The P2X(7 )receptor is a candidate product of murine and human lupus susceptibility loci: a hypothesis and comparison of murine allelic products

Systemic lupus erythematosus and its murine equivalent, modelled in the New Zealand Black and New Zealand White (NZB × NZW)F(1 )hybrid strain, are polygenic inflammatory diseases, probably reflecting an autoimmune response to debris from cells undergoing programmed cell death. Several human and murine loci contributing to disease have been defined. The present study asks whether the proinflammatory purinergic receptor P2X(7), an initiator of a form of programmed cell death known as aponecrosis, is a candidate product of murine and human lupus susceptibility loci. One such locus in (NZB × NZW)F(1 )mice is lbw3, which is situated at the distal end of NZW chromosome 5. We first assess whether NZB mice and NZW mice carry distinct alleles of the P2RX(7 )gene as expressed by common laboratory strains, which differ in sensitivity to ATP stimulation. We then compare the responses of NZB lymphocytes, NZW lymphocytes and (NZB × NZW)F(1 )lymphocytes to P2X(7 )stimulation. NZB and NZW parental strains express the distinct P2X(7)-L and P2X(7)-P alleles of P2RX(7), respectively, while lymphocytes from these and (NZB × NZW)F(1 )mice differ markedly in their responses to P2X(7 )receptor stimulation. NZB mice and NZW mice express functionally distinct alleles of the proinflammatory receptor, P2X(7). We show that current mapping suggests that murine and human P2RX(7 )receptor genes lie within lupus susceptibility loci lbw3 and SLEB4, and we argue that these encode a product with the functional characteristics consistent with a role in lupus. Furthermore, we argue that aponecrosis as induced by P2X(7 )is a cell death mechanism with characteristics that potentially have particular relevance to disease pathogenesis.