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Restricted use of V H 4 Germline segments in an acute multiple sclerosis brain
Author(s) -
Owens Gregory P.,
Kannus Hanna,
Burgoon Mark P.,
SmithJensen Tracey,
Devlin Mary E.,
Gilden Donald H.
Publication year - 1998
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.410430214
Subject(s) - germline , complementarity determining region , biology , germline mutation , multiple sclerosis , microbiology and biotechnology , polyclonal antibodies , somatic cell , antigen , cerebrospinal fluid , mutation , genetics , immunoglobulin light chain , immunology , antibody , gene , neuroscience
Abstract Multiple sclerosis (MS) cerebrospinal fluid and brain contain increased IgG and oligoclonal bands. Whether this oligoclonal and polyclonal IgG is directed against a disease‐relevant antigen remains unknown. To distinguish between random activation versus a targeted B‐cell response, we analyzed the IgG heavy chain variable region (V H ) repertoire expressed in different lesions of an acute MS brain. To obtain a representative sample of the V H repertoire, we constructed directional complementary DNA libraries from plaque‐periplaque messenger RNA and amplified V H regions from the library by nested polymerase chain reaction. When MS V H sequences were aligned to germline segments, about 60% of different V H sequences in the acute MS brain were V H 4 germline segments, significantly greater than the known approximately 20% V H 4 germline prevalence. Specific V H sequences were overrepresented and expressed at multiple plaque sites. Within some overexpressed populations, there were distinct sequence differences (clonal variants) indicative of clonal expansion. Alignment of V H sequences to their closest germline counterparts revealed extensive somatic mutation and the preferential accumulation of amino acid replacement mutations in complementarity determining regions. These observations suggest the limited B‐cell response found in this acute MS brain was antigen driven.