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

Mary, Charles
Laporte, Catherine
Parzy, Daniel
Stefani, F.
Parkhouse, R. Michael
O'Keefe, T. L.
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Published in Journal of Immunology. 2000, vol. 165, no. 6, p. 2987-2996
Abstract 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 approximately 20-120 nucleotide insertions upstream of the coding region between exons 2 and 3, and/or approximately 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.
Keywords Alternative Splicing/immunologyAnimalsAntigens, CD/biosynthesis/ geneticsAntigens, CD22Antigens, Differentiation, B-Lymphocyte/biosynthesis/ geneticsB-Lymphocytes/immunology/metabolismBase SequenceCell Adhesion MoleculesExonsGene Expression Regulation/ immunologyImmunologic Deficiency Syndromes/geneticsIntronsLectinsLipopolysaccharides/immunologyLupus Nephritis/ genetics/ immunologyLymphocyte Activation/geneticsMaleMiceMice, Inbred AKRMice, Inbred C3HMice, Inbred C57BLMice, Inbred CBAMice, Inbred DBAMice, Inbred MRL lprMice, Inbred NZBMice, Mutant StrainsMolecular Sequence DataMutagenesis, Insertional/ immunologyRNA Precursors/genetics/metabolismRNA, Messenger/biosynthesisSequence DeletionShort Interspersed Nucleotide Elements/ immunologySpleen/cytologyUp-Regulation/immunologyY Chromosome/immunology
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PMID: 10975807
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