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Enhanced T cell responsiveness to citrulline-containing myelin basic protein in multiple sclerosis patients

Neuroimmunology Branch, NINDS, NIH, Bethesda, Maryland, MD 20892-1400 USA

Ligong Cao

Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, AL 35233-7340 USA, Center for Neuroimmunology of the University of Alabama at Birmingham, Birmingham, Alabama, AL 35294 USA

Nicholas C Ling

Neurocrine Biosciences, San Diego, California, CA 92121 USA

Hubert Kalbacher

Physiologisch-Chemisches Institut der Universität, Tübingen University Medical School, 72076 Tübingen, Germany

Roland M Martin

Neuroimmunology Branch, NINDS, NIH, Bethesda, Maryland, MD 20892-1400 USA

John N Whitaker

Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama, AL 35233-7340 USA, Center for Neuroimmunology of the University of Alabama at Birmingham, Birmingham, Alabama, AL 35294 USA, Neurology and Research Services of the Birmingham Veterans Medical Center, Birmingham, Alabama, AL 35233 USA

Myelin basic protein (MBP), a candidate autoantigen in multiple sclerosis (MS), exists in different isoforms and charge isomers generated by differential splicing of exons and by a combination of posttranslational modifications, respectively. These various isoforms and charge isomers of MBP vary in abundance and most likely serve different functions during myelinogenesis and remyelination. The least cationic among the charge isomers of MBP is citrullinated and is referred to as MBP-C8. MBP-C8 is relatively increased in the population of MBP isomers in more developmentally immature myelin and in MS brain tissue. In a previous study, we found that MBP-C8-reactive T cells could be detected in CD4+ T cell lines (TCL) generated with MBP from both MS patients and normal controls. Here, we examined the frequency and peptide specificity of MBPC8-specific TCL generated with MBP-C8 in MS patients and controls. Ten subjects grouped in five sets, each an MS patient and a control, were studied. In all cases, the MS patient had either a higher overall number of MBP-C8-responding lines, responded with greater sensitivity to the MBPC8 antigen or both. Few lines responded to the MBP-C8 peptides but, if they did, they appeared to be specific to the carboxyl-half of the MBP-C8 molecule. Given the large amounts of citrullinated MBP in MS brain tissue, a preferential T cell response to MBP-C8 may be involved in the induction and perpetuation of this disease.

Key Words: multiple sclerosis • MBP • citrulline • T cells • human • isomer

Multiple Sclerosis, Vol. 6, No. 4, 220-225 (2000)
DOI: 10.1177/135245850000600402


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