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.
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.
Zhang
J
J
Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Markovic-Plese
S
S
Lacet
B
B
Raus
J
J
Weiner
H L
HL
Hafler
D A
DA
D000328:Adult; D015703:Antigens, CD / Q000097:blood / Q000134:cerebrospinal fluid; D002460:Cell Line; D005260:Female; D005434:Flow Cytometry; D006683:HLA-DQ Antigens / Q000097:blood / Q000134:cerebrospinal fluid; D006684:HLA-DR Antigens / Q000097:blood / Q000134:cerebrospinal fluid; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood / Q000134:cerebrospinal fluid / Q000276:immunology*; D004676:Myelin Basic Protein / Q000276:immunology*; D009185:Myelin Proteins / Q000276:immunology; D018991:Myelin Proteolipid Protein; D009422:Nervous System Diseases / Q000097:blood / Q000134:cerebrospinal fluid / Q000276:immunology; D011994:Recombinant Proteins / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D015703:Antigens, CD; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D007376:Interleukin-2; D004676:Myelin Basic Protein; D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein; D011994:Recombinant Proteins