International Immunology Advance Access originally published online on March 28, 2006
International Immunology 2006 18(5):661-669; doi:10.1093/intimm/dxl003
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Increased negative selection impairs neonatal B cell repertoire but does not directly lead to generation of disease-associated IgM auto-antibodies
1 Department of Pathobiology and
2 Department of Molecular and Cellular Biology, University of Guelph, Guelph, Ontario N1G 2W1, Canada
Correspondence to: A. K. Kaushik; E-mail: akaushik{at}uoguelph.ca
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.
Keywords: B lymphocyte, IgM auto-antibodies, negative B cell selection, SHP-1, VDJ rearrangement, VHJ558 gene
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