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Accumulation of Clonally Related B Lymphocytes in the Cerebrospinal Fluid of Multiple Sclerosis Patients¹

Monica Colombo^*,, Mariella Dono^*, Paola Gazzola, Silvio Roncella^*,§, Angelo Valetto^¶, Nicholas Chiorazzi^¶, Giovanni L. Mancardi and Manlio Ferrarini^2,*,||

^* Servizio di Immunologia Clinica, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy; Istituto di Medicina Interna, Università degli Studi di Milano, Milan, Italy; Dipartimento di Scienze Neurologiche e della Visione, Università degli Studi di Genova, Genova, Italy; ^§ Divisione di Anatomia Patologica, Ospedale Sant’Andrea, 19100 La Spezia, Italy; ^¶ Department of Medicine, North Shore University Hospital and New York University School of Medicine, Manhasset, New York, NY 77030; and ^|| Dipartimento di Oncologia, Biologia e Genetica, Università degli Studi di Genova, Genova, Italy

The accumulation of B lymphocyte clones in the cerebrospinal fluid (CSF) of patients with multiple sclerosis (MS) and patients with other neurological disorders was investigated using PCR technologies. Oligoclonal B cell accumulations were detected in 10 of 10 MS patients, but only in 3 of 10 of the patients with other neurological disorders. Analyses of the Ig V(D)J sequences on the CSF from MS patients disclosed that V_H3 and V_H4 genes were extensively mutated compared with germline sequences. Moreover, a substantial proportion of the molecular clones analyzed shared the same third CDR of the H chain variable region gene (HCDR3) and the same V_H genes, albeit with different numbers and locations of point mutations, thus indicating an ongoing process of intraclonal diversification. A larger number of clonally related V_H sequences could be obtained by using a V_H3 gene-specific PCR so that genealogical trees depicting the process of diversification could be drawn. Analyses of the Ig V(D)J from the CSF of a patient with viral meningitis and oligoclonal B cell accumulations revealed that V_H3 genes were extensively mutated. However, no intraclonal diversification could be observed even using V_H3 gene-specific PCR methodologies. Clone-specific PCR and sequencing was used to detect the V(D)J found in the CSF of one MS patient in the PBL of the same patient. Only 1/3 of the V(D)J sequences investigated could be demonstrated in the PBL, indicating that the V(D)J genes utilized by B cells in the CSF are much less represented in the PBL. Collectively, the data suggest that in MS there is a compartmentalized clonal expansion.