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V_H4 Gene Segments Dominate the Intrathecal Humoral Immune Response in Multiple Sclerosis¹

Gregory P. Owens^2,*, Kimberly M. Winges^*, Alanna M. Ritchie^*, Sydni Edwards^*, Mark P. Burgoon^*, Laura Lehnhoff^*, Kirsten Nielsen^*, John Corboy^*, Donald H. Gilden^*, and Jeffrey L. Bennett^*,

^* Department of Neurology, Department of Microbiology, and Department of Ophthalmology, University of Colorado Health Sciences Center, Denver, CO 80262

A characteristic feature of the CNS inflammatory response in multiple sclerosis (MS) is the intrathecal synthesis of IgG and the presence of oligoclonal bands. A strong correlation between CD138⁺ plasma blast numbers in MS cerebrospinal fluid (CeSF) and intrathecal IgG synthesis suggests that these cells are the major Ab-secreting cell type in MS CeSF. Sequencing of V regions from CD138⁺ cells in MS CeSF has revealed somatically mutated and expanded IgG clonotypes consistent with an Ag-targeted response. In the present study, single-cell RT-PCR analysis of CD138⁺ cells from 11 MS patients representing differing clinical courses and stages of disease identified expansion of CD138⁺ cells with functionally rearranged V_H4 gene segments as an overriding feature of MS CeSF repertoires. V_H4 dominance was attributed to the preferential selection of specific V_H4 genes, particularly gene segment V_H4-39, which displayed a significant enrichment in CeSF compared with MS peripheral blood B cells. A modest increase in V_H4 prevalence among MS peripheral blood IgG memory cells was also noted, suggesting that factors shaping the CD138 repertoire in CeSF might also influence the peripheral IgG memory cell pool. These results indicate a highly restricted B cell response in MS. Identifying the targets of CeSF plasma cells may yield insights into disease pathogenesis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Public Health Service Grants NS32623 (to D.H.G., G.P.O.), EY014573 (to J.L.B.), NS041549 (to M.P.B.), and the National Multiple Sclerosis Society Research Grant RG3908 (to J.L.B.). K.M.W. is a medical student supported by a Howard Hughes Medical Institute Fellowship Award.

² Address correspondence and reprint requests to Dr. Gregory P. Owens, Department of Neurology, University of Colorado Health Sciences Center, Mail Stop B-182, 4200 East Ninth Avenue, Denver, CO 80262. E-mail address: greg.owens{at}uchsc.edu

³ Abbreviations used in this paper: MS, multiple sclerosis; CeSF, cerebrospinal fluid; OCB, oligoclonal band; CIS, clinically isolated demyelinating syndrome; SSPE, subacute sclerosing panencephalitis; RT, reverse transcription; MNC, mononuclear cell.