RESUMO
Granulomatosis with polyangiitis (GPA) is a systemic vasculitis with a potential to involve any organ system. It remains an important cause of kidney related morbidity and mortality. Early diagnosis can be difficult and requires high index of suspicion in all patients, but especially in cases with atypical presentation. We report a case with GPA, which was diagnosed only after new and advancing symptoms belied the original diagnosis of bilateral facial palsy and aortic mural thrombus.
RESUMO
We report a patient with scleroderma, renal cell carcinoma (RCC) and membranous nephropathy (MN). Certain clinical and laboratory features suggested that RCC caused or enhanced the other two conditions. A 55-year-old man developed scleroderma which progressed rapidly during its first 2 years with development of hypertension and acute renal failure, peak serum creatinine (SCr) 327 micromol/l (3.7 mg/dl) and partial improvement of the renal function (SCr 239 micromol/l or 2.7 mg/dl) after initiation of an angiotensin converting enzyme inhibitor. He subsequently developed nephrotic syndrome (urine protein excretion 9 gm/24-h) and progressive renal failure, with SCr 469 +/- 18 micromol/l (5.3 +/- 0.2 mg/dl). An anti-nuclear mitotic apparatus protein (NUMA) antibody, which is uncommon in scleroderma but has been linked to certain malignancies, was found in his serum. A left upper pole RCC was removed by heminephrectomy. MN was found in the renal parenchyma adjacent to the excised tumor. In the 3.5 years following surgery, the clinical manifestations of scleroderma have been arrested while the medications prescribed for this condition have been greatly reduced. Proteinuria is consistently less than 1 gm/24-h and 42 months after surgery serum creatinine was 256 micromol/l (2.9 mg/dl). Nutrition has also improved. Although this case may represent chance occurrence of three uncommon diseases (scleroderma, RCC, MN) in the same individual, the sustained improvement of the manifestations of scleroderma and MN after resection of the RCC contrasted to the rapid course of these conditions until the surgery, and the presence in the patient's serum of an autoantibody which is uncommon in patients with scleroderma, but has been linked to malignancy, suggest a pathogenetic relationship between the three conditions.
Assuntos
Carcinoma de Células Renais/complicações , Carcinoma de Células Renais/patologia , Glomerulonefrite Membranosa/complicações , Neoplasias Renais/complicações , Neoplasias Renais/patologia , Escleroderma Sistêmico/complicações , Carcinoma de Células Renais/terapia , Glomerulonefrite Membranosa/diagnóstico , Glomerulonefrite Membranosa/terapia , Humanos , Neoplasias Renais/terapia , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/terapiaRESUMO
In systemic lupus erythematosus, antibodies against double-stranded DNA are a major contributor to renal disease. We have previously demonstrated that the pentapeptide Asp/Glu-Trp-Asp/Glu-Tyr-Ser/Gly is a molecular mimic of double-stranded DNA. This sequence is also present in the extracellular domain of murine and human NMDA (N-methyl-D-aspartate) receptor subunits NR2a and NR2b. Here we show that the NR2 receptor is recognized by both murine and human anti-DNA antibodies. Moreover, anti-DNA antibodies with this cross-reactivity mediate apoptotic death of neurons in vivo and in vitro. Finally, we show that the cerebrospinal fluid of a patient with systemic lupus erythematosus contains these antibodies and also mediates neuronal death via an apoptotic pathway. These observations indicate that lupus antibodies cross-react with DNA and NMDA receptors, gain access to cerebrospinal fluid and may mediate non-thrombotic and non-vasculitic abnormalities of the central nervous system.
Assuntos
Anticorpos Antinucleares/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Receptores de N-Metil-D-Aspartato/imunologia , Animais , Anticorpos Antinucleares/líquido cefalorraquidiano , Apoptose , Células Cultivadas , Reações Cruzadas , Humanos , Técnicas In Vitro , Lúpus Eritematoso Sistêmico/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/imunologia , Neurônios/patologiaRESUMO
The zinc finger protein ZPR1 translocates from the cytoplasm to the nucleus after treatment of cells with mitogens. The function of nuclear ZPR1 has not been defined. Here we demonstrate that ZPR1 accumulates in the nucleolus of proliferating cells. The role of ZPR1 was examined using a gene disruption strategy. Cells lacking ZPR1 are not viable. Biochemical analysis demonstrated that the loss of ZPR1 caused disruption of nucleolar function, including preribosomal RNA expression. These data establish ZPR1 as an essential protein that is required for normal nucleolar function in proliferating cells.
Assuntos
Proteínas de Transporte/metabolismo , Nucléolo Celular/metabolismo , Proteínas de Saccharomyces cerevisiae , Sequência de Aminoácidos , Animais , Proteínas de Transporte/química , Proteínas de Transporte/genética , Divisão Celular/efeitos dos fármacos , Nucléolo Celular/ultraestrutura , Núcleo Celular/metabolismo , Núcleo Celular/ultraestrutura , Clonagem Molecular , Sequência Consenso , Sequência Conservada , Fator de Crescimento Epidérmico/farmacologia , Biblioteca Gênica , Teste de Complementação Genética , Células HeLa , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Proteínas de Membrana Transportadoras , Camundongos , Dados de Sequência Molecular , Saccharomyces cerevisiae/genética , Schizosaccharomyces/genética , Alinhamento de Sequência , Homologia de Sequência de Aminoácidos , Células Tumorais Cultivadas , Dedos de ZincoRESUMO
We have previously developed a novel technique for isolation of cDNAs encoding M phase phosphoproteins (MPPs). In the work described herein, we further characterize MPP10, one of 10 novel proteins that we identified, with regard to its potential nucleolar function. We show that by cell fractionation, almost all MPP10 was found in isolated nucleoli. By immunofluorescence, MPP10 colocalized with nucleolar fibrillarin and other known nucleolar proteins in interphase cells but was not detected in the coiled bodies stained for either fibrillarin or p80 coilin, a protein found only in the coiled body. When nucleoli were separated into fibrillar and granular domains by treatment with actinomycin D, almost all the MPP10 was found in the fibrillar caps, which contain proteins involved in rRNA processing. In early to middle M phase of the cell cycle, MPP10 colocalized with fibrillarin to chromosome surfaces. At telophase, MPP10 was found in cellular structures that resembled nucleolus-derived bodies and prenucleolar bodies. Some of these bodies lacked fibrillarin, a previously described component of nucleolus-derived bodies and prenucleolar bodies, however, and the bulk of MPP10 arrived at the nucleolus later than fibrillarin. To further examine the properties of MPP10, we immunoprecipitated it from cell sonicates. The resulting precipitates contained U3 small nucleolar RNA (snoRNA) but no significant amounts of other box C/D snoRNAs. This association of MPP10 with U3 snoRNA was stable to 400 mM salt and suggested that MPP10 is a component of the human U3 small nucleolar ribonucleoprotein.
Assuntos
Nucléolo Celular/química , Mitose/fisiologia , Fosfoproteínas/análise , Ribonucleoproteínas Nucleares Pequenas/análise , Ribonucleoproteínas/análise , Sequência de Aminoácidos , Sequência de Bases , Fracionamento Celular , Proteínas Cromossômicas não Histona/análise , Clonagem Molecular , DNA Complementar/genética , Dactinomicina/farmacologia , Células HeLa , Humanos , Ponto Isoelétrico , Dados de Sequência Molecular , Peso Molecular , Proteínas Nucleares/análise , Proteínas Nucleares/química , Proteínas Nucleares/genética , Fosfoproteínas/química , Fosfoproteínas/genética , RNA Nuclear Pequeno/análise , Ribonucleoproteínas/química , Ribonucleoproteínas/genética , Ribonucleoproteínas Nucleares Pequenas/química , Ribonucleoproteínas Nucleares Pequenas/genética , Análise de Sequência de DNA , Especificidade da EspécieRESUMO
Keratosis lichenoides chronica is a rare dermatosis characterized by a distinctive seborrheic dermatitis-like facial eruption, together with violaceous, papular, and nodular lesions on the extremities and trunk typically arranged in a linear and reticulate pattern. We describe a patient with KLC who had the typical features of this disease and responded partially to treatment with oral isotretinoin.
Assuntos
Ceratose/diagnóstico , Erupções Liquenoides/diagnóstico , Adulto , Biópsia por Agulha , Doença Crônica , Diagnóstico Diferencial , Feminino , Humanos , Isotretinoína/administração & dosagem , Ceratolíticos/administração & dosagem , Ceratose/tratamento farmacológico , Erupções Liquenoides/tratamento farmacológico , Indução de Remissão , Pele/patologiaRESUMO
ZPR1 is a zinc finger protein that binds to the cytoplasmic tyrosine kinase domain of the epidermal growth factor receptor (EGFR). Deletion analysis demonstrated that this binding interaction is mediated by the zinc fingers of ZPR1 and subdomains X and XI of the EGFR tyrosine kinase. Treatment of mammalian cells with EGF caused decreased binding of ZPR1 to the EGFR and the accumulation of ZPR1 in the nucleus. The effect of EGF to regulate ZPR1 binding is dependent on tyrosine phosphorylation of the EGFR. ZPR1 therefore represents a prototype for a class of molecule that binds to the EGFR and is released from the receptor after activation.
Assuntos
Proteínas de Transporte/metabolismo , Receptores ErbB/metabolismo , Dedos de Zinco , Sequência de Aminoácidos , Animais , Proteínas de Transporte/química , Linhagem Celular , Núcleo Celular/metabolismo , Clonagem Molecular , Citoplasma/metabolismo , Fator de Crescimento Epidérmico/farmacologia , Receptores ErbB/química , Humanos , Immunoblotting , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Proteínas de Membrana Transportadoras , Camundongos , Dados de Sequência Molecular , Fosforilação , Fosfotirosina/metabolismo , Estrutura Secundária de Proteína , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Testículo/metabolismo , Fosfolipases Tipo C/metabolismo , Vanadatos/farmacologia , Domínios de Homologia de srcRESUMO
Galectin-3 is a member of a newly named family of beta-galactoside-binding animal lectins, which has been described with a number of possible important biological functions, including the regulation of cell growth and association with tumor transformation. This protein has a wide tissue distribution but is notably not expressed by normal lymphocytes. We have previously shown that galectin-3 is markedly up-regulated in HTLV-I-infected T cells, most likely mediated by the viral transactivating protein Tax. In this study, we surveyed various lymphomas by immunohistochemistry and found the expression of galectin-3 in all of the 8 cases of Ki-1+ anaplastic large-cell lymphoma (ALCL). Immunoreactivity for galectin-3 was found in a majority of the neoplastic cells in the ALCLs studied. In contrast, only 2 of the 35 cases of other types of lymphoma, including various Hodgkin's and non-Hodgkin's lymphomas, were positive. Unlike the cases of ALCL, immunoreactivity for galectin-3 in these 3 cases was found only sporadically in a small number of neoplastic cells. Thus, galectin-3 may prove to be a useful marker for ALCL and its expression in neoplastic cells in ALCL may contribute to the biological behavior of this specific type of lymphoma.
Assuntos
Antígenos de Diferenciação/análise , Biomarcadores Tumorais/análise , Linfoma Anaplásico de Células Grandes/química , Adulto , Idoso , Feminino , Galectina 3 , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Galectin-3 is a beta-galactoside-binding animal lectin formerly called epsilon protein, Mac-2, carbohydrate binding protein 35, CBH 30, L-29, or L34. The possible occurrence of autoantibodies to galectin-3 was investigated because crosslinking of galectins bound to IgE or Fc epsilon RI might produce mediator release from mast cells or basophils. Unexpectedly, a control serum from an individual free of current allergic symptoms was found to have a significantly elevated level of IgG anti-galectin-3 by ELISA employing galectin-3-coated wells incubated with test serum followed by HRPO-conjugated goat anti-human IgG. The reaction was not inhibitable by lactose, suggesting that it is not a result of binding of IgG by galectin-3 through lectin-carbohydrate interactions. The antibody activity was specifically adsorbed by galectin-3 and protein A-conjugated Sepharose and was associated primarily with subclass IgG1. The presence of the antibodies was confirmed by immunoblotting showing binding of IgG to the 30-kD galectin-3 band. The relevant epitopes were in the galectin-3 N-terminal domain. The propositus was subsequently found to have adenocarcinoma of the colon, and titers of IgG anti-galectin-3 were found to be sharply elevated after hemicolectomy. Similar antibody titers have not been found in family members, but small numbers of normal persons and patients with malignant neoplasms have been found to have evidence of IgG anti-galectin-3 antibodies at lower titers than the propositus. The pathogenesis of this autoimmune reaction is unclear, though there is a trend for it to occur in older persons.
Assuntos
Antígenos de Diferenciação/imunologia , Autoanticorpos/sangue , Imunoglobulina G/sangue , Lectinas/imunologia , Antígenos de Diferenciação/química , Autoanticorpos/classificação , Ensaio de Imunoadsorção Enzimática , Mapeamento de Epitopos , Galectina 3 , Humanos , Isotipos de Imunoglobulinas/sangue , Lectinas/química , Ligação ProteicaRESUMO
From a panel of monoclonal antibodies raised against fractions of rat liver nuclear envelopes (NEs), we have identified an antibody, RL30, which reacts with novel nuclear pore complex (NPC) antigens that are not O-glycosylated. By immunofluorescence staining of cultured cells, RL30 reacts exclusively with the NE in a punctate pattern that largely coincides with that of identified NPC proteins. RL30 labels only the cytoplasmic surface of the NPC in immunogold electron microscopy, predominantly in peripheral regions nearby the cytoplasmic ring. In immunoblots of isolated rat liver NEs and cultured rat cells, RL30 recognizes a 265-kD band, as well as a series of 175-265-kD bands in rat liver NEs that are likely to be proteolytic products of p265. Sequencing of peptides from the 175- and 265-kD RL30 antigens of rat liver revealed that they are both closely related to human Tpr, a protein whose amino-terminal 150-250 amino acids appear in oncogenic fusions with the kinase domains of the met, trk, and raf protooncogenes. We found that in vitro translation of human Tpr mRNA yields a major 265-kD band. Considered together, these data indicate that the 265-kD RL30 antigen in the NPC is the rat homologue of Tpr. Interestingly, Tpr contains an exceptionally long predicted coiled coil domain (approximately 1600 amino acids). The localization and predicted structure of Tpr suggest that it is a component of the cytoplasmic fibrils of the NPC implicated in nuclear protein import. Immunofluorescence microscopy shows that during NPC reassembly at the end of mitosis, Tpr becomes concentrated at the NE significantly later than O-linked glycoproteins, including p62. This indicates that reassembly of the NPC after mitosis is a stepwise process, and that the Tpr-containing peripheral structures are assembled later than p62.
Assuntos
Compartimento Celular , Polaridade Celular , Membrana Nuclear/química , Proteínas Proto-Oncogênicas/isolamento & purificação , Sequência de Aminoácidos , Animais , Artefatos , Sequência de Bases , Ativação Enzimática , Imunofluorescência , Humanos , Fígado , Glicoproteínas de Membrana/metabolismo , Microscopia Imunoeletrônica , Mitose/fisiologia , Dados de Sequência Molecular , Complexo de Proteínas Formadoras de Poros Nucleares , Proteínas Quinases/metabolismo , Estrutura Terciária de Proteína , Ratos , Homologia de Sequência de Aminoácidos , Relação Estrutura-AtividadeRESUMO
The study of animal lectins and glycoconjugates has become an important area of research in biomedical sciences, as these molecules are believed to play important roles in a variety of biological processes. This report describes a study of the expression of an animal lectin, IgE-binding protein (epsilon BP), also known as Mac-2 and CBP35, in human skin. We have analyzed cultured human keratinocytes as well as normal human skin and a number of epidermal neoplasms, by immunoblotting, immunofluorescence and immunohistochemistry. We showed that epsilon BP is expressed in human keratinocytes, hair follicles, sebaceous and sweat glands. We found that epsilon BP expression retains in various epidermal neoplasms, including basal cell carcinoma, squamous cell carcinoma and keratoacanthoma, although the level of expression appears to be reduced as compared to normal epidermis. The immunohistochemical analysis also suggests that the level of epsilon BP expression appears to be dependent on the degree of cellular differentiation of keratinocytes.
Assuntos
Antígenos de Diferenciação/biossíntese , Epiderme/imunologia , Queratinócitos/imunologia , Lectinas/biossíntese , Neoplasias Cutâneas/imunologia , Cálcio/farmacologia , Carcinoma Basocelular/imunologia , Carcinoma Basocelular/patologia , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Células Cultivadas , Células Epidérmicas , Galectina 3 , Cabelo/citologia , Cabelo/imunologia , Humanos , Immunoblotting , Técnicas Imunoenzimáticas , Ceratoacantoma/imunologia , Ceratoacantoma/patologia , Neoplasias Cutâneas/patologia , Glândulas Sudoríparas/citologia , Glândulas Sudoríparas/imunologia , Células Tumorais CultivadasRESUMO
Lamins A, B, and C are the major proteins of a polymeric structure called nuclear lamina, which is intercalated between chromatin and the inner membrane of the nuclear envelope. Using immunofluorescence on HEp-2 cells, specific enzyme-linked immunosorbent assay, and Western blotting performed against nuclear lamina preparation from Ehrlich ascites tumor cells, we characterized three patients, whose sera contained antibodies to nuclear lamins. The reaction pattern observed in two of the patients may result from single or combined occurrence of anti-lamin A and C antibodies. The third patient had antibodies that probably recognized an epitope in the carboxy-terminal region of lamin C. The sera were donated by a heterogeneous group of patients, and no common clinical or laboratory signs seemed to link them together.
Assuntos
Autoanticorpos/análise , Lamina Tipo A , Proteínas Nucleares/imunologia , Adulto , Anticorpos Antinucleares , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Immunoblotting , Laminas , Pessoa de Meia-IdadeRESUMO
Recently, the specificity of the Crithidia luciliae immunofluorescent assay for the detection of antibodies to double-stranded deoxyribonucleic acid (dsDNA) has been questioned. It has been proposed that the kinetoplast of this trypanosome-like organism contains antigenic determinants other than dsDNA, presumably histones. Using anti-H2A and monoclonal anti-H3 antihistone antibodies, we have proved that there are no histones present in the Crithidia luciliae kinetoplast. False-positive results from the assay may be due to binding of antibodies to unidentified kinetoplast acid-extractable antigens other than histones.