Background The role of the B1a subset in cells in autoimmunity remains controversial. Here we identify a spontaneous mutation in IkappaBNS associated with severe reduction in the peritoneal B1a, but not other B cell subsets and use this mutation to study its contribution to autoimmunity.
Materials and methods NZB, NZB.NZW-Lbw2, B6-Nfkbidbumble (IkappaBNS-deficient mice), and crosses were bred and maintained at TSRI and experiments approved by Scripps IACUC. Flow cytometry, mapping, sequencing, Ig and autoantibody ELISA, and direct Coomb’s test were by standard procedures. For in vivo poly(I:C) stimulation, 200 ug were given i.p. to 6–10 wk-old mice 2x/wk for 8 wks. B cells were stimulated in vitro with 30 ug/ml goat F(ab’)2 anti-mouse IgM in RPMI 10% FCS.
Results A chromosome 4 NZB subcongenic line, NZB.NZW-Lbw2SE, was discovered to exhibit very low B-1a cells in the peritoneal cavity and reduced serum IgM, but with no detectable effect on B cells in other lymphoid compartments including the MZ subset in the spleen. Mapping and a complementation study with Nfkbid (IkappaBNS gene)-deficient mice, identified a spontaneous hypomorphic K100N mutation of IkappaBNS, a member of the nuclear IkappaB family that serves as modulators of NF-kB function. Notably, in contrast to complete deletion of IkappaBNS, which affects multiple immune cell types, the phenotype of the NZB-SE mutation, named lowb1, was limited to peritoneal B-1a cells. The absence of low B-1a cells did not reduce susceptibility to spontaneous autoimmune hemolytic anaemia. However, lowb1 mice were resistant to poly(I:C)-induced autoimmune hemolytic anaemia indicating that B-1a cells could play a role in modulating environmental factors.
Conclusions These studies suggest a limited role for B1a cells in autoimmune hemolytic anaemia and identify the nuclear Ikappa family as a modulator of autoimmunity.
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