Autoantibodies in Mice Lacking Terminal Deoxynucleotidyl Transferase: Evidence for a Role of N Region Addition in the Polyreactivity and in the Affinities of Anti-DNA Antibodies

Sandra Weller, Carmen Conde, Anne Marie Knapp, Honey Levallois, Susan Gilfillan, Jean Louis Pasquali, Thierry Martin

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

The generation of terminal deoxynucleotidyl transferase knockout mice (TdT0) has demonstrated that TdT is the only major activity involved in N region addition. This enzyme generates diversity by adding random nucleotides at the V-D-J junctions and by disrupting the formation of repetitive "homology-directed" junctions. Several studies have demonstrated that the Ig heavy chain third complementarity-determining region (H-CDR3) and the N regions play a critical role: 1) in distinguishing between poly reactive and monospecific combining sites in natural and Ag-induced Abs; and 2) in the specificity and polyreactivity of natural autoantibodies (autoAbs) and in particular of anti-DNA Abs. To examine the impact of the lack of TdT on the natural autoAb repertoire in adult mice, we have stimulated TdT0 and TdT+ littermates with LPS. Serum studies demonstrate that TdT is not critical for the generation of B cells expressing autoAbs including anti-DNA Abs and rheumatoid factors. However, the generation of a large collection of hybridomas indicates that the frequencies of these cells are reduced in TdT0 mice mainly due to a lower incidence of polyreactivity; also, the lack of N region diversity seems to negatively affect the affinity of anti-DNA Abs. The physiologic relevance of these data is discussed.

Original languageEnglish
Pages (from-to)3890-3898
Number of pages9
JournalJournal of Immunology
Volume159
Issue number8
StatePublished - Oct 15 1997
Externally publishedYes

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