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T A Luger

Publications and source records attributed to T A Luger.

At least 19 recordsLinked to original sources
PubMed2001

Overexpression of CD40 ligand in murine epidermis results in chronic skin inflammation and systemic autoimmunity.

CD40-CD40 ligand (L) interactions play a pivotal role in immune-mediated inflammatory responses via the activation of antigen-presenting cells (APCs). To investigate the effects of continuous activation of resident tissue APCs, in this case the Langerhans cells (LCs) of the skin, CD40L expression was targeted to the basal keratinocytes of the epidermis of mice using the keratin-14 promoter. Approximately 80% of the transgenic (Tg) mice spontaneously developed dermatitis on the ears, face, tail, and/or paws. Compared with littermates, Tgs had a >90% decrease in epidermal LCs yet increased numbers within the dermis suggestive of enhanced emigration of CD40-activated LCs. Tgs also displayed massive regional lymphadenopathy with increased numbers of dendritic cells and B cells. Moreover, a decrease in IgM and an increase in IgG1/IgG2a/IgG2b/IgE serum concentrations was detectable. Screening for autoantibodies revealed the presence of antinuclear antibodies and anti-dsDNA antibodies implicative of systemic autoimmunity. Accordingly, renal Ig deposits, proteinuria, and lung fibrosis were observed. Adoptive transfer of T cells from Tgs to nonTg recipients evoked the development of skin lesions similar to those found in the Tgs. Dermatitis also developed in B cell-deficient CD40L Tg mice. These findings suggest that in situ activation of LCs by CD40L in the skin not only leads to chronic inflammatory dermatitis but also to systemic mixed-connective-tissue-like autoimmune disorders, possibly by breaking immune tolerance against the skin.

Animals↗
PubMed2001

Failure of alpha-melanocyte stimulating hormone to attenuate cerebral complications in experimental pneumococcal meningitis.

Alpha-melanocyte-stimulating hormone (alpha-MSH) is an endogenous neuroimmunomodulatory peptide that can inhibit a broad range of inflammatory mediators known to be involved in the pathophysiology of bacterial meningitis. We evaluated the effect of alpha-MSH in a rat model of pneumococcal meningitis. Rats were intracisternally infected with Streptococcus pneumoniae and treatment was started 6 h after infection. Both systemic and intracisternal alpha-MSH failed to influence blood-brain barrier disruption, increased intracranial pressure, brain cytokine concentrations (IL-1beta, IL-6, TNF-alpha, MIP-2, and IL-10), CSF bacterial titers, and clinical parameters of disease severity (weight loss, body temperature, and blood pressure), although the treatment strongly increased the CNS concentrations of alpha-MSH. However, systemic but not intracisternal alpha-MSH slightly reduced the CNS leukocyte accumulation, indicating that leukocyte extravasation is inhibited by alpha-MSH from the blood side. Our results show that alpha-MSH reduces the CNS leukocyte accumulation by its systemic action, but does not attenuate meningitis-associated intracranial complications.

Animals↗
PubMed2001

Neutral endopeptidase terminates substance P-induced inflammation in allergic contact dermatitis.

Sensory nerve-derived neuropeptides such as substance P demonstrate a number of proinflammatory bioactivities, but less is known about their role in inflammatory skin disease. The cell surface metalloprotease neutral endopeptidase (NEP) is the principal proteolytic substance P-degrading enzyme. This study tests the hypothesis that the absence of NEP results in dysregulated inflammatory skin responses. The effector phase of allergic contact dermatitis (ACD) responses was examined in NEP(-/-) knockout and NEP(+/+) wild-type mice and compared with the irritant contact dermatitis response in these animals. NEP was found to be normally immunolocalized in epidermal keratinocytes and dermal blood vessels. The ACD ear swelling response was 2.5-fold higher in animals lacking NEP and was accompanied by a significant increase in plasma extravasation and infiltration of inflammatory leukocytes. The augmented ACD response in NEP(-/-) animals was abrogated by either administration of a neurokinin receptor 1 antagonist or by repeated pretreatment with topical capsaicin. Similar to NEP(-/-) mice, the acute inhibition of NEP in NEP(+/+) animals resulted in an augmented ACD response. In contrast to the ACD responses, little differences were observed in the irritant contact dermatitis response of NEP(-/-) compared with NEP(+/+) animals after epicutaneous application of the skin irritants croton oil or SDS. Thus, these results indicate that NEP and cutaneous neuropeptides have a significant role in the pathogenesis of ACD.

Administration, Cutaneous↗
PubMed2001

[Cyclic neutropenia. Detection of a mutation in the gene for neutrophil elastase (ELA2)].

BACKGROUND AND OBJECTIVE: Cyclic neutropenia is a rare congenital hematopoietic disease which occurs sporadically or as an autosomal dominantly inherited disorder. Recently, the locus for cyclic neutropenia was mapped to chromosome 19p13.3. Autosomal dominant and sporadic cyclic neutropenia are now attributable to mutations of the ELA2 gene encoding neutrophil elastase. PATIENTS/METHODS: Based on a case report we review the clinical picture and diagnostic criteria of cyclic neutropenia and report about the recent molecular biological findings and current treatment options. RESULTS: Serial blood cell counts revealed the characteristic oscillations of the circulating neutrophils with 21-day periodicity from near normal to extremely low levels. The neutrophil nadir lasted 3-5 days. The neutropenia was associated with fever, malaise, painful oral aphthous ulcers and lymphadenopathy. Mutational analysis of the patient's genomic DNA revealed a single base-pair transition (nt 4716, G-->A) in intron 4 of ELA2. Since the initiation of therapy with subcutaneous recombinant human granulocyte-stimulating colony factor (rHuG-CSF) 24 months ago, the patient has been free of symptoms. CONCLUSIONS: Despite the typical medical history with onset of the symptoms in early infancy the diagnosis of cyclic neutropenia was not established until the age of 9 years. A common reason for the delayed diagnosis of cyclic neutropenia may be unawareness of the rare but distinctive disorder and the practice of obtaining screening blood counts without leukocyte differentials. Patients with cyclic neutropenia should be enrolled to the Severe Chronic Neutropenia International Registry (SCNIR).

Base Pairing↗
PubMed2001

[Cytokines: current status and prospects in the treatment of skin tumors].

Various therapeutic options using cytokines have been described in the treatment of melanoma, T cell lymphoma, B cell lymphoma, squamous cell carcinoma, basal cell carcinoma and Merkel cell carcinoma. The treatment regimens include cytokine substitution, cytokine induction, cytokine transfection and therapeutic cytokine constructs. In the adjuvant treatment of melanomas, IFN-alpha has become well established. Statistical evaluations of different adjuvant trials show that a significant prolongation of recurrence-free intervals can be achieved. IL-2 has a role in the therapy of advanced melanomas as well as in vaccination strategies. Further possible therapeutic immune modulations, which have been evaluated in experimental approaches and pilot studies, include treatment with IL-4, IL-7 and GM-CSF. Treatment with IL-12 promises to open new perspectives. A well established regimen in the treatment of T cell lymphoma stages Ia-IIb is the combination of PUVA and IFN-alpha. In vitro data also indicate an important (patho)physiological role for IL-12, so that this agent has been tested in phase I studies. IL-2, IFN-gamma, and the fused cytokine-toxin molecules DAB389IL-2 offer further therapeutic alternatives. B cell lymphomas are treated with antibody-IL-2 fusion proteins. Advanced or inoperable squamous cell carcinoma and basal cell carcinoma may be treated with local IFN-alpha injections. IFN-alpha or TNF-alpha may be considered for the treatment of recurrent or advanced Merkel cell carcinoma. In dermatological oncology cytokine treatment focuses on melanome an T cell lymphome. Cytokine application is mainly an integral part of multimodal regimens.

Animals↗
PubMed2001

Differential storage of hydroxyethyl starch (HES) in the skin: an immunoelectron-microscopical long-term study.

Hydroxyethyl starch (HES) is widely used as a plasma substitute. Serious side effects occur only rarely, whereas a high incidence of severe pruritus has been reported. Moreover, tissue storage of HES has been demonstrated in various organs. The aim of the current study has been to examine precisely the intracellular uptake and long-term storage of HES in the skin. Skin biopsies from 119 patients who received HES of various preparations and cumulative dosage were obtained 30 min to 130 months after infusion therapy. The samples were analysed by ultrastructural and immunoelectron microscopy with HES-specific monoclonal and polyclonal antibodies. A characteristic vacuolisation of perivascular histiocytes was a regular finding in all skin biopsies as early as 1 day after a single infusion of 30 g. Immunoreactivity for HES was demonstrable within the vacuoles. Generally, the size and number of vacuoles in the histiocytes increased concomitantly with the cumulative dosage. Following administration of higher HES dosages, vacuoles were demonstrable in endothelial cells of blood and lymphatic vessels, basal keratinocytes, epithelia of sweat glands and in small peripheral nerves, the last mentioned being associated with pruritus. A subsequent reduction of the vacuoles in size and number could be demonstrated within 52 months. In nerves, HES deposits persisted no longer than 17 months paralleling the cessation of pruritus. Biopsies taken after 94 months exhibited no HES deposits in the skin. The condensation and final dissolution of the vacuoles may either indicate the release and subsequent redistribution of HES into the circulation or lysosomal degradation.

Adolescent↗
PubMed2001

Neuroimmunology.

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Animals↗
PubMed2001

Different pathways leading to cutaneous leukocytoclastic vasculitis in mice.

To investigate the pathomechanisms of leukocytoclastic vasculitis (LcV) we compared mouse models of LcV with non-vasculitic irritant contact dermatitis (ICD). Criteria for LcV as met by the immune complex-mediated Arthus reaction (Art-r) were also fulfilled by the localized Shwartzman reaction (Shw-r) and by cutaneous Loxoscelism (Lox) (injection of venom from Loxosceles reclusa containing sphingomyelinase D). After depletion of PMN (by gamma-irradiation) vessel damage could not be elicited in these models, distinguishing them from models of direct endothelial insult (necrotizing ICD). Depletion of complement could only delay, but not inhibit the Art-r, and did not change ICD, Lox or the Shw-r. The Shw-r exclusively revealed a sustained local expression of vascular adhesion molecules for 24 h in the preparatory phase (LPS s.c.), not observed in the Art-r, in Lox or ICD. Subsequent challenge with LPS i.p. was associated with upregulation of Mac-1 and ICAM-1 on PMN, but not of VLA-4 or LFA-1 (FACS analysis). Cytokines which were able to replace LPS in priming for LcV in the Shw-r (TNF-alpha and IL-1beta) also induced sustained expression of adhesion molecules, whereas IL-12 and IFN-gamma did neither. Neutralizing IL-12 or IFN-gamma also inhibited neither LcV nor sustained expression of adhesion molecules, whereas anti-TNF-alpha inhibited both. Anti-TNF-alpha had no marked inhibitory effects in the Art-r, in Lox or ICD. Combined (but not separate) neutralization of both E-selectin and VCAM-1 by antibodies suppressed LcV independent from reducing influx of PMN, proving that their sustained expression is decisive for the Shw-r and interferes with normal diapedesis. Since Loxosceles venom is known to dysregulate diapedesis and degranulation of PMN in vitro, since adherent immune complexes activate PMN at the vessel wall, and since adhesion molecules are dysregulated in the Shw-r, we suggest that LcV develops when activation of PMN coincides with vascular alterations which interfere with normal diapedesis.

Animals↗
PubMed2001

Interleukin-6-resistant melanoma cells exhibit reduced activation of STAT3 and lack of inhibition of cyclin E-associated kinase activity.

Development of cytokine resistance is an important feature of melanoma cells during tumor progression. To study the mechanisms of interleukin-6 resistance, we examined an interleukin-6 sensitive (WM35) and an interleukin-6 unresponsive cell line (WM9). Interleukin-6 treatment resulted in rapid inhibition of cyclin-dependent kinase 2/cyclin E activity and accumulation of the hypophosphorylated retinoblastoma protein in WM35 but not in WM9 cells. In contrast to previous reports, no differences in the expression of the cyclin-dependent kinase 2 inhibitor p21Cip1/WAF1 upon interleukin-6 treatment were found in both cell lines. Interleukin-6-induced inhibition of cyclin-dependent kinase 2 was also not due to changes in protein expression of cyclin-dependent kinase 2, cyclin E, p27Kip1 and cdc25A, a phosphatase positively regulating cyclin-dependent kinase 2 activity. As it is established that interleukin-6 resistance of WM9 cells is not caused by differential interleukin-6 receptor expression, we studied whether this is due to defective interleukin-6 signaling in which activation of signal transducer and activator of transcription 3 is a critical step. WM9 cells showed reduced tyrosine phosphorylation, DNA binding, and delayed nuclear translocation of signal transducer and activator of transcription 3 as compared with WM35 cells. The kinase upstream of signal transducer and activator of transcription 3, Janus kinase 1, was constitutively tyrosine-phosphorylated in WM9 cells and did not respond to interleukin-6 with increased phosphorylation. As compared with WM35 cells, interleukin-6 treatment of WM9 cells was not paralleled by reduced activity of the mitogen-activated protein kinase kinase-1, which suppresses activation of signal transducer and activator of transcription 3. Our data suggest that resistance of advanced melanoma cells to interleukin-6 is associated with reduced inhibition of cyclin-dependent kinase 2, which appears to be a consequence of a complex alteration in interleukin-6 signal transduction.

CDC2-CDC28 Kinases↗
PubMed2001

Human dermal fibroblasts express prohormone convertases 1 and 2 and produce proopiomelanocortin-derived peptides.

In the last few years it has become apparent that the skin is a locoregional source for several proopiomelanocortin-derived peptides including alpha-melanocyte-stimulating hormone, adrenocorticotropin, and beta-endorphin. The enzymes that regulate expression of these neuropeptides are the prohormone convertases 1 and 2. In this study we demonstrate, by reverse transcriptase polymerase chain reaction and Western immunoblotting, that cultured human dermal fibroblasts express prohormone convertases 1 and 2 as well as 7B2, which is an essential cofactor for enzymatic activity of prohormone convertase 2. Immunofluorescence studies revealed prohormone convertase 1 to be mainly expressed in the perinuclear region in vesicular structures resembling the trans-Golgi network, whereas prohormone convertase 2 was found in the trans-Golgi network as well as in vesicular structures diffusely distributed in the peripheral cytoplasm. Expression of both enzymes was also confirmed in fibroblasts of normal adult human skin by immunohistochemistry using antibodies against prohormone convertases 1 and 2 and vimentin. To assess the relevance of prohormone convertase 1 and 2 expression in human dermal fibroblasts, we studied the expression of proopiomelanocortin and proopiomelanocortin-derived peptides. Proopiomelanocortin expression was detected by reverse transcriptase polymerase chain reaction and Western immunoblotting. Alpha-melanocyte-stimulating hormone, adrenocorticotropin, and beta-endorphin were mainly located in vesicular structures as demonstrated by immunofluorescence. Production of these peptides was confirmed by radioimmunoassay, immunoradiometric assay, or enzyme immunoassay. Among several stimuli tested, interleukin-1 was found to upregulate production of alpha-melanocyte-stimulating hormone in human dermal fibroblasts. In summary, we have shown that human dermal fibroblasts express the enzymatic machinery for proopiomelanocortin processing and make proopiomelanocortin, alpha-melanocyte-stimulating hormone, adrenocorticotropin, and beta-endorphin. Production of proopiomelanocortin peptides by human dermal fibroblasts may be relevant for fibroblast functions such as collagen degradation and/or regulation of dermal immune responses.

Adrenocorticotropic Hormone↗
PubMed2001

High-dose intravenous immunoglobulins: an approach to treat severe immune-mediated and autoimmune diseases of the skin.

Adjuvant high-dose intravenous immunoglobulins (IVIgs) are being used increasingly in a range of immune-mediated and autoimmune diseases. Although numerous immunomodulatory mechanisms have been suggested, the exact mechanisms of action are poorly understood. The efficacy of IVIg in certain diseases has been proven in clinical trials, insofar as IVIg is approved as the therapy of choice for Kawasaki syndrome or idiopathic thrombocytopenic purpura. IVIg treatment has been shown to be safe, without the many drug-related adverse effects, including systemic immunosuppression, that are related to corticosteroids and other immunosuppressive agents. Current dermatologic uses of IVIg are increasing, which calls for adequately controlled clinical trials. This review focuses on experiences with IVIg therapy for skin diseases and discusses current opinion concerning its potential immunomodulating mechanisms.

Autoimmune Diseases↗
PubMed2001

Diffuse melanosis arising from metastatic melanoma: pathogenetic function of elevated melanocyte peptide growth factors.

The origin of diffuse melanosis resulting from metastatic melanoma is unknown. We examined the light microscopic and ultrastructural changes in the skin of an affected 35-year-old woman and determined the peripheral blood levels of melanocyte growth factors. A total of 7 biopsy specimens were examined by light and electron microscopy and immunohistology (S-100, HMB45, MART1, CD68, MAC387). Serum/plasma levels of melanocyte growth factors of the patient were determined by enzyme-linked immunosorbent assays and compared with those of normal volunteers (n = 10) and amelanotic patients with metastatic melanoma (n = 10), matched to the UICC stage of the affected patient. Hyperpigmented but otherwise apparently normal skin of the patient displayed epidermal melanocyte hyperplasia, increased melanogenesis, and dermal pigment stored in histiocytes and other cells along with extracellular deposits. Blood levels of alpha-melanocyte stimulating hormone, hepatocyte growth factor, and endothelin-1 were significantly elevated in the affected patient. Aberrant production of these factors may not only be responsible for activation of the pigment system in diffuse melanosis of metastatic melanoma, but also for increased proliferation, motility, and pigment incontinence of normal and malignant melanocytes.

Adult↗
PubMed2001

Terbinafine-induced subacute cutaneous lupus erythematosus.

BACKGROUND: Recently, the induction of subacute cutaneous lupus erythematosus (SCLE) and exacerbation of systemic lupus erythematosus by terbinafine have been reported. OBJECTIVE: We describe 4 cases of SCLE, one associated with chilblain lupus, which occurred during therapy with oral terbinafine for onychomycosis. METHODS: Of 21 consecutive patients with SCLE attending the outpatient dermatology department at Muenster University clinic during a 1-year period, 4 patients with terbinafine-induced SCLE were seen. Patients were examined fully and photographed; histologic findings as well as serologic and follow-up data were evaluated. RESULTS: In addition to high titers of antinuclear antibodies (ANA) with a homogeneous pattern, anti-Ro(SS-A) antibodies were present; in 3 of 4 women, anti-La(SS-B) antibodies were also found. All patients had anti-histone antibodies as in drug-induced lupus and showed the characteristic genetic association of SCLE with the HLA-B8,DR3 haplotype; moreover, in 2 cases, HLA-DR2 was also present. After discontinuation of terbinafine, ANA titers decreased; anti-histone antibodies also became undetectable within 4(1/2) months in 3 patients concomitant with subsidence of the SCLE eruption in all patients. CONCLUSION: Terbinafine is a drug that appears to infrequently induce SCLE with high titers of ANAs and anti-histone antibodies in genetically susceptible persons.

Administration, Oral↗
PubMed2001

Keratinocytes in epidermal immune responses.

Recent studies have advanced our understanding that the regulation of immune responses is not only confined to immunocompetent cells. Upon stimulation, keratinocytes are capable of releasing various factors and expressing receptors that are significantly involved in immunoregulation. Dysregulation and the abnormal production of cytokines and other inflammatory mediators as well as their receptors can be observed in various skin diseases. An understanding of keratinocytes as important regulators of the skin immune system opens new opportunities for the treatment of various skin diseases.

Cytokines↗