B cell repertoire diversity and clonal expansion in multiple sclerosis brain lesions

J Immunol. 1999 Nov 1;163(9):5133-44.

Abstract

Multiple sclerosis (MS) lesions in the CNS are characterized by disseminated demyelination with perivascular infiltrates of macrophages, T cells, and B cells. To investigate the origin and characteristics of the B cell population found in MS plaque tissue, we performed molecular studies in 10 MS patients and 4 non-MS control samples. Ig transcripts from the perivascular infiltrated brain lesions were analyzed by complementary-determining region 3 spectratyping to ascertain the B cell heavy chain gene rearrangement repertoire expressed in MS brains. Significant rearrangement diversity and deviation from the normal Ig heavy (H) chain repertoire was observed. The cloning and sequencing of RT-PCR products from families VH1 and VH4 showed a correlation with the profiles obtained by spectratyping. Generally, restricted spectratyping patterns concurred with repetition of in-frame complementary-determining region 3 identical sequences. The analysis of heavy chain variable (VH), diversity (D), and joining (JH) gene segments revealed the increased usage of VH1-69, VH4-34, and VH4-39. Similarly, gene segments from families D2, D3, and JH4 were over-represented. The presence of restricted patterns of rearranged Ig mRNA within the plaque lesion suggests that Ab production in the demyelinating plaque is a local phenomenon and supports the idea that in MS an Ag-driven immune response might be responsible for demyelination.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Antibody Diversity / genetics
  • B-Lymphocyte Subsets / chemistry
  • B-Lymphocyte Subsets / immunology*
  • B-Lymphocyte Subsets / pathology*
  • Brain / immunology*
  • Brain / pathology*
  • Brain Chemistry / genetics
  • Brain Chemistry / immunology
  • Cell Division / immunology
  • Clone Cells
  • Cloning, Molecular
  • Gene Rearrangement, B-Lymphocyte, Heavy Chain
  • Genes, Immunoglobulin
  • Humans
  • Immunoglobulin Heavy Chains / genetics
  • Immunoglobulin Joining Region / genetics
  • Immunoglobulin Variable Region / genetics
  • Immunophenotyping / methods
  • Molecular Sequence Data
  • Multiple Sclerosis / genetics
  • Multiple Sclerosis / immunology*
  • Multiple Sclerosis / pathology*
  • Polymerase Chain Reaction / methods

Substances

  • Immunoglobulin Heavy Chains
  • Immunoglobulin Joining Region
  • Immunoglobulin Variable Region