First Author | Cassady-Cain RL | Year | 2006 |
Journal | Int Immunol | Volume | 18 |
Issue | 5 | Pages | 661-9 |
PubMed ID | 16569683 | Mgi Jnum | J:108900 |
Mgi Id | MGI:3625249 | Doi | 10.1093/intimm/dxl003 |
Citation | Cassady-Cain RL, et al. (2006) Increased negative selection impairs neonatal B cell repertoire but does not directly lead to generation of disease-associated IgM auto-antibodies. Int Immunol 18(5):661-9 |
abstractText | 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 </= 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 </= 0.01) mice. A higher DFL D-gene expression is noted in J558(+) VDJCmu rearrangements from me(v)/me(v) (P-value </= 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. |