3 hours daily. RESULTS: A total of 9 patients achieved a complete clinical response (CCR), defined as no disease activity present; 2 achieved an almost CCR, defined as the reduction by more than 90% of disease activity; and 1 achieved a partial response, ie, reduction by more than 50% of disease activity. A CCR was achieved in all the patients with stage IA disease and in 3 of the 6 patients with stage IB disease. Of the 9 with a CCR, 6 also showed histopathologic clearing. Duration of the remissions, during which no therapy was allowed except for emollients, lasted from 2 to 9 months (mean: 5 months). No serious short-term side effects were recorded. CONCLUSION: CDS appears to be an effective, well-tolerated therapy for patch-stage mycosis fungoides.
The popularity of laser-assisted hair removal has grown rapidly since April 3, 1995 when the Food and Drug Administration approved the introduction of the first hair removal laser system. Lasers with wavelengths in the red and infrared portion of the electromagnetic spectrum are most often used for hair removal because they effectively target melanin in the hair follicle and can potentially penetrate to the appropriate depth of the dermis. Despite all efforts to protect the skin from damage, photoepilation may result in clinically significant adverse reactions. The most common and known side effects of laser hair removal include transient erythema, perifollicular edema, pain, folliculitis, hyper-pigmentation, hypopigmentation, crusting, purpura, erosions and scarring. The present report describes the appearance of a reticulate erythema after diode laser treatment for hair removal, encountered in 10 patients in our clinics in London and Israel. To the best of our knowledge, this is the first report of this side effect. The aim of this work is to detail the clinical manifestations, histological findings, and follow-up of these patients in order to expand the clinical spectrum of laser-assisted hair removal side effects and to alert dermatologists to the possibility of this type of net-like erythema.
Alefacept is the first biologic agent approved for the treatment of chronic, moderate to severe plaque-type psoriasis. It is a fully human fusion toxin, which binds to CD2, blocks costimulatory signaling, and selectively induces apoptosis of activated memory T cells involved in the pathogenesis of psoriasis. Alefacept has a slow onset of action, peaking approximately 18 weeks after the first injection of a 12-week course. However, it has several important advantages over the existing conventional immunosuppressive therapies for psoriasis: it is associated with long remissions without the need for maintenance therapy; its efficacy improves with subsequent courses; and it has a high safety profile. This review summarizes the mechanism of action of alefacept and the results of the clinical trials, with special emphasis on efficacy, pharmacodynamic effects on circulating lymphocytes, and safety and tolerability. Current guidelines based on the best available data to date are also presented.
Interferon regulatory factor 3 (IRF3) mediates the transcriptional induction of interferon-stimulated genes (ISGs) in response to viral and bacterial infections. Here we show that the hydroxystilbene piceatannol inhibits the LPS-mediated activation of IRF3 and subsequent ISG induction. Consequently, piceatannol blocks the LPS-induced up-regulation of critical mediators of the inflammatory response such as interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), intercellular adhesion molecule 1 (ICAM-1), and macrophage chemoattractant protein (MCP-1). Furthermore, the LPS-mediated induction of tissue factor (TF), a cell surface protein responsible for initiating the coagulation cascade, is also inhibited by piceatannol. The effectiveness of piceatannol in blocking both the inflammatory response and the coagulation pathway is evidenced by its ability to confer protection against LPS-induced septic shock in a murine model. Thus, IRF3 appears to be a promising target for pharmacologic intervention in the prevention or treatment of septic shock syndrome.
Type I and II interferons (IFNs) exert opposing effects on the progression of multiple sclerosis, even though both IFNs use the signal transducer and activator of transcription 1 (STAT1) as a signaling mediator. Here we report that STAT1-deficient mice expressing a transgenic T cell receptor against myelin basic protein spontaneously develop experimental autoimmune encephalomyelitis with dramatically increased frequency. The heightened susceptibility to this autoimmune disease appears to be triggered by a reduced number as well as a functional impairment of the CD4+ CD25+ regulatory T cells in STAT1-deficient animals. Adoptive transfer of wild-type regulatory T cells into STAT1-deficient hosts is sufficient to prevent the development of autoimmune disease. These results demonstrate an essential role of STAT1 in the maintenance of immunological self-tolerance.