RESUMEN
CD24 is expressed on a broad range of cells in the immune and central nervous systems and appears to be required for development of experimental autoimmune encephalomyelitis in mice. Association of a CD24 Ala/Val coding polymorphism with susceptibility to and progression of multiple sclerosis was recently reported. We typed this coding polymorphism in a combined cohort of 1,180 cases and 1,168 unrelated and family-based controls from Belgium and the UK, but were unable to confirm either association. Since the CD24 gene is part of a segmental duplication, special care is required for the identification and genotyping of single nucleotide polymorphisms.
Asunto(s)
Alanina/genética , Antígeno CD24/genética , Esclerosis Múltiple Crónica Progresiva/genética , Polimorfismo de Nucleótido Simple , Valina/genética , Quimiotaxis de Leucocito/efectos de los fármacos , Quimiotaxis de Leucocito/inmunología , Método Doble Ciego , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Mitoxantrona/uso terapéutico , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Esclerosis Múltiple Crónica Progresiva/patología , Receptores de Quimiocina/biosíntesisRESUMEN
Phase II clinical trials revealed that the lymphocyte-depleting humanized monoclonal antibody alemtuzumab (Campath-1H) is highly effective in the treatment of early relapsing-remitting multiple sclerosis. However, 30% of patients develop autoimmunity months to years after pulsed exposure to alemtuzumab, usually targeting the thyroid gland and, more rarely, blood components. In this study, we show that autoimmunity arose in those patients with greater T cell apoptosis and cell cycling in response to alemtuzumab-induced lymphocyte depletion, a phenomenon that is driven by higher levels of IL-21. Before treatment, patients who went on to develop secondary autoimmunity had more than 2-fold greater levels of serum IL-21 than the nonautoimmune group. We suggest that serum IL-21 may, therefore, serve as a biomarker for the risk of developing autoimmunity months to years after alemtuzumab treatment. This has implications for counseling those patients with multiple sclerosis who are considering lymphocyte-depleting therapy with alemtuzumab. Finally, we demonstrate through genotyping that IL-21 expression is genetically predetermined. We propose that, by driving cycles of T cell expansion and apoptosis to excess, IL-21 increases the stochastic opportunities for T cells to encounter self antigen and, hence, for autoimmunity.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Antineoplásicos/uso terapéutico , Autoinmunidad , Interleucinas/fisiología , Depleción Linfocítica , Esclerosis Múltiple/tratamiento farmacológico , Adulto , Alemtuzumab , Anticuerpos Monoclonales Humanizados , Apoptosis , Caspasa 3/metabolismo , Células Cultivadas , Femenino , Genotipo , Humanos , Interleucinas/genética , Activación de Linfocitos , Masculino , Esclerosis Múltiple/inmunología , Linfocitos T/inmunologíaRESUMEN
Several lines of evidence suggest that mitochondrial genetic factors may influence susceptibility to multiple sclerosis. To explore this hypothesis further, we re-sequenced the mitochondrial genome (mtDNA) from 159 patients with multiple sclerosis and completed a haplogroup analysis including a further 835 patients and 1,506 controls. A trend towards over-representation of super-haplogroup U was the only evidence for association with mtDNA that we identified in these samples. In a parallel analysis of nuclear encoded mitochondrial genes, we also found a trend towards association with the complex I gene, NDUFS2. These results add to the evidence suggesting that variation in mtDNA and nuclear encoded mitochondrial genes may contribute to disease susceptibility in multiple sclerosis.
Asunto(s)
ADN Mitocondrial/genética , Predisposición Genética a la Enfermedad , Esclerosis Múltiple/genética , Secuencia de Bases , Mapeo Cromosómico , Complejo I de Transporte de Electrón/genética , Frecuencia de los Genes , Variación Genética , Genoma , Genotipo , Humanos , Valores de Referencia , Población Blanca/genéticaRESUMEN
OBJECTIVE: Variation in the major histocompatibility complex (MHC) on chromosome 6p21 is known to influence susceptibility to multiple sclerosis with the strongest effect originating from the HLA-DRB1 gene in the class II region. The possibility that other genes in the MHC independently influence susceptibility to multiple sclerosis has been suggested but remains unconfirmed. METHODS: Using a combination of microsatellite, single nucleotide polymorphism, and human leukocyte antigen (HLA) typing, we screened the MHC in trio families looking for evidence of residual association above and beyond that attributable to the established DRB1*1501 risk haplotype. We then refined this analysis by extending the genotyping of classical HLA loci into independent cases and control subjects. RESULTS: Screening confirmed the presence of residual association and suggested that this was maximal in the region of the HLA-C gene. Extending analysis of the classical loci confirmed that this residual association is partly due to allelic heterogeneity at the HLA-DRB1 locus, but also reflects an independent effect from the HLA-C gene. Specifically, the HLA-C*05 allele, or a variant in tight linkage disequilibrium with it, appears to exert a protective effect (p = 3.3 x 10(-5)). INTERPRETATION: Variation in the HLA-C gene influences susceptibility to multiple sclerosis independently of any effect attributable to the nearby HLA-DRB1 gene.