Axon Reactive B Cells Clonally Expanded in the Cerebrospinal Fluid of Patients with Multiple Sclerosis
- 90 Downloads
Demyelination and axonal loss have been described as the histological hallmarks of inflammatory lesions of multiple sclerosis (MS) and are the pathological correlates of persistent disability. However, the immune mechanisms underlying axonal damage in MS remain unknown. Here, we report the use of single chain-variable domain fragments (scFv) from clonally expanded cerebrospinal fluid (CSF) B cells to show the role of an anti-axon immune response in the central nervous system (CNS) in MS. The cellular and subcellular distribution of the antigen(s) recognized by these CSF-derived clonal scFv antibodies (CSFC-scFv Abs) was studied by immunochemical staining of brain tissues obtained at autopsy from patients with MS. Immunochemistry showed specific binding of CSFC-scFv Abs to axons in acute MS lesions. The stained axons showed three major types of axonal pathological changes: 1) linear axons, axonal ovoid formation, and axonal transection were seen in the myelinated white matter adjacent to the lesion; 2) accumulation of axonal ovoid formations and Wallerian degeneration were seen at the border between demyelinated lesions and the adjacent white matter; and 3) Wallerian degeneration occurred at the center and edge of acute demyelinated lesions. These findings suggest a B cell axonal specific immune response in the CNS in MS.
Key WordsCSF B cell clonal expansion CSFC-scFv antibody axonal immunity multiple sclerosis
Unable to display preview. Download preview PDF.
- 3.Robinson WH, DiGennaro C, Hueber W, Haab BB, Kamachi M, Dean EJ, Fournel S, Fong D, Genovese MC, de Vegvar HE, Skriner K, Hirschberg DL, Morris RI, Muller S, Pruijn GJ, van Venrooij WJ, Smolen JS, Brown PO, Steinman L, Utz PJ: Autoantigen microarrays for multiplex characterization of autoantibody responses. Nat Med 8:295–301, 2002CrossRefPubMedGoogle Scholar
- 4.Chabas D, Baranzini SE, Mitchell D, Bernard CC, Rittling SR, Denhardt DT, Sobel RA, Lock C, Karpuj M, Pedotti R, Heller R, Oksenberg JR, Steinman L: The influence of the proinflammatory cytokine, osteopontin, on autoimmune demyelinating disease. Science 294:1731–1735, 2001CrossRefPubMedGoogle Scholar
- 13.Qin Y, Duquette P, Zhang Y, Olek M, Da RR, Richardson J, Antel JP, Talbot P, Cashman NR, Tourtellotte WW, Wekerle H, Van Den Noort S: Intrathecal B-cell clonal expansion, an early sign of humoral immunity, in the cerebrospinal fluid of patients with clinically isolated syndrome suggestive of multiple sclerosis. Lab Invest 83:1081–1088, 2003CrossRefPubMedGoogle Scholar
- 19.Welschof M, Terness P, Kolbinger F, Zewe M, Dubel S, Dorsam H, Hain C, Finger M, Jung M, Moldenhauer G, et al.: Amino acid sequence based PCR primers for amplification of rearranged human heavy and light chain immunoglobulin variable region genes. J Immunol Methods 179:203–214, 1995CrossRefPubMedGoogle Scholar
- 20.Hanahan D: Techniques for transformation of E. coli. Washington DC, IRL, 1985, p 109Google Scholar
- 29.Paolillo A, Pozzilli C, Gasperini C, Giugni E, Mainero C, Giuliani S, Tomassini V, Millefiorini E, Bastianello S: Brain atrophy in relapsing-remitting multiple sclerosis: Relationship with ‘black holes,’ disease duration and clinical disability. J Neurol Sci 174:85–91, 2000CrossRefPubMedGoogle Scholar