Increased frequency of interleukin 2-responsive T cells specific for myelin basic protein and proteolipid protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis

• Published in: The Journal of experimental medicine Vol. 179; no. 3; pp. 973 - 984
• Main Authors: Zhang, J, Markovic-Plese, S, Lacet, B, Raus, J, Weiner, H L, Hafler, D A
• Format: Journal Article
• Language: English
• Published: New York, NY Rockefeller University Press 01.03.1994; The Rockefeller University Press
• Subjects: Adult; Antigens, CD - blood; Antigens, CD - cerebrospinal fluid; Biological and medical sciences; Cell Line; Female; Flow Cytometry; HLA-DQ Antigens - blood; HLA-DQ Antigens - cerebrospinal fluid; HLA-DR Antigens - blood; HLA-DR Antigens - cerebrospinal fluid; Humans; Interleukin-2 - pharmacology; Male; Medical sciences; Middle Aged; Multiple Sclerosis - blood; Multiple Sclerosis - cerebrospinal fluid; Multiple Sclerosis - immunology; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Myelin Basic Protein - immunology; Myelin Proteins - immunology; Myelin Proteolipid Protein; Nervous System Diseases - blood; Nervous System Diseases - cerebrospinal fluid; Nervous System Diseases - immunology; Neurology; Recombinant Proteins - pharmacology; T-Lymphocyte Subsets - immunology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Human; Nervous system diseases; Multiple sclerosis; Myelin; Pathogenesis; Cytokine; Activation; Lipoprotein; Cerebrospinal fluid; Blood; Inflammatory disease; Specificity; Interleukin 2; Basic protein; Central nervous system disease; T-Lymphocyte; Proteolipid
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.179.3.973

Equal numbers of CD4+ T cells recognizing myelin basic protein (MBP) and proteolipid protein (PLP) are found in the circulation of normal individuals and multiple sclerosis (MS) patients. We hypothesized that if myelin-reactive T cells are critical for the pathogenesis of MS, they would exist in a different state of activation as compared with myelin-reactive T cells cloned from the blood of normal individuals. This was investigated in a total of 62 subjects with definitive MS. While there were no differences in the frequencies of MBP- and PLP-reactive T cells after primary antigen stimulation, the frequency of MBP or PLP but not tetanus toxoid-reactive T cells generated after primary recombinant interleukin (rIL-2) stimulation was significantly higher in MS patients as compared with control individuals. Primary rIL-2-stimulated MBP-reactive T cell lines were CD4+ and recognized MBP epitopes 84-102 and 143-168 similar to MBP-reactive T cell lines generated with primary MBP stimulation. In the cerebrospinal fluid (CSF) of MS patients, MBP-reactive T cells generated with primary rIL-2 stimulation accounted for 7% of the IL-2-responsive cells, greater than 10-fold higher than paired blood samples, and these T cells also selectively recognized MBP peptides 84-102 and 143-168. In striking contrast, MBP-reactive T cells were not detected in CSF obtained from patients with other neurologic diseases. These results provide definitive in vitro evidence of an absolute difference in the activation state of myelin-reactive T cells in the central nervous system of patients with MS and provide evidence of a pathogenic role of autoreactive T cells in the disease.