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 (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.
Mary
C
C
Institut National de la Santé et de la Recherche Médicale Unité, Marseille, France.
Laporte
C
C
Parzy
D
D
Santiago
M L
ML
Stefani
F
F
Lajaunias
F
F
Parkhouse
R M
RM
O'Keefe
T L
TL
Neuberger
M S
MS
Izui
S
S
Reininger
L
L
D020121:5' Untranslated Regions / Q000096:biosynthesis / Q000235:genetics; D017398:Alternative Splicing / Q000276:immunology; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000096:biosynthesis / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D001483:Base Sequence; D015815:Cell Adhesion Molecules; D005091:Exons; D005786:Gene Expression Regulation / Q000276:immunology*; D007153:Immunologic Deficiency Syndromes / Q000235:genetics; D007438:Introns; D037102:Lectins; D008070:Lipopolysaccharides / Q000276:immunology; D008181:Lupus Nephritis / Q000235:genetics* / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008811:Mice, Inbred DBA; D019463:Mice, Inbred MRL lpr; D008814:Mice, Inbred NZB; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional / Q000276:immunology*; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D017384:Sequence Deletion; D020086:Short Interspersed Nucleotide Elements / Q000276:immunology*; D051918:Sialic Acid Binding Ig-like Lectin 2; D013154:Spleen / Q000166:cytology; D015854:Up-Regulation / Q000276:immunology; D014998:Y Chromosome / Q000276:immunology
D020121:5' Untranslated Regions; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; C497868:Cd22 protein, mouse; D015815:Cell Adhesion Molecules; D037102:Lectins; D008070:Lipopolysaccharides; D012322:RNA Precursors; D012333:RNA, Messenger; D051918:Sialic Acid Binding Ig-like Lectin 2