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1.
Ann Neurol ; 77(3): 447-57, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25581547

RESUMEN

OBJECTIVE: Progressive multifocal leukoencephalopathy (PML) is a serious side effect associated with natalizumab treatment in multiple sclerosis (MS). PML risk increases in individuals seropositive for anti-John Cunningham virus (JC) antibodies, with prolonged duration of natalizumab treatment, and with prior exposure to immunosuppressants. We explored whether the presence of lipid-specific immunoglobulin M oligoclonal bands in cerebrospinal fluid (CSF; IgM bands), a recognized marker of highly inflammatory MS, may identify individuals better able to counteract the potential immunosuppressive effect of natalizumab and hence be associated with a reduced risk of developing PML. METHODS: We studied 24 MS patients who developed PML and another 343 who did not suffer this opportunistic infection during natalizumab treatment. Patients were recruited at 25 university hospitals. IgM bands were studied by isoelectric focusing and immunodetection. CSF lymphocyte counts were explored in 151 MS patients recruited at Ramon y Cajal Hospital in Madrid, Spain. RESULTS: IgM bands were independently associated with decreased PML risk (odds ratio [OR] = 45.9, 95% confidence interval [CI] = 5.9-339.3, p < 0.0001) in patients treated with natalizumab. They were also associated with significantly higher CSF CD4, CD8, and B-cell numbers. Patients positive for IgM bands and anti-JC antibodies had similar levels of reduced PML risk to those who were anti-JC negative (OR = 1.55, 95% CI = 0.09-25.2, p = 1.0). Higher risk was observed in patients positive for anti-JC antibodies and negative for IgM bands (19% of the total cohort, OR = 59.71, 95% CI = 13.6-262.2). INTERPRETATION: The presence of IgM bands reflects a process that may diminish the risk of PML by counteracting the excess of immunosuppression that may occur during natalizumab therapy.


Asunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Biomarcadores/líquido cefalorraquídeo , Leucoencefalopatía Multifocal Progresiva/líquido cefalorraquídeo , Leucoencefalopatía Multifocal Progresiva/inducido químicamente , Esclerosis Múltiple/líquido cefalorraquídeo , Bandas Oligoclonales/líquido cefalorraquídeo , Adulto , Femenino , Humanos , Virus JC/inmunología , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/tratamiento farmacológico , Natalizumab , Riesgo
2.
BMC Neurosci ; 15: 110, 2014 Sep 22.
Artículo en Inglés | MEDLINE | ID: mdl-25242463

RESUMEN

BACKGROUND: Cell-derived microparticles are secreted in response to cell damage or dysfunction. Endothelial and platelet dysfunction are thought to contribute to the development of multiple sclerosis (MS). Our aim here is, first, to compare the presence of microparticles of endothelial and platelet origin in plasma from patients with different clinical forms of MS and with clinically isolated syndrome. Second, to investigate the effect of microparticles on endothelial barrier function. RESULTS: Platelet-poor plasma from 95 patients (12 with clinically isolated syndrome, 51 relapsing-remitting, 23 secondary progressive, 9 primary progressive) and 49 healthy controls were analyzed for the presence of platelet-derived and endothelium-derived microparticles by flow cytometry. The plasma concentration of platelet-derived and endothelium-derived microparticles increased in all clinical forms of MS and in clinically isolated syndrome versus controls. The response of endothelial barriers to purified microparticles was measured by electric cell-substrate impedance sensing. Microparticles from relapsing-remitting MS patients induced, at equivalent concentrations, a stronger disruption of endothelial barriers than those from healthy donors or from patients with clinically isolated syndrome. MS microparticles acted synergistically with the inflammatory mediator thrombin to disrupt the endothelial barrier function. CONCLUSIONS: Plasma microparticles should be considered not only as markers of early stages of MS, but also as pathological factors with the potential to increase endothelial permeability and leukocyte infiltration.


Asunto(s)
Plaquetas/metabolismo , Micropartículas Derivadas de Células/metabolismo , Enfermedades Desmielinizantes/fisiopatología , Endotelio Vascular/metabolismo , Esclerosis Múltiple Crónica Progresiva/fisiopatología , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Adolescente , Adulto , Anciano , Permeabilidad Capilar , Niño , Impedancia Eléctrica , Femenino , Citometría de Flujo , Humanos , Masculino , Persona de Mediana Edad , Trombina/metabolismo , Adulto Joven
3.
Hum Immunol ; 69(4-5): 235-40, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18486757

RESUMEN

Recent studies demonstrated that dysregulation of NKG2D and its ligands, leading to activation of autoreactive effector cells, can trigger autoimmune diseases, but soluble forms of these ligands can downmodulate NKG2D expression in T effector cells. We investigated the presence of soluble major histocompatibility complex class I chain-related A or B (MICA or MICB) molecules in sera of multiple sclerosis (MS) patients and whether they play a role in the progression of the disease. Although soluble MICA serum levels did not differ, soluble MICB serum levels were higher in MS patients compared with controls. Moreover, the highest MICB levels were in MS patients during relapses. Using immunohistochemistry techniques, it was possible to locate MIC expression in neurons of MS demyelinating plaques that were intracellularly accumulated. Elevated soluble MICB levels exist in serum of multiple sclerosis patients related with disease activity. This may contribute to the modulation of immune response activity during relapses.


Asunto(s)
Antígenos de Histocompatibilidad Clase I/sangre , Esclerosis Múltiple Recurrente-Remitente/inmunología , Adulto , Astrocitos/inmunología , Astrocitos/patología , Progresión de la Enfermedad , Femenino , Humanos , Inmunohistoquímica , Estudios Longitudinales , Masculino , Microscopía Confocal , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/patología , Neuronas/inmunología , Neuronas/patología
4.
Am J Case Rep ; 17: 47-50, 2016 Jan 27.
Artículo en Inglés | MEDLINE | ID: mdl-26813773

RESUMEN

BACKGROUND: Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a recently described inflammatory disease of the central nervous system, distinguished by brainstem- and spinal cord-centered lesions with a characteristic contrast enhancement on MRI, a lymphocytic perivascular infiltrate on pathological exam, and a dramatic response to and dependence on steroids therapy. Since its initial description in 2010, different glucocorticoid-sparing agents, mostly immunosuppressant drugs, have been used to minimize the dosage, but these therapies also carry the risk of important secondary effects. We present the first reported case of CLIPPERS treated with interferon beta 1a as add-on therapy. CASE REPORT: A previously healthy 31-year-old man presented with gait ataxia and dysarthria. MRI showed pons-centered hyperintense patchy lesions on T2-weighted images. Additional tests ruled out other possible diagnoses and symptoms reversed with intravenous methylprednisolone. Over the years the patient presented with several episodes of deterioration each year, which were partly reversed with glucocorticoid therapy, but leaving him with growing sequelae. Four years after the initial event, treatment with interferon-beta-1a was initiated, achieving reduced frequency of the relapses to 1 every 4 years, which were no longer associated to increasing disability. This allowed reducing glucocorticoids to 30 mg of Deflazacort every other day. CONCLUSIONS: Interferon beta-1a could be an alternative to corticosteroid-combined therapy in CLIPPERS and its more benign profile of secondary effects compared to immunosuppressants could make it an attractive choice.


Asunto(s)
Adyuvantes Inmunológicos/uso terapéutico , Encefalomielitis/tratamiento farmacológico , Interferón beta-1a/uso terapéutico , Enfermedades Linfáticas/tratamiento farmacológico , Adulto , Antiinflamatorios/administración & dosificación , Humanos , Imagen por Resonancia Magnética , Masculino , Puente/patología , Pregnenodionas/administración & dosificación
5.
BMJ Case Rep ; 20112011 Dec 20.
Artículo en Inglés | MEDLINE | ID: mdl-22669987

RESUMEN

All three siblings (one female/two males) of a family presented successively with cerebrovascular events at the ages of 55, 63 and 65. The first one manifested extensive left subcortical haemorrhage and both the second and third patient, showed left lacunar ischemic stroke. Their mother had died from vascular dementia at the age of 60 after several subcortical ischaemic strokes. Their maternal grandfather had died in his fifties from haemorrhagic stroke. All of them showed extensive white matter involvement. The genetic study revealed a mutation in exon 11 of the Notch3 gene in two family members. They were diagnosed with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Although CADASIL is a well-established disease, little is known about this disorder. The fact that all three siblings presented with CADASIL successively may appear disheartening, further studies are needed in order to control the clinical course of this devastating and unavoidable disorder.


Asunto(s)
CADASIL , Anciano , CADASIL/diagnóstico , CADASIL/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad
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