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

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.

Dendritic Cells from Lupus-Prone Mice Are Defective in Repressing Immunoglobulin Secretion

“…Anergic B cells fail to secrete Ab in response to LPS or Ag immunization due to receptor unresponsiveness (17,18,20). Some anergic B cells exhibit reduced surface IgM levels (21,22), decreased lifespan (20,23), and exclusion from the lymphoid follicle (23,24). In the case of B cells specific for the lupus-associated Ag, Smith (Sm), a partially anergic phenotype is evident.…”

Antinuclear Antigen B Cells That Down-Regulate Surface B Cell Receptor during Development to Mature, Follicular Phenotype Do Not Display Features of Anergy In Vitro

“…HKIR knockin mice, expressing the canonical R55 V H gene, and HKI65 mice, expressing the canonical V H lacking the R55 mutation, were created in an identical fashion by replacing the entire J H locus with a targeting vector differing only in the sequence of V H codon 55 (34,35). For many experiments, these lines were crossed to lines in which the entire J H locus had been deleted (JHD mice) (38) (a gift from Dr. R. Hardy, Fox Chase Cancer Center, Philadelphia, PA, USA) or the IgM transmembrane exon had been disrupted ( MT mice) (39) to preclude the development of B cells expressing the endogenous IgH locus.…”

“…We have previously described two lines of V H "knockin" mice that differ only in the presence or absence of a single mutation to arginine (R) at position 55 in the CDR2 subregion of the V H gene used to replace the endogenous J H locus (34,35). We term these lines of mice HKIR and HKI65, respectively.…”

“…Abs with the R55 form of the V domain also display reactivity for nuclear autoantigens such as chromatin and can cause kidney dysfunction via glomerular deposition in vivo. B cells expressing BCRs containing both types of V domains develop to mature follicular phenotype, reside in follicles, and are not short-lived (34). However, peripheral B cells expressing the R55 form are characterized by substantially reduced levels of sIgM and sIgD as compared with B cells expressing the form lacking this mutation (34,35).…”

“…B cells expressing BCRs containing both types of V domains develop to mature follicular phenotype, reside in follicles, and are not short-lived (34). However, peripheral B cells expressing the R55 form are characterized by substantially reduced levels of sIgM and sIgD as compared with B cells expressing the form lacking this mutation (34,35). Along with the results of previous studies discussed above indicating a correlation between sBCR down-regulation and reduced responsiveness of autoreactive B cells, these latter data suggested that the follicular B cells in HKIR mice expressing the canonical R55 BCR might be anergic.…”