RESUMEN
There is growing evidence that implicates B lymphocytes and their products in the pathogenesis of multiple sclerosis (MS). A subpopulation of B lymphocytes expressing the CD5 antigen are involved in several autoimmune disorders through the release of autoantibodies. In this study, we used three-color flow cytometry to examine the expression of CD5 antigen on B lymphocytes from patients with relapsing-remitting MS, and correlated this expression with features of disease activity and circulating levels of autoantibodies against myelin basic protein. CD5 expression on B lymphocytes was significantly higher in patients with active MS when compared to patients with clinically stable MS or those with inflammatory or noninflammatory neurologic disorders. CD5(+) B lymphocytes from patients with active MS correlated significantly with the number of gadolinium-enhancing MRI lesions, and inversely with disease duration. The expression of CD5 on B lymphocytes in MS patients also correlated with circulating levels antibodies against myelin basic protein. Results presented here indicate that clinically active MS is associated with an expanded population of peripheral CD5(+) B lymphocytes.
Asunto(s)
Autoanticuerpos/sangre , Linfocitos B/inmunología , Antígenos CD5/inmunología , Esclerosis Múltiple Recurrente-Remitente/inmunología , Antígenos CD19/inmunología , Relación CD4-CD8 , Progresión de la Enfermedad , Humanos , Esclerosis Múltiple Recurrente-Remitente/sangre , Proteína Básica de Mielina/inmunología , Valor Predictivo de las Pruebas , Linfocitos T/inmunologíaRESUMEN
The pathogenesis of multiple sclerosis (MS) is thought to involve T- and B-lymphocyte-mediated autoimmunity. However, the mechanisms that regulate lymphocyte activity in MS are poorly understood. In normal circumstances, programmed cell death (apoptosis) contributes to the maintenance of lymphocytes homeostasis and the deletion of autoreactive cells. Cellular commitment to apoptosis is partly regulated by the cell death receptor Fas, and the anti-apoptosis proteins Bcl-2 and FLIP. Although there is emerging evidence that dysregulations of apoptotic pathways play a role in T-cell autoimmunity in MS, the expression of apoptosis-regulatory proteins in B cells from MS patients is largely unknown. In this study, we analyzed the expression profiles of Fas, Bcl-2, and FLIP proteins in peripheral B lymphocytes from patients with relapsing-remitting and progressive MS, and from appropriate controls. We observed a significant up-regulation of Bcl-2 and FLIP proteins in B cells from relapsing-remitting MS when compared to corresponding expression in progressive MS, or in noninflammatory neurologic controls and healthy individuals. This cellular overexpression of Bcl-2 and FLIP proteins was not affected by treatment with interferon-beta, but was also observed in B cells from patients with systemic inflammatory diseases. Our findings suggest that cellular overexpression of the apoptosis-inhibitory proteins in patients with relapsing MS may promote apoptotic resistance of potentially pathogenic, autoreactive B lymphocytes and consequently, may allow for continuing autoimmune tissue destruction.
Asunto(s)
Apoptosis/inmunología , Autoinmunidad/inmunología , Linfocitos B/inmunología , Proteínas Portadoras/inmunología , Péptidos y Proteínas de Señalización Intracelular , Esclerosis Múltiple/inmunología , Proteínas Proto-Oncogénicas c-bcl-2/inmunología , Receptor fas/inmunología , Adulto , Empalme Alternativo/inmunología , Linfocitos B/metabolismo , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD , Femenino , Expresión Génica/efectos de los fármacos , Expresión Génica/inmunología , Humanos , Interferón beta/farmacología , Interferón beta/uso terapéutico , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/sangre , Esclerosis Múltiple/fisiopatología , Isoformas de Proteínas/inmunologíaRESUMEN
The pathologic basis of disease progression in multiple sclerosis (MS) is thought to involve axonal degeneration, which contributes to the accumulation of neurological disability. Recent reports suggest that intrathecal concentrations of the neurofilament protein in relapsing remitting MS correlate with disease activity and the degree of disability. We sought to investigate the intrathecal levels of other cytoskeletal components of axons, primarily actin, tubulin and the light subunit of neurofilament (NFL) in patients with progressive MS and relevant controls and correlate results with clinical parameters of disease severity. Cerebrospinal fluid (CSF) concentrations of actin, tubulin and NFL were significantly increased in MS patients when compared to corresponding levels in patients with other inflammatory or non-inflammatory neurological diseases. Moreover, the intrathecal release of actin and tubulin, and to a lesser extent NFL, was significantly more marked in patients with primary and secondary progressive MS when compared to patients with relapsing remitting disease and was correlated with clinical disability. Our findings suggest that progressive MS is associated with the heightened intrathecal release of axonal cytoskeletal proteins, and that CSF actin, tubulin and NFL are reliable markers of axonal damage.
Asunto(s)
Actinas/líquido cefalorraquídeo , Axones/metabolismo , Esclerosis Múltiple/líquido cefalorraquídeo , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Tubulina (Proteína)/líquido cefalorraquídeo , Citoesqueleto/metabolismo , Evaluación de la Discapacidad , Progresión de la Enfermedad , Humanos , Valor Predictivo de las PruebasRESUMEN
The pathogenesis of multiple sclerosis (MS) is thought to involve failure of programmed cell death (apoptosis) to eliminate potentially pathogenic, autoreactive T lymphocytes. This failure may be caused by multiple abnormalities of the cell death machinery. The inhibitors of apoptosis (IAP) proteins are central regulators of cell death that inhibit apoptosis induced by a variety of stimuli. In this study, we investigated the dynamics of cellular IAP-1, IAP-2, and X-linked IAP, in resting and mitogen stimulated T lymphocytes from MS patients and relevant controls. The expression of IAP proteins was significantly higher in mitogen stimulated T lymphocytes from patients with clinically active MS when compared to corresponding expressions from patients with stable MS or from other controls. Heightened expression of IAP proteins in patients with active MS correlated with clinical features of disease activity, and with T lymphocyte resistance to apoptosis. In contrast, cellular expression of the anti-apoptosis protein Bcl-2 did not differ between active and stable MS, and was relatively similar between MS patients and controls. These findings suggest that overexpression of IAP proteins in stimulated T lymphocytes is a feature of clinically active multiple sclerosis.
Asunto(s)
Proteínas de Insectos/biosíntesis , Esclerosis Múltiple/inmunología , Proteínas , Linfocitos T/inmunología , Linfocitos T/metabolismo , Adulto , Apoptosis/inmunología , Femenino , Humanos , Proteínas Inhibidoras de la Apoptosis , Masculino , Persona de Mediana Edad , Mitógenos/farmacología , Esclerosis Múltiple/etiología , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Linfocitos T/efectos de los fármacos , Receptor fas/biosíntesisRESUMEN
Interferon-beta reduces clinical exacerbations in multiple sclerosis (MS) through several immunomodulatory mechanisms that may involve augmentation of programmed cell death (apoptosis) of T lymphocytes. The anti-apoptosis protein FLIP (Fas-associated death domain-like interleukin-1beta-converting enzyme inhibitory protein) has been recently identified as a potent regulator of T lymphocyte susceptibility to apoptosis. In a prospective study, we evaluated the expression of FLIP and other apoptosis regulatory proteins in ex vivo activated T lymphocytes from MS patients, before and serially after treatment with interferon-beta. We also investigated the long-term effects of interferon-beta on T cell apoptosis in a cross-sectional study of MS patients receiving chronic drug therapy. Treatment with interferon-beta reduced the expression of FLIP isoforms in activated T lymphocytes. This reduced expression correlated with augmented T cell susceptibility to apoptosis and with clinical response to treatment. In contrast, interferon-beta therapy did not alter cellular expression of the anti-apoptotic protein Bcl-2. This downregulatory effect of interferon-beta on cellular FLIP expression was maintained following long-term therapy. Our findings suggest that interferon-beta therapy exerts a regulatory effect on peripheral T lymphocytes through a pro-apoptosis mechanism that involves the downregulation of cellular FLIP expression.
Asunto(s)
Apoptosis/efectos de los fármacos , Proteínas Portadoras/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Interferón beta/administración & dosificación , Péptidos y Proteínas de Señalización Intracelular , Esclerosis Múltiple/tratamiento farmacológico , Linfocitos T/efectos de los fármacos , Adulto , Apoptosis/inmunología , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD , Proteínas Portadoras/inmunología , Proteínas Portadoras/metabolismo , Caspasa 8 , Caspasa 9 , Caspasas/efectos de los fármacos , Caspasas/metabolismo , Células Cultivadas/efectos de los fármacos , Células Cultivadas/inmunología , Células Cultivadas/metabolismo , Regulación hacia Abajo/inmunología , Femenino , Humanos , Interferón beta/efectos adversos , Estudios Longitudinales , Masculino , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Estudios Prospectivos , Inducción de Remisión/métodos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Factores de Tiempo , Resultado del Tratamiento , Receptor fas/efectos de los fármacos , Receptor fas/metabolismoRESUMEN
The cellular caspase-inhibitory protein FLIP has been recently identified as a potent regulator of T lymphocyte susceptibility to Fas-mediated programmed cell death (apoptosis). Since impairment of apoptosis may be involved in multiple sclerosis (MS), we investigated the dynamics of cellular FLIP in unstimulated and activated T lymphocytes from MS patients, inflammatory and non-inflammatory neurological disorders, and healthy subjects. Cellular expression of the long and short forms of FLIP protein was similar in unstimulated T cells from MS patients and controls, but was significantly higher in activated T cells from patients with clinically active MS. This high FLIP expression in active MS correlated with cellular resistance to Fas-mediated apoptosis. In contrast, cellular expression of the anti-apoptotic protein Bcl-2 did not differ between active and stable disease, and was relatively similar between the MS group and controls. These findings suggest that cellular overexpression of the anti-apoptotic protein FLIP is a feature of clinically active multiple sclerosis.
Asunto(s)
Apoptosis/fisiología , Proteínas Portadoras/fisiología , Péptidos y Proteínas de Señalización Intracelular , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Linfocitos T/metabolismo , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD , Proteínas Portadoras/metabolismo , Humanos , Inflamación/metabolismo , Esclerosis Múltiple Recurrente-Remitente/metabolismo , Enfermedades del Sistema Nervioso/metabolismo , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Valores de Referencia , Receptor fas/metabolismo , Receptor fas/fisiologíaRESUMEN
BACKGROUND: There is a close association between intestinal metaplasia (IM) and the development of gastric cancer as well as a relationship between Helicobacter pylori, IM, and gastric cancer. Our aim was to study the frequency and subtypes of IM in a Saudi population with dyspepsia, a population with a low prevalence of gastric cancer. METHODS: Endoscopic antral biopsy specimens were histologically studied for the presence of IM and H. pylori in consecutive patients who underwent upper gastrointestinal endoscopy for evaluation of dyspepsia. Hematoxylin and eosin and Giemsa stain were used to study IM, inflammation, and H. pylori, whereas Alcian blue, pH 2.5/periodic acid-Schiff and high iron diamine/Alcian blue, pH 2.5, were used to study IM subtypes. RESULTS: Seven hundred and seventy-eight consecutive patients were recruited in this study, 415 men and 363 women, with a mean age of 43 +/- 17.6 years. Of the 778 patients, IM was identified in 118 (15.2%). The mean ages of patients with IM (48.8 +/- 18.7) and without IM (41.9 +/- 17.4) were statistically significant (P < 0.0001), whereas the patients' sex did not influence the presence of IM. Most had type-I IM (59.3%), whereas 26.3% and 14.4% had types II and III, respectively. The overall rate of infection with H. pylori was 75.4%. There was no difference in the frequency of IM in patients with or without H. pylori (15.5% versus 14.1%; P = 0.65). Of the 118 patients with IM, the 91 patients (77.1%) who also had H. pylori were older (55 +/- 23 years) than those without H. pylori (47 +/- 17 years, P = 0.05). CONCLUSION: This study has documented mainly that the prevalence of IM and IM subtype III is low in our population. Furthermore, we found no significant relationship between a high rate of H. pylori infection with either IM in general or with IM subtype III in particular, possibly accounting for a low incidence of gastric cancer in the Saudi population.
Asunto(s)
Infecciones por Helicobacter/epidemiología , Helicobacter pylori/aislamiento & purificación , Antro Pilórico/microbiología , Antro Pilórico/patología , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Biopsia , Niño , Femenino , Humanos , Masculino , Metaplasia/epidemiología , Metaplasia/patología , Persona de Mediana Edad , Prevalencia , Arabia SauditaRESUMEN
Three hundred and thirty-four cases of confirmed malaria seen in the Asir Central Hospital, Abha, in southwestern Saudi Arabia, were studied retrospectively. Two hundred and eighty-two of these (84.4%) were Saudis and the majority (72.2%) were living in the lowlands of Tihama. Transmission was found to occur throughout the year, with peaks following the rainy season and in the summer. In Saudis, falciparum malaria is more common than vivax (97.2% vs. 2.8%), while vivax malaria is more commonly seen in expatriates (46.2%). Poor response of falciparum malaria to chloroquine was more prevalent in expatriates than in Saudis (46.4% vs. 23%). Most of the expatriates gave a history of recent travel to countries known to be endemic with resistant malaria. The possibility of the emergence of chloroquine-resistant malaria in the southwestern region of Saudi Arabia was discussed.
RESUMEN
In a five-year case-control study (1988 to 1993) at Assir Central Hospital (ACH), Abha (8,000 feet above sea level), Saudi Arabia, 92 of 129 patients suspected of deep venous thrombosis (DVT) were studied with ascending contrast venography (CV) (74 patients, 80.4%) or Doppler ultrasonography (DUS) (18 patients, 19.6%). Female-to-male ratio was 2.3 to 1. Age range of patients was twelve to ninety years; mean age was 44.45 yrs +/- 17.38 years. DVT hospital incidence was 18 per 10,000 admissions. The most common associated factors included immobilization due to chronic diseases (21.7%), trauma and surgery (19.6%), and pregnancy and oral contraceptives usage (16.3%). The most common symptom and sign were limb pain and tenderness (95.6%). Limb swelling was noted in 93.5% of patients. The left lower limb was more commonly affected than the right. There was a definite increase of DVT during the winter months. Altitude was not a contributory factor. Pulmonary embolism was the greatest complication.