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Complement receptors and lupus
Arthritis Research & Therapyvolume 4, Article number: 75000 (2002)
Among the genetic factors contributing to lupus susceptibility, the Sle1 locus, conserved in mouse and human chromosome 1, has been linked to murine and human lupus. In mouse models, the specific contribution of Sle1 to the pathogenesis of lupus has been dissected by individually segregating this locus from the original lupus prone NZBM2410 strain to a C57BL/6 background (B6.Sle1). B6.Sle1 mice show a loss of tolerance to chromatin, as indicated by the development of high levels of antinuclear antibodies, whereas additional loci are needed for the full spectrum of immunological and clinical manifestations. The Sle1c locus contains the Cr2 gene, which encodes complement receptors 1 and 2 (CR1 and CR2) by alternative splicing.
The authors identified structural differences, when comparing CR1 and CR2 proteins, between B6.Sle1c lupus mice and their normal counterparts. The difference is due to a single nucleotide polymorphism that introduces a novel N-linked glycosylation site in the ligand binding domain of CR1/CR2 receptors. By using tetrameric C3 degradation products, the ability of B6.Sle1c splenic cells to bind this ligand was shown to be decreased. Intracellular calcium responses of B6.Sle1c B cells to C3 degradation products were decreased, and in vivo these mice displayed diminished immune responses to a T-dependent antigen. Molecular modeling of the mouse CR2 sequence suggests that the glycoslyation at the polymorphism site interferes with dimerization of the CR2 receptor rather than with ligand binding.
The authors demonstrated a functionally significant phenotype associated with the lupus prone allele Sle1c that has been linked to lupus in multiple human ethnic groups and mouse strains. These observations suggest that the antichromatin humoral response is associated with defective binding and signaling of C3 and C4 degradation products through CR1/CR2 receptors, although the mechanism of this association remains to be elucidated. The authors propose defective induction of B-cell tolerance or qualitative changes in processing of autoantigens through this pathway as the potential mechanisms operating in mice and humans with genetically diminished CR1/CR2 responses.
Immunoprecipitation, sequence analysis, flow cytometric analysis, fluorescent intracellular calcium analysis, immunization of mice with dinitrophenol (DNP), ELISA analysis of anti-DNP antibodies, molecular modeling.
Boackle SA, Holers VM, Chen X, Szakonyi G, Karp DR, Wakeland EK, Morel L: Cr2, a candidate gene in the murine Sle1c lupus susceptibility locus, encodes a dysfunctional protein . Immunity. 2001, 15: 775-785. ,