Increased negative selection impairs neonatal B cell repertoire but does not directly lead to generation of disease-associated IgM auto-antibodies

Abstract

To determine if increased negative B cell selection, due to lowered signaling threshold of responsiveness to a ligand as a result of SHP-1 deficiency, during ontogeny leads to the origin of disease-associated IgM auto-antibodies (AAbs), 47 VHJ558+ VDJCμ rearrangements from SHP-1-deficient viable motheaten (mev/ mev) and 24 J558+ VDJCμ rearrangements from normal mev/+ neonatal (<24 h post-birth) B cells were examined for their structural properties. None of the J558+ VDJCμ rearrangements from autoimmune-prone mev/ mev had the characteristic CDR3H size restriction or arginine residues noted in disease-associated IgM AAbs. However, the MVAR2/10 genes are expressed at a high frequency in mev/mev (31.9%) as compared with mev/+ (16.7%), and pM11 gene expression is exclusively (14.9%) noted in mev/mev B cells. Clearly, there is a trend toward higher expression of pM11 genes (P-value ≤ 0.09) in autoimmune-prone mev/mev strain. The CDR2H region of J558+ VDJCμ recombinations from mev/mev has increased hotspot triplets predisposing to mutations as compared with mev/+ (P-value ≤ 0.01) mice. A higher DFL D-gene expression is noted in J558+ VDJCμ rearrangements from mev/mev (P-value ≤ 0.1) in contrast to mev/+. The sophisticated logistic regression and odds ratio analysis of V-, D- and J-gene expressions in neonatal B cells from mev/mev and mev/+ mice demonstrates differential composition of the germ line IgM repertoire as a result of SHP-1 deficiency. These observations suggest that increased negative B cell selection during ontogeny impairs the developing IgM antibody repertoire but does not directly lead to generation of disease-associated IgM AAbs. © 2006 Oxford University Press.