Dysregulated expression of the Cd22 gene as a result of a short interspersed nucleotide element insertion in Cd22a lupus-prone mice

The Cd22 gene encodes a B cell-specific adhesion molecule that modulates B cell Ag receptor-mediated signal transduction, and is allelic to a lupus-susceptibility locus in New Zealand White (NZW) mice. In this study, we show that, in addition to the wild-type transcripts, NZW (Cd22(a)) mice synthesize aberrant CD22 mRNAs that contain similar to 20-120 nucleotide insertions upstream of the coding region between exons 2 and 3, and/or similar to 100-190 nucleotide deletions of exon 4, Sequence analysis revealed that these aberrant mRNA species arose by alternative splicing due to the presence in the NZW strain of a 794-bp sequence insertion in the second intron, containing a fluster of short interspersed nucleotide elements. Both the presence of sequence insertion and aberrantly spliced mRNAs were specific to mice bearing the Cd22(a) and Cd22(c) alleles, Up-regulation of CD22 expression after LPS activation appeared impaired in Cd22(a) spleen cells (twice lower than in Cd22(b) B cells). Furthermore, we show that partial CD22 deficiency, i.e., heterozygous level of CD22 expression, markedly promotes the production of IgG anti-DNA autoantibodies in C57BL/6 (Cd22(b)) mice bearing the Y chromosome-linked autoimmune acceleration gene, Yaa, Taken together, these results suggest that a lower up-regulation of CD22 on activated B cells (resulting from Cd22 gene anomaly in Cd22(a) mice or from CD22 heterozygosity in mutants obtained by gene targeting) is implicated in autoantibody production, providing support for Cd22(a) as a possible candidate allele contributing to lupus susceptibility.