RESUMEN

There is emerging evidence that failure of apoptosis (programmed cell death) of potentially pathogenic T lymphocytes may be involved in the pathogenesis of multiple sclerosis (MS). The commitment of T lymphocytes to die is partly regulated by the Bcl-2 family proteins, which act as a checkpoint upstream of mitochondrial dysfunction. These proteins include the death antagonists Bcl-2 and Bcl-X(L), and death agonists Bax and Bad. Recent studies suggest that altered expression of Bcl-2 family proteins in T lymphocytes is involved in promoting cellular resistance to apoptosis in patients with MS. However, the relationship between these alterations in Bcl-2 proteins expression and clinical disease activity has not yet been evaluated. In this study, we analyzed the expression ratios of pro- to anti-apoptosis Bcl-2 family proteins in patients with clinically active MS and compared results to corresponding ratios in patients with stable MS and relevant control groups. We observed a significant reduction in the expression ratios of pro- to anti-apoptosis Bcl-2 members in peripheral lymphocytes from patients with active MS when compared to corresponding ratios in patients with stable MS or other controls. This imbalance in the expression ratios of pro- and anti-apoptosis proteins was functionally active in reducing cellular susceptibility to apoptosis in active MS. It also correlated with clinical features of disease activity, such as the number of gadolinium-enhancing MRI lesions and clinical relapses. Our findings indicate that dysregulated expression of Bcl-2 family proteins in peripheral lymphocytes is a feature of clinically active multiple sclerosis.

Asunto(s)

Apoptosis/inmunología , Quimiotaxis de Leucocito/inmunología , Esclerosis Múltiple/inmunología , Proteínas Proto-Oncogénicas c-bcl-2/inmunología , Linfocitos T/inmunología , Apoptosis/genética , Proteínas Portadoras/sangre , Proteínas Portadoras/inmunología , División Celular/inmunología , Quimiotaxis de Leucocito/genética , Grupo Citocromo c/sangre , Femenino , Regulación de la Expresión Génica/inmunología , Humanos , Masculino , Esclerosis Múltiple/sangre , Esclerosis Múltiple/fisiopatología , Proteínas Proto-Oncogénicas/sangre , Proteínas Proto-Oncogénicas/inmunología , Proteínas Proto-Oncogénicas c-bcl-2/sangre , Recurrencia , Linfocitos T/metabolismo , Proteína X Asociada a bcl-2 , Proteína Letal Asociada a bcl , Proteína bcl-X , Receptor fas/sangre , Receptor fas/inmunología

RESUMEN

Programmed cell death (apoptosis) is critical for the normal development and homeostasis of the immune system. There is emerging evidence that failure of apoptosis to eliminate potentially pathogenic, autoreactive T lymphocytes may be involved in the pathogenesis of multiple sclerosis (MS). This failure is related to multiple abnormalities of apoptosis-regulatory molecules that involve survivin, a recently described cell cycle-regulated anti-apoptosis protein. In this study, we investigated the relationship between survivin expression in peripheral T lymphocytes and clinical features of MS. We detected a significant over-expression of survivin in mitogen stimulated T lymphocytes from patients with active MS when compared with corresponding expression in patients with stable MS or those with inflammatory and non-inflammatory neurologic disorders. This over-expression of survivin in patients with active MS correlated with cellular resistance to apoptosis and with features of disease activity, such as disease duration and the number of enhanced lesions on cranial magnetic resonance imaging. There was no correlation between cellular survivin levels and the expression of other apoptosis-inhibitory proteins, such as Bcl-2 and Fas-associated death domain-like interleukin-1beta-converting enzyme inhibitory protein (FLIP). Our findings indicate that cellular over-expression of the novel anti-apoptosis protein survivin is a feature of clinically active MS.

Asunto(s)

Apoptosis/inmunología , Autoinmunidad/inmunología , Péptidos y Proteínas de Señalización Intracelular , Proteínas Asociadas a Microtúbulos/inmunología , Esclerosis Múltiple/inmunología , Linfocitos T/inmunología , Regulación hacia Arriba/inmunología , Edad de Inicio , Proteína Reguladora de Apoptosis Similar a CASP8 y FADD , Proteínas Portadoras/inmunología , Células Cultivadas , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/patología , Sistema Nervioso Central/fisiopatología , Expresión Génica/inmunología , Humanos , Proteínas Inhibidoras de la Apoptosis , Imagen por Resonancia Magnética , Mitógenos , Esclerosis Múltiple/fisiopatología , Proteínas de Neoplasias , Proteínas Proto-Oncogénicas c-bcl-2/inmunología , Survivin , Linfocitos T/metabolismo , Receptor fas/inmunología

RESUMEN

Treatment with interferon-beta reduces clinical exacerbations in multiple sclerosis (MS) through several immunomodulatory mechanisms that involve the augmentation of programmed cell death (apoptosis) of peripheral T lymphocytes. The recently identified family of inhibitor of apoptosis (IAP) proteins is a potent regulator of cell death. The expression of IAP-1, IAP-2, and X-linked IAP (XIAP) is upregulated in mitogen stimulated T lymphocytes from MS patients, and this expression correlates with MS disease activity. In this study, we sought to evaluate the effect of interferon-beta on cellular expression of IAP proteins and other apoptosis regulatory molecules. In a prospective study, we evaluated the expression of IAP proteins, the anti-apoptosis Bcl-2 protein, and the death receptor Fas in in vitro stimulated T lymphocytes from MS patients, before and serially after treatment with interferon-beta. We also investigated the long-term effects of interferon-beta on cellular expression of these proteins and T lymphocyte apoptosis in a cross-sectional study of MS patients receiving drug therapy for a mean of 4.8 years. Treatment with interferon-beta reduced the expression of IAP-1, IAP-2 and XIAP in stimulated T lymphocytes. This reduced expression correlated with increased T cell susceptibility to apoptosis and with clinical response to treatment. In contrast, interferon-beta therapy did not alter cellular expression of Bcl-2 protein or the death receptor Fas. This downregulatory effect of interferon-beta on cellular expression of IAP proteins was maintained following long-term therapy. Our findings suggest that interferon-beta therapy exerts a regulatory effect on peripheral T lymphocytes through an anti-apoptosis mechanism that involves the downregulation of cellular IAP proteins expression.

Asunto(s)

Apoptosis/efectos de los fármacos , Regulación hacia Abajo/efectos de los fármacos , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/inmunología , Proteínas/efectos de los fármacos , Linfocitos T/efectos de los fármacos , Adulto , Apoptosis/inmunología , Células Cultivadas , Regulación hacia Abajo/inmunología , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Humanos , Proteínas Inhibidoras de la Apoptosis , Estudios Longitudinales , Esclerosis Múltiple/metabolismo , Estudios Prospectivos , Proteínas/inmunología , Proteínas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/efectos de los fármacos , Proteínas Proto-Oncogénicas c-bcl-2/inmunología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Inducción de Remisión , Linfocitos T/inmunología , Regulación hacia Arriba/inmunología , Proteína Inhibidora de la Apoptosis Ligada a X , Receptor fas/efectos de los fármacos , Receptor fas/inmunología , Receptor fas/metabolismo

RESUMEN

The mechanism for the initiation of blood-brain barrier damage and intrathecal inflammation in multiple sclerosis (MS) is poorly understood. We have recently reported that levels of tumor necrosis factor-alpha (TNF-alpha) correlate with blood-brain barrier damage in patients with active MS. Stimulation of endothelial cells by TNF-alpha induces the expression of intercellular adhesion molecule-1 (ICAM-1), which is an important early marker of immune activation and response. We report herein for the first time the detection of high levels of free circulating ICAM-1 in serum and cerebrospinal fluid of patients with active MS. Levels of circulating ICAM-1 in these patients correlated with CSF pleocytosis, TNF-alpha levels and blood-brain barrier damage. These findings have important implications for the understanding and investigation of the intrathecal inflammatory response in active MS.

Asunto(s)

Barrera Hematoencefálica , Moléculas de Adhesión Celular/sangre , Moléculas de Adhesión Celular/líquido cefalorraquídeo , Esclerosis Múltiple/metabolismo , Factor de Necrosis Tumoral alfa/análisis , Adulto , Moléculas de Adhesión Celular/fisiología , Humanos , Inflamación/etiología , Molécula 1 de Adhesión Intercelular

RESUMEN

The relationship between the interleukin-2 (IL-2) system and the humoral response against human immunodeficiency virus type-I (HIV-1) is important in understanding the immune reaction before the development of AIDS. Levels of IL-2 and soluble IL-2 receptor (sIL-2R) in serum and cerebrospinal fluid (CSF) samples from 31 asymptomatic HIV-1 seropositive individuals were measured and correlated with levels of anti-1 IgG and IgM antibodies. High IL-2 levels were detected in the CSF of 20 (65%) subjects, 18 (90%) of whom had evidence of intrathecal synthesis of HIV-1-specific IgM antibodies. Similarly, IgG antibodies were detected in 10 subjects who had elevated IL-2 levels in the CSF. Moreover, intrathecal levels of IL-2 and sIL-2R correlated with intrathecal synthesis of both IgG and IgM antibodies. Local release of IL-2 seems to play an important role in the initiation of the antibody response against HIV-1 in early stages of infection and may be utilised in devising effective therapeutic strategies.

Asunto(s)

Seropositividad para VIH/metabolismo , VIH-1 , Interleucina-2/biosíntesis , Receptores de Interleucina-2/metabolismo , Médula Espinal/metabolismo , Adolescente , Adulto , Ensayo de Inmunoadsorción Enzimática , Femenino , Seropositividad para VIH/líquido cefalorraquídeo , VIH-1/inmunología , Humanos , Inmunoglobulina G/biosíntesis , Inmunoglobulina G/inmunología , Inmunoglobulina M/biosíntesis , Inmunoglobulina M/inmunología , Interleucina-2/líquido cefalorraquídeo , Masculino , Persona de Mediana Edad

RESUMEN

The mechanism for the initiation of blood-brain barrier damage and intrathecal inflammation in patients infected with the human immunodeficiency virus (HIV) is poorly understood. We have recently reported that tumour necrosis factor-alpha (TNF-alpha) mediates active neural inflammation and blood-brain barrier damage in HIV-1 infection. Stimulation of endothelial cells by TNF-alpha induces the expression of intercellular adhesion molecule-1 (ICAM-1), which is an important early marker of immune activation and response. We report herein for the first time the detection of high levels of free circulating ICAM-1 in serum and cerebrospinal fluid of patients with HIV-1 infection. Free circulating ICAM-1 in these patients correlated with TNF-alpha concentrations and with the degree of blood-brain barrier damage and were detected predominantly in patients with neurologic involvement. These findings have important implications for the understanding and investigation of the intrathecal inflammatory response in HIV-1 infection.