Abstract
Systemic lupus erythematosus and its murine equivalent, modelled in the New Zealand Black and New Zealand White (NZB × NZW)F1 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 P2X7, 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)F1 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 P2RX7 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)F1 lymphocytes to P2X7 stimulation. NZB and NZW parental strains express the distinct P2X7-L and P2X7-P alleles of P2RX7, respectively, while lymphocytes from these and (NZB × NZW)F1 mice differ markedly in their responses to P2X7 receptor stimulation. NZB mice and NZW mice express functionally distinct alleles of the proinflammatory receptor, P2X7. We show that current mapping suggests that murine and human P2RX7 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 P2X7 is a cell death mechanism with characteristics that potentially have particular relevance to disease pathogenesis.
Highlights
Systemic lupus erythematosus (SLE) is a polygenic disease, the genes contributing towards the disease are unknown
New Zealand White (NZW))F1 and New Zealand Black (NZB) lymphocytes We initially confirmed that NZW mice are homozygous for the P2X-P allele of P2RX7 [9] associated with high sensitivity to stimulation, and we showed that NZB mice are homozygous for the low sensitivity allele P2X-L
We have shown that polymorphism of the P2X7 receptor between NZW and NZB strains is associated with marked differences in P2X7-stimulated proinflammatory responses, consistent with high responsiveness and low responsiveness previously reported for the two alleles
Summary
Systemic lupus erythematosus (SLE) is a polygenic disease, the genes contributing towards the disease are unknown. Several human susceptibility loci have been identified, with eight of the strongest candidates mapping to 1q23, 1q25-31, 1q41-42, 2q35-37, 4p16-15.2, 6p1121, 12q24 and 16q12 [1]. The New Zealand Black and New Zealand White (NZB × NZW)F1 hybrid strain is widely studied due to its similarity to human disease and its female preponderance. As with human SLE, the disorder of (NZB × NZW)F1 mice is polygenic with a contribution from both parents. In a study of (NZB × NZW)F2 mice, eight susceptibility loci were identified [2]. Originally mapped to 88 cM on murine chromosome 5 [2], more recent data locate the microsatellite used to define lbw at 81 cM (discussed later)
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