Identification of the gene responsible of the development of systemic lupus erythematosus

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We found previously that cationic anti-DNA autoantibodies have nephritogenic potential and usage of a specific germline Vk gene, A30, has major influences on cationic charge of the autoantibodies in human lupus nephritis. By using PCR technique, we found that A30 gene locus in the genome was defective in 8 out of 9 SLE patients without nephritis. In contrast, 9 out of 9 patients with lupus nephritis had intact A30 gene. The presence or absence of A30 gene was associated with the development of lupus nephritis or not. It is reported the A30 is a potentially functional but rarely expressed Vk gene in humans. It is possible that normal B cells edit primarily rearranged A30 gene with autoreactive potentials by receptor editing mechanism, for changing the affinity of the B cell Ag receptor to avoid self-reactivity, whereas SLE B cells mayhave a defect in this mechanism. Indeed, we found that normal B cells edit A30-JK2 gene in their genome possibly by inversion mechanism, whereas SLE B cells contain rearranged A30-Jk2-Ck gene in the genome and express A30-associated mRNA,suggesting that receptor editing mechanism is also defective in patients with SLE.Our study suggests that polymorphism of lg Vk locus, and failure of receptor editing may contribute to the development of pathogenic anti-DNA responses in humans.