Lolli Francesco, Mulinacci Barbara, Carotenuto Alfonso, Bonetti Bruno, Sabatino Giuseppina, Mazzanti Benedetta, D'Ursi Anna Maria, Novellino Ettore, Pazzagli Marta, Lovato Laura, Alcaro Maria C, Peroni Elisa, Pozo-Carrero Maria C, Nuti Francesca, Battistini Luca, Borsellino Giovanna, Chelli Mario, Rovero Paolo, Papini Anna Maria
Laboratory of Peptide and Protein Chemistry and Biology, Polo Scientifico, University of Florence, I-50019 Sesto Fiorentino, Italy.
Proc Natl Acad Sci U S A. 2005 Jul 19;102(29):10273-8. doi: 10.1073/pnas.0503178102. Epub 2005 Jul 12.
Multiple sclerosis (MS) is a complex disease that seems to depend on several pathophysiological processes. Because of its varied clinical presentation, natural history, and response to therapeutic interventions, MS can be considered to be a group of diseases that have not been yet characterized, thus resulting in difficult evaluation of prognosis. In the last few years, the role of autoAbs in MS has been reevaluated, and, therefore, their identification as specific biomarkers became a relevant target. In this paper, we demonstrate that an aberrant N-glucosylation is a fundamental determinant of autoAb recognition in MS. Thus, we developed CSF114(Glc), an antigenic probe accurately measuring IgM autoAbs in the sera of a patient population, as disease biomarker. The relevance of CSF114(Glc) is demonstrated by its clinical application and correlation with disease activity and prognosis. In fact, CSF114(Glc), a structure-based designed glycopeptide, is able to recognize, by ELISA, the presence of specific IgM autoAbs in the sera of a MS patient population but not in blood donors and other autoimmune conditions. AutoAbs specific for CSF114(Glc) isolated from MS patients recognized myelin and oligodendrocyte antigens by immunohistochemistry but not other nonrelevant tissues. We demonstrate that CSF114(Glc) is a reliable, specific probe in a longitudinal study of untreated MS patients. Development of IgG/IgM anti-CSF114(Glc) Abs paralleled clinical activity and brain lesions positive to MRI. Therefore, a CSF114(Glc)-based immunoassay on sera may have important prognostic value in monitoring MS disease progression guiding optimal therapeutic treatment.
多发性硬化症（MS）是一种复杂的疾病，似乎取决于多种病理生理过程。由于其临床表现多样、自然病程以及对治疗干预的反应各异，MS可被视为一组尚未明确特征的疾病，因此对其预后的评估较为困难。在过去几年中，自身抗体在MS中的作用得到了重新评估，因此，将它们鉴定为特定生物标志物成为了一个相关目标。在本文中，我们证明异常的N-糖基化是MS中自身抗体识别的一个基本决定因素。因此，我们开发了CSF114(Glc)，这是一种抗原探针，可准确测量患者群体血清中的IgM自身抗体，作为疾病生物标志物。CSF114(Glc)的相关性通过其临床应用以及与疾病活动和预后的相关性得到了证明。事实上，CSF114(Glc)是一种基于结构设计的糖肽，通过酶联免疫吸附测定（ELISA）能够识别MS患者群体血清中特定IgM自身抗体的存在，而在献血者和其他自身免疫性疾病患者的血清中则无法识别。从MS患者中分离出的针对CSF114(Glc)的自身抗体通过免疫组织化学可识别髓鞘和少突胶质细胞抗原，但不能识别其他无关组织。我们证明CSF114(Glc)在未经治疗的MS患者的纵向研究中是一种可靠、特异的探针。IgG/IgM抗CSF114(Glc)抗体的产生与临床活动以及MRI显示的脑损伤呈平行关系。因此，基于血清的CSF114(Glc)免疫测定在监测MS疾病进展以指导最佳治疗方面可能具有重要的预后价值。
