RESUMEN
Common genetic variants of IL-7 receptor alpha (IL-7Ralpha) have recently been shown to affect susceptibility to multiple sclerosis (MS) and type 1 diabetes, and survival following bone marrow transplantation. Transcription of the gene produces two dominant isoforms, with or without exon 6, which code for membrane-bound or soluble IL-7Ralpha, respectively. The haplotypes produce different isoform ratios. We have tested IL-7Ralpha mRNA expression in cell subsets and in models of T cell homeostasis, activation, tolerance, and differentiation into regulatory T cell/Th1/Th2/Th17, memory, and dendritic cells (DCs) under the hypothesis that the conditions in which haplotype differences are maximal are those likely to be the basis for their association with disease pathogenesis. Maximal differences between haplotypes were found in DCs, where the ligand is mainly thymic stromal lymphopoietin (TSLP). The MS-protective haplotype produces a much lower ratio of soluble to membrane-bound receptor, and so potentially, DCs of this haplotype are more responsive to TSLP. The TSLP/IL-7Ralpha interaction on DCs is known to be critical for production of thymic regulatory T cells, and reduced production of these cells in MS susceptibility haplotypes may be a basis for its association with this disease. IL-7Ralpha mRNA expression varies greatly through cell differentiation so that it may be a useful marker for cell states. We also show that serum levels of soluble receptor are much higher for the MS susceptibility haplotype (p = 4 x 10(-13)). Because signaling through IL-7Ralpha controls T cell regulation, this haplotype difference is likely to affect the immunophenotype and disease pathogenesis.
Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Células Dendríticas/metabolismo , Perfilación de la Expresión Génica , Haplotipos , Receptores de Interleucina-7/genética , Empalme Alternativo , Linfocitos T CD4-Positivos/citología , Células Cultivadas , Citocinas/metabolismo , Células Dendríticas/citología , Ensayo de Inmunoadsorción Enzimática , Femenino , Genotipo , Homeostasis/genética , Humanos , Interleucina-17/metabolismo , Masculino , Esclerosis Múltiple/genética , Unión Proteica , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Receptores de Interleucina-7/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Linfocitos T Colaboradores-Inductores/citología , Linfocitos T Colaboradores-Inductores/metabolismo , Células TH1/citología , Células TH1/metabolismo , Células Th2/citología , Células Th2/metabolismo , Linfopoyetina del Estroma TímicoRESUMEN
Multiple sclerosis (MS) is a complex autoimmune disease characterized by the destruction of the myelin sheath of neurons. Interferon beta (IFN-beta) is currently the major drug used to treat MS. Some patients fail to respond to this treatment, in some cases due to the development of neutralizing antibodies (NAb) to IFN-beta. We used microarray analysis and RT-PCR to measure gene expression in whole blood, 9-15 h postinjection, in patients with and without NAbs to IFN-beta. The canonical marker of biological response to IFN-beta, myxovirus resistance protein A, was upregulated in all NAb- patients while remaining unchanged in NAb+ patients. Genes functioning in immune response pathways were dominant in the set of differentially expressed genes: 73 immune response genes were identified as upregulated and 29 genes were identified as downregulated. B-cell activating factor (BAFF) is a strong candidate marker for biological and clinical response as well as for predisposition to NAb development. We demonstrate that it is responsive to IFN-beta in vitro and in vivo, and that its soluble form is elevated in serum from NAb- but not NAb+ patients. We conclude BAFF is a good biomarker for IFN-beta response, and requires further studies to determine its value as a marker for clinical response and NAb predisposition.