Cd22 a PRE-mRNA Dysregulated Expression of the Cd22 Gene as a Result of a Short Interspersed Nucleotide Element Insertion in Cd22 a Lupus-Prone Mice

• Published in: The Journal of immunology (1950) 2000-09, Vol.165 (6), p.2987-2996
• Main Authors: Mary, Charles, Laporte, Catherine, Parzy, Daniel, Santiago, Marie-Laure, Stefani, Franck, Lajaunias, Frédéric, Parkhouse, R. Michael E., O’Keefe, Theresa L., Neuberger, Michael S., Izui, Shozo, Reininger, Luc
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.165.6.2987

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 (Cd22a) mice synthesize aberrant CD22 mRNAs that contain ∼20–120 nucleotide insertions upstream of the coding region between exons 2 and 3, and/or ∼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 cluster of short interspersed nucleotide elements. Both the presence of sequence insertion and aberrantly spliced mRNAs were specific to mice bearing the Cd22a and Cd22c alleles. Up-regulation of CD22 expression after LPS activation appeared impaired in Cd22a spleen cells (twice lower than in Cd22b 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 (Cd22b) 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 Cd22a mice or from CD22 heterozygosity in mutants obtained by gene targeting) is implicated in autoantibody production, providing support for Cd22a as a possible candidate allele contributing to lupus susceptibility.