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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 Mice¹

Charles Mary^*, Catherine Laporte^*, Daniel Parzy, Marie-Laure Santiago^2,*, Franck Stefani^*, Frédéric Lajaunias, R. Michael E. Parkhouse^§, Theresa L. O’Keefe^3,¶, Michael S. Neuberger^¶, Shozo Izui and Luc Reininger^4,*

^* Institut National de la Santé et de la Recherche Médicale Unité 399, Marseille, France; Institut de Médecine Tropicale du Service de Santé des Armées, Marseille, France; Department of Pathology, University of Geneva, Geneva, Switzerland; ^§ Institute for Animal Health, Pirbright, United Kingdom; and ^¶ Medical Research Council Laboratory of Molecular Biology, Cambridge, United Kingdom

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 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 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.

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