Increased negative selection impairs neonatal B cell repertoire but does not directly lead to generation of disease-associated IgM auto-antibodies.
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 V(H)J558+ VDJCmu rearrangements from SHP-1-deficient viable motheaten (me(v)/me(v)) and 24 J558+ VDJCmu rearrangements from normal me(v)/+ neonatal (<24 h post-birth) B cells were examined for their structural properties. None of the J558+ VDJCmu rearrangements from autoimmune-prone me(v)/me(v) 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 me(v)/me(v) (31.9%) as compared with me(v)/+ (16.7%), and pM11 gene expression is exclusively (14.9%) noted in me(v)/me(v) B cells. Clearly, there is a trend toward higher expression of pM11 genes (P-value < or = 0.09) in autoimmune-prone me(v)/me(v) strain. The CDR2H region of J558+ VDJCmu recombinations from me(v)/me(v) has increased hotspot triplets predisposing to mutations as compared with me(v)/+ (P-value < or = 0.01) mice. A higher DFL D-gene expression is noted in J558+ VDJCmu rearrangements from me(v)/me(v) (P-value < or = 0.1) in contrast to me(v)/+. The sophisticated logistic regression and odds ratio analysis of V-, D- and J-gene expressions in neonatal B cells from me(v)/me(v) and me(v)/+ 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.
Cassady-Cain
Robin L
RL
Department of Pathobiology, University of Guelph, Guelph, Ontario N1G 2W1, Canada.
Kaushik
Azad K
AK
D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis / Q000097:blood* / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D003627:Data Interpretation, Statistical; D015723:Gene Library; D005838:Genotype; D007075:Immunoglobulin M / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D007148:Immunoglobulin mu-Chains / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010802:Phylogeny; D012641:Selection, Genetic
D001323:Autoantibodies; D007075:Immunoglobulin M; D007148:Immunoglobulin mu-Chains