RESUMO
Werner syndrome (WS) is a premature aging disorder caused by mutations in a RecQ-family DNA helicase, WRN. Mice lacking part of the helicase domain of the WRN orthologue exhibit many phenotypic features of WS, including metabolic abnormalities and a shorter lifespan. Yet, little is known about the impact of WRN mutations on the central nervous system in both humans and mouse models of WS. In the current study, we have performed a longitudinal behavioral assessment on mice bearing a Wrn helicase deletion. Behavioral tests demonstrated a loss of motor activity and coordination, reduction in perception, increase in repetitive behavior, and deficits in both spatial and social novelty memories in Wrn mutant mice compared to age-matched wild type mice. These neurological deficits were associated with biochemical and histological changes in the brain of aged Wrn mutant mice. Microglia, resident immune cells that regulate neuronal plasticity and function in the brain, were hyper-ramified in multiple regions involved with the behavioral deficits of Wrn mutant mice. Furthermore, western analyses indicated that Wrn mutant mice exhibited an increase of oxidative stress markers in the prefrontal cortex. Supporting these findings, electron microscopy studies revealed increased cellular aging and oxidative stress features, among microglia and neurons respectively, in the prefrontal cortex of aged Wrn mutant mice. In addition, multiplex immunoassay of serum identified significant changes in the expression levels of several pro- and anti-inflammatory cytokines. Taken together, these findings indicate that microglial dysfunction and neuronal oxidative stress, associated with peripheral immune system alterations, might be important driving forces leading to abnormal neurological symptoms in WS thus suggesting potential therapeutic targets for interventions.
Assuntos
Helicase da Síndrome de Werner/fisiologia , Síndrome de Werner/genética , Animais , Senescência Celular/fisiologia , Dano ao DNA/fisiologia , Modelos Animais de Doenças , Feminino , Estudos Longitudinais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Atividade Motora/genética , Atividade Motora/fisiologia , Proteínas Mutantes , Neurônios/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , RecQ Helicases/genética , RecQ Helicases/metabolismo , Síndrome de Werner/imunologia , Síndrome de Werner/fisiopatologia , Helicase da Síndrome de Werner/genéticaRESUMO
Aging, and especially human aging, can be explained by the emerging concept of parainflammation-driven inflammaging, i.e. a combination of inflammation and aging. Inflammaging posits that aging either physiologically or pathologically can be driven by the pro-inflammatory cytokines and substances produced by the innate immune system. Animals must maintain homeostasis as they age despite incessant attack from both intrinsic and extrinsic stimuli/antigens. These potentially harmful pro-inflammatory signals at a later stage of life may act antagonistically to the beneficial role they had in an earlier stage of life, like serving as developmental engines for body system formation. The concept of inflammaging is based on an antagonistic pleiotropy theory programmed during evolution. Clinical trials including caloric restriction, sirtuin activators, and p38 MAPK inhibitors against both pathological aging such as metabolic syndrome, diabetes mellitus, rheumatoid arthritis, and Werner syndrome and physiological aging have been proposed.
Assuntos
Envelhecimento/fisiologia , Inflamação/fisiopatologia , Animais , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Humanos , Imunidade Inata/fisiologia , Síndrome de Werner/imunologia , Síndrome de Werner/metabolismoRESUMO
Human immunodeficiency virus (HIV)-induced immunodeficiency and immune-system aging share some analogies. Since Werner (WRN) and Bloom (BLM) helicases are crucial in cell repair and aging, their peripheral blood mononuclear cells (PBMC) mRNA levels were compared in HIV-1 infected patients and in normal donors. The mean levels of WRN mRNA were 3.7-fold higher in PBMCs from HIV-1 infected individuals in comparison to healthy donors, whereas BLM mRNA mean levels were slightly higher, although not significantly. WRN increase was positively correlated to CD4 and CD8 T-cell numbers, and also the percentage of naive T lymphocytes, and was observed also in T-cell subsets. Interestingly, a general trend toward increased WRN mRNA levels in individuals with lower viral load was observed, without association with patient age, time of seroconversion, and on/off antiretroviral therapy regimen. On the whole, this study shows that WRN and BLM are differentially modulated in HIV infection, as WRN--but not BLM--is significantly increased, suggesting that mechanisms different from defect or loss of helicase function, observed in WRN and BLM syndromes, may be at the basis of T-cell aging in HIV infection.
Assuntos
Adenosina Trifosfatases/genética , Síndrome de Bloom/genética , DNA Helicases/genética , Infecções por HIV/genética , HIV-1 , RecQ Helicases/genética , Síndrome de Werner/genética , Adulto , Síndrome de Bloom/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Exodesoxirribonucleases , Feminino , Infecções por HIV/imunologia , Humanos , Contagem de Leucócitos , Leucócitos Mononucleares , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Linfócitos T/imunologia , Síndrome de Werner/imunologia , Helicase da Síndrome de WernerRESUMO
Werner syndrome (WS) is a heredofamilial disorder characterized by clinicopathological premature aging. In healthy individuals, structural alteration of serum IgG oligosaccharides is known to be an aging phenotype. In the present study, we determined and compared oligosaccharide structures of serum IgG among WS patients, healthy age-sex-matched individuals, and healthy elderly individuals from both sexes in order to reveal whether WS patients exhibit an aging phenotype in terms of IgG oligosaccharide structure. Sialylation and galactosylation levels of IgG oligosaccharides from WS patients were similar to those from healthy elderly individuals in which sialylation and galactosylation levels were significantly lower than those from the healthy age-sex-matched individuals. In contrast, the bisecting N-acetylglucosaminylation level of IgG oligosaccharides from WS patients was comparable to that from the healthy age-sex-matched controls and significantly lower than that of the healthy elderly controls. There was no significant sexual difference in these modifications of IgG oligosaccharides. These results suggest that WS patients exhibit an aging phenotype for structural alterations such as sialylation and galactosylation in the outer arms of IgG oligosaccharides.
Assuntos
Imunoglobulina G/química , Oligossacarídeos/química , Síndrome de Werner/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Carboidratos , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão , Feminino , Galactose/química , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Estrutura Molecular , Oligossacarídeos/sangue , Fenótipo , Ácidos Siálicos/químicaRESUMO
Werner syndrome, caused by the homologous mutation of RecQ3 RNA/DNA helicase (WRN), is often misdiagnosed as systemic sclerosis (SSc) because of apparent similar skin changes and its relatively high frequency in Japan. The present study was undertaken to determine whether anti-WRN antibodies assayed by specific enzyme-linked immunosorbent assay occur in 41 SSc patients (30 diffuse and 11 limited types) and, if so, to determine any clinical association, such as skin sclerosis. Serum level of IgG anti-WRN antibody in SSc was significantly higher than that from 30 age- and sex-matched normal volunteers (P < 0.001). The serum level of IgG anti-WRN antibody in diffuse type SSc was significantly higher than the limited type (P < 0.05). A significant correlation was observed between serum levels of IgG anti-topoisomerase I antibody and IgG anti-WRN antibody in the same samples from SSc (P < 0.05). Moreover, in 119 normal healthy individuals aged from 0 to 99 years, a statistically significant correlation (P < 0.001) existed between serum level of IgG anti-WRN antibody and advancing age. A significantly higher level of IgG autoantibody specific for WRN detected in diffuse than in limited type SSc and normal may contribute to the pathogenesis of skin sclerosis in SSc.
Assuntos
Autoanticorpos/sangue , DNA Helicases/imunologia , Escleroderma Sistêmico/imunologia , Síndrome de Werner/imunologia , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/imunologia , Criança , Pré-Escolar , DNA Topoisomerases Tipo I/imunologia , Ensaio de Imunoadsorção Enzimática , Exodesoxirribonucleases , Feminino , Humanos , Imunoglobulina G/sangue , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , RecQ Helicases , Escleroderma Sistêmico/epidemiologia , Escleroderma Sistêmico/patologia , Estudos Soroepidemiológicos , Pele/imunologia , Pele/patologia , Síndrome de Werner/epidemiologia , Síndrome de Werner/patologia , Helicase da Síndrome de WernerRESUMO
In HIV infection, continuous immune activation leads to accelerated ageing of the adaptive immune system, similar to that observed in elderly people. We investigated the expression of WRN and BLM (genes involved in disorders characterized by premature ageing, genomic instability and cancer predisposition) in peripheral blood mononuclear cells (PBMC) activated in vitro with phytohaemagglutinin (PHA) and infected with different HIV-1 strains. The steady state levels of mRNA were analysed by reverse transcription-polymerase chain reaction (RT-PCR), and protein expression was assayed using immunocytochemistry and Western blot techniques. In uninfected PBMC, PHA stimulation induced an increase in BLM mRNA and protein expression, while WRN expression remained virtually unchanged. When PBMC were infected in vitro with a lymphotropic HIV-1 strain, the level of BLM mRNA showed a peak at 24 h of infection, followed by a decline to uninfected culture levels. A similar result failed to be seen using an R5-tropic HIV-1 strain. In accordance with mRNA expression, in HIV-infected cultures PBMC were stained more frequently and more intensely by a BLM-specific antibody as compared to uninfected cultures, staining peaking at 24. Conversely, WRN expression was not modulated by HIV-1. The proportion of cells showing BLM up-regulation, established by immunocytochemical staining, was much greater than the proportion of productively infected PBMC, as established by proviral DNA measurement. This result indicates that BLM up-regulation is probably a result of an indirect bystander cell effect. Activation of the BLM gene in infected PBMC suggests that premature ageing could be a further immunopathogenetic mechanism involved in HIV-induced immunodeficiency, and points to a possible new candidate target for innovative therapeutic intervention.
Assuntos
Adenosina Trifosfatases/genética , Síndrome de Bloom/genética , DNA Helicases/genética , Infecções por HIV/imunologia , HIV-1/imunologia , Leucócitos Mononucleares/imunologia , Síndrome de Werner/genética , Adenosina Trifosfatases/imunologia , Síndrome de Bloom/imunologia , Células Cultivadas , DNA Helicases/imunologia , Exodesoxirribonucleases , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Infecções por HIV/genética , HIV-1/genética , Humanos , Imuno-Histoquímica/métodos , Proteínas Nucleares/genética , Proteínas Nucleares/imunologia , Fito-Hemaglutininas/imunologia , RNA Mensageiro/análise , RNA Viral/análise , RecQ Helicases , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Síndrome de Werner/imunologia , Helicase da Síndrome de WernerAssuntos
Progéria , Progéria/diagnóstico , Progéria/fisiopatologia , Síndrome de Werner/diagnóstico , Síndrome de Werner/fisiopatologia , Senescência Celular/fisiologia , DNA Helicases/genética , Exodesoxirribonucleases , Fibroblastos/fisiologia , Humanos , Progéria/genética , Progéria/imunologia , RecQ Helicases , Síndrome de Werner/genética , Síndrome de Werner/imunologia , Helicase da Síndrome de WernerRESUMO
Werner's syndrome (WS) is a valuable model of accelerated ageing and results from mutations in a recQ helicase (wrn). WS fibroblasts show a mutator phenotype, replication fork stalling, increased rates of mean telomeric loss and accelerated cellular senescence. Senescence has been proposed as a candidate mechanism for the ageing of mitotic tissue. However, some mitotic tissues (such as the immune system) seem unaffected in WS. Is this evidence against a role for cell senescence in ageing? Two experiments resolve this paradox (i) the demonstration that the abbreviated replicative lifespan of WS fibroblasts can be corrected by the ectopic expression of telomerase and (ii) the demonstration that T cells derived from WS patients have the mutator phenotype characteristic of the disease but show no reduction in replicative potential. Since T cells can upregulate telomerase naturally these findings are consistent with a model in which the only wrn-mediated deletions that have a significant effect on replicative lifespan are those at or near the telomere. These data are thus supportive of a role for senescence in the ageing of the immune system. Emerging data on divisional counting mechanisms have the potential to produce many other apparent WS "paradoxes". Accordingly, we propose a general model for the phenotypic presentation of WS, which includes a modification of the Olovnikov model of telomere erosion. Somewhat unexpectedly, this predicts that accelerated senescence should not be observed in all telomerase-negative WS cell types.
Assuntos
Envelhecimento/fisiologia , Síndrome de Werner/fisiopatologia , Envelhecimento/genética , Envelhecimento/imunologia , Animais , Senescência Celular/genética , Senescência Celular/fisiologia , DNA Helicases/genética , Exodesoxirribonucleases , Fibroblastos/fisiologia , Humanos , Modelos Biológicos , Fenótipo , RecQ Helicases , Síndrome de Werner/genética , Síndrome de Werner/imunologia , Helicase da Síndrome de WernerRESUMO
Werner syndrome (WS) is a human premature aging syndrome, which is associated with high frequencies of neoplasia and genetic instability. We have examined the occurrence of microsatellite instability, which may result from defective mismatch repair, in lymphoblastoid cell lines derived from nine WS patients. Instability was measured at the D2S123 locus by gel analysis of PCR products. Three WS cell lines had 4-13% altered alleles, compared with 0% in the other six lines. The increased frequency of microsatellite instability could not readily be associated with overt cancer or any other known clinical condition in the three patients. To examine whether the WS defect affected the humoral immune system, we measured the hypermutation of immunoglobulin variable genes in peripheral blood cells from the WS patient who donated the cell line with the highest frequency of microsatellite instability. The frequency and pattern of mutation was similar to that from normal individuals, suggesting that the Werner protein is not involved in generating hypermutation.
Assuntos
Rearranjo Gênico de Cadeia Pesada de Linfócito B , Região Variável de Imunoglobulina/genética , Repetições de Microssatélites , Mutação , Síndrome de Werner/genética , Sequência de Bases , Linhagem Celular , Regiões Determinantes de Complementaridade , DNA Complementar , Humanos , Dados de Sequência Molecular , Síndrome de Werner/imunologiaRESUMO
We analyzed mRNAs that were up- or down-regulated in fibroblasts from Werner syndrome (WS) patients compared with those from normal individuals. The mRNAs from normal and WS cells were first screened by differential display, and those mRNAs that were apparently up- or down-regulated were selected except for mRNAs related to extra-cellular matrix (ECM) proteins that are already known to be up-regulated in WS fibroblasts. Then, the expression levels of these mRNAs were semiquantified by northern blot analysis, and six up-regulated and two down-regulated mRNAs were identified in WS cell lines. Among the six up-regulated mRNAs were three mRNAs that coded TGFbeta-1 and two proteins, their expressions of which were increased by TGFbeta-1. These results together with the fact that TGFbeta-1 up-regulates the expression of ECM proteins strongly suggest that TGFbeta-1 has a key role in accelerated cellular senescence of fibroblasts of WS patients.
Assuntos
RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fator de Crescimento Transformador beta/genética , Síndrome de Werner/genética , Sequência de Bases , Northern Blotting , Estudos de Casos e Controles , Primers do DNA/genética , Fibroblastos/metabolismo , Expressão Gênica , Humanos , Técnicas In Vitro , Síndrome de Werner/imunologia , Síndrome de Werner/metabolismoRESUMO
Although immunological methods are widely used to diagnose various infectious diseases, they have rarely been employed to detect genetic diseases. In this study, we have established an immunoblot analysis system for the diagnosis of Werner syndrome (WS), a recessive genetic disorder causing premature aging and an enhanced risk of rare cancers. The method uses an immunoblot technique with specific monoclonal antibodies to WS gene product, and B-lymphoblastoid cell lines (LCLs) transformed by Epstein-Barr virus; these cell lines express an increased level of normal WS gene product DNA helicase. The method clearly distinguishes normal from patient LCLs containing any of the mutation types found so far in Japan, primarily because of the drastically reduced levels of mutated gene products, and secondarily because of the truncated product sizes. A comparison of this immunological diagnosis with the symptom-based clinical diagnosis has narrowed down the criteria of symptoms essential for WS diagnosis. This procedure is compatible with, and has some advantage over, the genetic method, because WS patients can be diagnosed without determining the mutated gene sequences. The method exemplified in WS may also be applied to detect some other genetic diseases.
Assuntos
Immunoblotting/métodos , Síndrome de Werner/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais , Linfócitos B , Estudos de Casos e Controles , Linhagem Celular Transformada , DNA Helicases/genética , DNA Helicases/imunologia , Exodesoxirribonucleases , Feminino , Herpesvirus Humano 4 , Humanos , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Mutação , Regiões Promotoras Genéticas , RecQ Helicases , Síndrome de Werner/genética , Síndrome de Werner/imunologia , Helicase da Síndrome de WernerRESUMO
The case of a 40-year-old woman with Werner's syndrome associated with systemic lupus erythematosus (SLE) is reported. The patient exhibited short stature, slender extremities, thinned hair, high-pitched voice, cataracts, ulceration of the fingers, and mental retardation. Malar erythema, photosensitivity, and proteinuria had been noted since age 34. The serum contained high titers of antibodies to dsDNA, Sm, nRNP, and SS-A/Ro. The simultaneous presence of Werner's syndrome and SLE could be a coincidental occurrence of the two diseases, although it might be due to an abnormality in replication or degeneration of DNA leading to the development of both diseases.
Assuntos
Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/imunologia , Síndrome de Werner/complicações , Síndrome de Werner/imunologia , Adulto , Anticorpos Antinucleares/imunologia , Biópsia , Feminino , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/patologia , Metilprednisolona/administração & dosagem , Metilprednisolona/uso terapêutico , Prednisolona/administração & dosagem , Prednisolona/uso terapêutico , Síndrome de Werner/tratamento farmacológico , Síndrome de Werner/patologiaRESUMO
Normal human fibroblasts display a limited lifespan in culture, which is due to a steadily decreasing fraction of cells that are able to proliferate. Using antibodies that react with antigens present in proliferating cells only, in an indirect immunofluorescence assay, we have estimated the fraction of proliferating cells in cultures of normal human fibroblasts. Furthermore, we have estimated the rate of decline in the fraction of proliferating cells during the process of cellular ageing by application of the assay to normal human fibroblasts throughout their lifespan in culture. Werner's Syndrome is an autosomal recessive disease in which individuals display symptoms of ageing prematurely. Werner's Syndrome fibroblasts display a reduced lifespan in culture compared with normal human fibroblasts. Like normal human fibroblasts, the growth of Werner's Syndrome fibroblasts is characterised by a decreasing fraction of cells reacting with the proliferation-associated antibodies throughout their lifespan in culture. However, the rate of loss of proliferating cells in Werner's Syndrome fibroblasts during the process of cellular ageing is accelerated 5- to 6-fold compared with the rate determined for normal human fibroblasts.
Assuntos
Antígenos/metabolismo , Senescência Celular/imunologia , Fibroblastos/citologia , Fibroblastos/imunologia , Síndrome de Werner/imunologia , Síndrome de Werner/patologia , Divisão Celular/imunologia , Células Cultivadas , Imunofluorescência , Humanos , Antígeno Ki-67 , Proteínas de Neoplasias/imunologia , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/imunologia , Proteínas Nucleares/metabolismo , Antígeno Nuclear de Célula em ProliferaçãoAssuntos
Síndrome de Werner/genética , Síndrome de Werner/imunologia , Adulto , Dano ao DNA , Reparo do DNA , Humanos , Imunofenotipagem , MasculinoRESUMO
Lymphocyte proliferation and nucleoid sedimentation were studied in a patient with premature aging resembling the Werner's syndrome (WS). Onset of patchy brown hyperpigmentations at the age of 9 months permitted distinction from classical WS and suggested a WS-like premature aging disease. By photometric recording of density changes during cell culture, we examined the course of cell proliferation after PHA stimulation over 7 days and compared these results to those obtained in two normal controls. Cultured cells of the patient displayed an aberrant proliferation pattern characterized by continuous growth without an initial reduction phase. The markedly reduced proliferative capacity of purified cells from the patient could in part be corrected by fetal bovine serum. The cells of the patient displayed a characteristic nucleoid sedimentation profile after ultraviolet irradiation indicating retarded DNA replication, which may be a common feature of various premature aging diseases. The absence of thermolability of cell proliferation and the presence of a high number of chromatid aberrations disclosed differences from classical WS.
Assuntos
Replicação do DNA , Ativação Linfocitária , Progéria/diagnóstico , Síndrome de Werner/diagnóstico , Divisão Celular , Células Cultivadas , Aberrações Cromossômicas , Diagnóstico Diferencial , Humanos , Masculino , Pessoa de Meia-Idade , Progéria/genética , Progéria/imunologia , Pigmentação da Pele , Raios Ultravioleta , Síndrome de Werner/genética , Síndrome de Werner/imunologiaRESUMO
Several immunological assessments of the Werner syndrome are described, including detection of antibodies frequently found in autoimmune diseases and analysis of age-related changes of cell subpopulations. By using sensitive techniques such as fluorescence-activated cell sorting and solid-phase radioimmunoassay, anti-lymphocyte antibodies and anti-DNA antibodies were frequently detected in the sera from patients with the Werner syndrome. Anti-nuclear antibodies were also detected in a conventional manner; however, the titers of these antibodies were very low. Examination of cell populations revealed marked decreases in the T cell subsets reactive to both antilymphocytic antibodies and anti-brain associated T cell antigen antibodies.
Assuntos
Síndrome de Werner/imunologia , Adolescente , Adulto , Anticorpos Antinucleares/análise , Complexo Antígeno-Anticorpo/análise , Autoanticorpos/análise , Centrômero/imunologia , DNA/imunologia , Humanos , Imunoglobulinas/biossíntese , Técnicas In Vitro , Ativação Linfocitária , Linfócitos/classificação , Masculino , Pessoa de Meia-Idade , Receptor de Insulina/imunologia , Espermatozoides/imunologiaAssuntos
Antígenos/análise , Autoantígenos/análise , Sobrevivência Celular , Regulação da Expressão Gênica , RNA de Transferência/análise , Adulto , Idoso , Células Cultivadas , Criança , Cromatografia Líquida de Alta Pressão , Feminino , Fibroblastos/análise , Humanos , Masculino , Pessoa de Meia-Idade , Nucleotídeos/análise , Aminoacil-RNA de Transferência/análise , Ribonucleoproteínas/imunologia , Síndrome de Werner/imunologia , Síndrome de Werner/metabolismoRESUMO
Natural killing (NK) activities were measured in peripheral blood lymphocytes (PBL) from 14 patients with Werner's syndrome (WS), and the results were compared with those of 187 normal individuals at different ages. The NK activities of healthy donors were demonstrated a characteristic and invariable manner in accordance with the age and the sex, whereas the activities of WS patients were considerably reduced irrespective of the age and the sex. When normal PBL were preincubated with WS sera containing anti-lymphocyte antibodies (ALA) plus rabbit complement, the NK activities of the surviving PBL were markedly reduced when compared with those of PBL treated with other heterologous ALA of rabbit origin in the same manner. PBL from WS patients treated with purified human leucocyte interferon augmented the NK activity even beyond the range of controls. These results suggested that NK activities in WS patients were reduced in a manner similar to that in normal old individuals. The ALA reactive to NK cells in WS patients may participate in the reduction of NK activities. The augmentative effect of interferon on NK activities in WS patients may also suggest the possible blocking of potent NK activities by an unknown mechanism rather than an intrinsic defect of their NK cells.
Assuntos
Citotoxicidade Imunológica , Interferons/farmacologia , Linfócitos/imunologia , Síndrome de Werner/imunologia , Adolescente , Adulto , Idoso , Envelhecimento , Complexo Antígeno-Anticorpo/análise , Soro Antilinfocitário/imunologia , Criança , Pré-Escolar , Relação Dose-Resposta Imunológica , Estrogênios/sangue , Feminino , Humanos , Imunoglobulina M , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-IdadeRESUMO
To assess the immunologic disturbance in WErner syndrome, antibodies to "intrinsic" (auto)antigens (anti-DNA antibodies and rheumatoid factors) and "natural" antibodies to "extrinsic" antigens (hemagglutinins for sheep red cells and antibodies against ABO blood type antigens) were measured in serum samples from 16 patients with Werner syndrome and compared with those from 150 healthy persons ranging in age from less than a year to 98. Employing a sensitive solid-phase radioimmunoassay, we found that the levels of both anti-double-stranded and anti-single-stranded DNA antibodies in the IgG class gradually increased with age in normal donors; a more abrupt increase with age was observed in those with Werner syndrome, although they lacked any complication of renal disease and hypocomplementemia. The titers of rheumatoid factor detected by sensitized sheep cell agglutination also gradually rose in normal persons and patients with Werner syndrome. In contrast, the titers of natural antibodies declined with age in both groups. These disturbances in antibody production suggested that Werner syndrome expresses an accelerated form of aging in immunologic aspect.