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Biomedical subjects

J H Saurat

Publications and source records attributed to J H Saurat.

At least 19 recordsLinked to original sources
PubMed2001

The hemidesmosomal protein bullous pemphigoid antigen 1 and the integrin beta 4 subunit bind to ERBIN. Molecular cloning of multiple alternative splice variants of ERBIN and analysis of their tissue expression.

The bullous pemphigoid antigen 1 (eBPAG1) is a constituent of hemidesmosomes (HDs), cell-substrate adhesion complexes in stratified epithelia. Although its COOH terminus interacts with intermediate filaments, its NH(2) terminus is important for its recruitment into HDs. To identify proteins that interact with the NH(2) terminus of human eBPAG1, we performed a yeast two-hybrid screen, which uncovered a protein belonging to the LAP/LERP (for LRR and PDZ domain) protein family with 16 NH(2)-terminal leucine-rich repeats and a COOH-terminal PDZ domain. The gene for this LAP/LERP protein comprises at least 26 exons located on the long arm of chromosome 5. In most human tissues, several transcripts were detected differing in the coding region situated upstream of or within the PDZ domain. One of the encoded variants was found to correspond to the recently described protein ERBIN. In yeast and in vitro binding experiments, ERBIN was shown to interact not only with eBPAG1 but also with the COOH-terminal region of the cytoplasmic domain of the integrin beta4 subunit, another component of HDs. Antibodies raised against the COOH terminus showed that ERBIN is expressed in keratinocytes. In transfected epithelial cells the protein, however, was not localized in HDs but was either diffusely distributed over the cytoplasm or concentrated at the basolateral plasma membrane. Because ERBIN had been shown previously to interact with the transmembrane tyrosine kinase receptor Erb-B2, which in turn associates with the integrin beta4 subunit, we suggest that ERBIN provides a link between HD assembly and Erb-B2 receptor signaling.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Selective expression of FLIP in malignant melanocytic skin lesions.

FLIP (FLICE Inhibitory Protein) is a recently identified intracellular inhibitor of caspase-8 activation that potently inhibits cell death mediated by all death receptors including Fas and TRAIL. FLIP has recently been shown to favor tumor growth and immune escape in mouse tumor models. We analyzed FLIP expression by immunohistochemistry in a panel of 61 benign and malignant human melanocytic skin lesions. FLIP expression was undetectable in all but one benign melanocytic lesion (31/32, 97%). In contrast, FLIP was strongly expressed in most melanomas (24/29 = 83%). Overexpression of FLIP by transfection in a Fas- and TRAIL-sensitive human melanoma cell line rendered this cell line more resistant to death mediated by both TRAIL and FasL. Selective expression of FLIP by human melanomas may confer in vivo resistance to FasL and TRAIL, thus representing an additional mechanism by which melanoma cells escape immune destruction.

Antibody Specificity↗
PubMed2001

Plectin, an unusual target antigen in bullous pemphigoid.

BACKGROUND: Bullous pemphigoid (BP) is a blistering disease associated with autoantibodies directed against two components of hemidesmosomes, BP180 and BP230. OBJECTIVES: To assess whether BP patients have autoantibodies targeting plectin, another hemidesmosomal component showing extensive homology to BP230. METHODS: Examination of sera from 16 patients with BP, using immunoprecipitation studies followed by immunoblotting. RESULTS: Serum of one of the 16 (6%) patients with BP contain autoantibodies binding to plectin, while no reactivity was found with sera from three control subjects. Sera from all 16 BP patients immunoprecipitated BP230 from extracts of biosynthetically radiolabelled human keratinocytes. CONCLUSIONS: Our results indicate that sera from BP patients might contain autoantibodies binding to plectin. Although this protein and BP230 are closely sequence-related, the occurrence of autoantibodies binding to plectin is a rare phenomenon in BP.

Autoantibodies↗
PubMed2001

Autoantibodies to the extracellular and intracellular domain of bullous pemphigoid 180, the putative key autoantigen in bullous pemphigoid, belong predominantly to the IgG1 and IgG4 subclasses.

BACKGROUND: Autoantibodies to the extracellular domain (ECD) of bullous pemphigoid (BP) antigen 180 (BP180) are thought to play a crucial part in the pathophysiology of BP. OBJECTIVES: As the various IgG subclasses have different biological properties, we have sought to assess the relative isotype distribution of IgG to BP180 and their reactivity against the ECD and intracellular domain (ICD) of BP180. METHODS: The reactivity of 27 sera from patients with BP was assayed by immunoblotting against recombinant proteins covering the ECD and ICD of BP180. RESULTS: Twenty-seven (100%) and 21 (77%) of 27 BP sera, respectively, contained IgG1 and IgG4 autoantibodies binding to the ECD of BP180. Fourteen (82%) and six (35%) of the 17 BP sera that were reactive with the ICD of BP180 had autoantibodies of the IgG1 and IgG4 subclass, respectively. The profile of the isotype restriction appeared to be similar when the response to the ECD vs. that to the ICD was compared. IgG2 and IgG3 reactivity with BP180 was found less frequently. Patients with BP of longer duration showed a tendency to have, in addition to IgG1, an IgG4 response. CONCLUSIONS: Consistent with prior evidence indicating that subepidermal blister formation in BP is dependent upon complement activation, the frequent finding of complement-fixing IgG1 autoantibodies to both the ECD and ICD of BP180 might have pathogenic relevance in BP. These findings provide new insights relevant for our understanding of the immune response to BP180, the putative key autoantigen in BP.

Aged↗
PubMed2001

Chronic borreliosis presenting with morphea- and lichen sclerosus et atrophicus-like cutaneous lesions. a case report.

We report on a case of chronic cutaneous borreliosis with manifestations clinically compatible with morphea and lichen sclerosus et atrophicus. The histopathologic features of these lesions were those of acrodermatitis chronica atrophicans. Our case illustrates the concept that clinical aspects of morphea and lichen sclerosus et atrophicus pertain to the spectrum of cutaneous borreliosis.

Abdomen↗
PubMed2001

Acute generalized exanthematous pustulosis associated with STI571 in a patient with chronic myeloid leukemia.

The tyrosine kinase inhibitor STI571 is a novel promising class of anticancer drugs. We report a case of cutaneous adverse reactions to STI571 in a young woman with blast crisis of chronic myeloid leukemia. She had first typical acute generalized exanthematous pustulosis mimicking mercury rash and then urticarial eruption. We suggest that cell pathways mediated by some tyrosine kinases might be involved in the pathogenesis of these skin eruptions.

Acute Disease↗
PubMed2001

Acute genitocrural intertrigo: a sign of primary human immunodeficiency virus type 1 infection.

We describe a 49-year-old male patient who presented with an acute illness associated with a widespread maculopapular eruption and eroded lesions in the inguinal folds consistent with an acute intertrigo, for which search of mycological and bacteriological causes remained negative. Serological tests disclosed a high viral HIV-1 load and p24 antigenemia, while anti-HIV-1 antibodies were absent, a profile typical of acute HIV-1 infection. Since the maculopapular eruption regressed concomitantly with the orogenital lesions as well as the eroded inguinal lesions prior to specific therapy, our observation indicates that intertriginous lesions may constitute one of the early cutaneous markers of primary HIV-1 infection.

Acute Disease↗
PubMed2001

Topical delivery of retinoids counteracts the UVB-induced epidermal vitamin A depletion in hairless mouse.

UVB irradiation depletes all-trans-retinol (ROL) and all-trans-retinyl esters (RE) from the hairless mouse epidermis. Prevention of this may be of relevance in counter-acting the long-term side effects of UVB exposure. We studied the effects of a topical treatment with natural retinoids before and after UVB exposure on three parameters involved in vitamin A metabolism: the amount of epidermal ROL and RE, the level of functional cellular retinol-binding protein I (CRBP-I), which is likely to protect ROL from UVB, as well as the cytosolic and microsomal enzyme activities which generate ROL and RE, i.e. all-trans-retinaldehyde (RAL) reductase, acylCoA:retinol acyltransferase (ARAT) and retinyl-ester hydrolase (REH). Topical pretreatment with retinoids promoted a dramatic increase of epidermal ROL, RE and CRBP-I levels, a transient increase of RAL reductase and ARAT activities as well as a decreased activity of REH, indicating a direction of epidermal vitamin A metabolism toward storage. In untreated mice UVB irradiation induced a depletion of epidermal ROL and RE in 10 min and a 50% decrease of CRBP-I after 24 h. In mice treated with topical retinoids, and then exposed to UVB, epidermal RE levels were higher than in vehicle-treated, nonirradiated mice. In contrast, ROL was as much depleted after UVB in pretreated as in untreated animals in spite of an induction of CRBP-I, indicating that CRBP-I does not actually protect ROL from UVB-induced depletion in this model. However, the reconstitution of both epidermal ROL and RE, after their depletion induced by UVB, was accelerated by previous topical treatment with RAL. Our results indicate that topical delivery of retinoids partly counteracts UVB-induced vitamin A depletion and promotes recovery.

Acyltransferases↗
PubMed2001

Retinoids for the treatment of psoriasis: outlook for the future.

Despite the demonstrated clinical success of retinoid therapy in psoriasis, its mechanism of action has not been fully elucidated, and investigators are confronted with two paradoxes. Firstly, the binding of retinoids to nuclear retinoic acid receptors (RARs) does not match their therapeutic efficacy. Secondly, formation of retinoic acid is probably increased in the psoriatic lesions. Answering these questions should result in: (i) the better use of acitretin, an oral synthetic retinoid, and tazarotene, the first compound for topical use; (ii) the development of new retinoids with specific pharmacological profile such as subtype-selective retinoids including molecules with an 'antiretinoid' activity and dissociating antiproliferative retinoids; and (iii) the better characterization of non-genomic effects of retinoids.

Animals↗
PubMed2000

Dendritic cells containing apoptotic melanoma cells prime human CD8+ T cells for efficient tumor cell lysis.

Dendritic cells (DCs) phagocytose apoptotic influenza-infected monocytes and cross-present influenza antigen to CD8+ T cells, generating a specific CTL response. We investigated whether apoptotic melanoma cells, presented by this mechanism, can lead to CTL responses to tumor-associated antigens and melanoma cells. Apoptotic HLA-A2- MEL-397 melanoma cells were internalized by HLA-A2+ immature monocyte-derived DCs but failed to induce maturation of DCs. When exposed to interleukin 6, interleukin 1beta, tumor necrosis factor alpha, and prostaglandin E2, DCs containing apoptotic MEL-397 cell material matured normally [cross-presenting DCs (cp-DCs)]. Autologous CD8+ CTL lines generated with cp-DCs produced tumor necrosis factor when stimulated with HLA-A2-binding immunodominant peptides from MelanA/MART1 and MAGE-3 (expressed by MEL-397 cells) but not tyrosinase (absent in MEL-397). T2 target cells loaded with the respective peptides were lysed by these cell lines, although to a lesser extent than by CTL lines generated in the presence of mature DCs and peptides from melanoma-associated h antigens. In contrast, lines generated with cp-DCs lysed HLA-A2+ MEL-526 melanoma cells or allogenic HLA-A2+ cp-DCs efficiently, whereas the CTL generated with DCs and peptides had little lytic activity. Mature DCs containing apoptotic tumor cells may thus represent an alternative approach for the therapy of malignant tumors.

Antigen Presentation↗