Progressive Surface B Cell Antigen Receptor Down-Regulation Accompanies Efficient Development of Antinuclear Antigen B Cells to Mature, Follicular Phenotype

Lynn Heltemes-Harris, Xiaohe Liu, Tim Manser

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Previous studies have suggested that B cell Ag receptor (BCR) down-regulation by potentially pathological autoreactive B cells is associated with pathways leading to developmental arrest and receptor editing, or anergy. In this study we compare the primary development of B cells in two strains of mice expressing transgenic BCRs that differ by a single amino acid substitution that substantially increases reactivity for nuclear autoantigens such as DNA. Surprisingly, we find that both BCRs promote efficient development to mature follicular phenotype, but the strongly autoreactive BCR fails to promote marginal zone B cell development. The follicular B cells expressing the strongly autoreactive BCR do not appear to be anergic, as they robustly respond to polyclonal stimuli in vitro, are not short-lived, and can participate in germinal center reactions. Strikingly however, substantial and progressive down-modulation of surface IgM and IgD takes place throughout their primary development in the BM and periphery. We propose that BCR-autoantigen interactions regulate this pathway, resulting in reduced cellular avidity for autoantigens. This process of "learned ignorance" could allow autoreactive B cells access to the foreign Ag-driven memory B cell response, during which their self-reactivity would be attenuated by somatic hypermutation and selection in the germinal center.

Original languageEnglish (US)
Pages (from-to)823-833
Number of pages11
JournalJournal of Immunology
Volume172
Issue number2
DOIs
StatePublished - Jan 15 2004
Externally publishedYes

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