Approximately 0.05% of the Western population suffers from systemic lupus erythematosus (SLE) — a complex autoimmune disease. Although several susceptibility loci for SLE have been identified, the nature of the genes and mutations that underlie this disease have remained unknown. Now, Prokunina et al. report in Nature Genetics the association of the programmed cell death gene 1 ( PDCD1 ) with SLE. Importantly, they also propose how a particular sequence variant of PDCD1 might contribute to the disease's aetiology.

In a previous study of a Nordic population, the authors identified a susceptibility locus for SLE on chromosome 2. One gene in this region stood out as a potential candidate, PDCD1. This is because PDCD1 encodes an immunoreceptor that belongs to the immunoglobulin family and that is known to regulate peripheral self-tolerance in T and B cells. Moreover, Pdcd1 −/− mice suffer from SLE-like symptoms.

By sequencing PDCD1 in five healthy unrelated individuals and in five SLE sufferers from the Nordic population, the authors discovered seven SNPs in this gene, three of which constituted a disease-associated haplotype that could account for all of the LOD score seen in the original population sample. These SNPs were then genotyped in five sets of families with different ethnic origins. The results were clear — only one SNP, which lies in an enhancer-like region in intron 4 of PDCD1, consistently associated with SLE. This region of intron 4 contains binding sites for transcription factors that are known to be involved in haematopoietic differentiation and in inflammation. In particular, the SNP disrupts a putative binding site for RUNX1, which is inactivated in translocations that lead to acute myeloid leukaemia. Using an electrophoretic mobility shift assay, the authors confirmed that RUNX1 indeed binds to this sequence and that this binding is abolished by the sequence change that is associated with the SNP.

The authors propose that RUNX1 binding to the wild-type PDCD1 modulates its transcription and ensures its correct expression. Because PDCD1 contains an immunoreceptor tyrosine-based inhibitory motif, it might be involved in preserving self-tolerance by inhibiting auto-reactive cells. It remains to be confirmed whether, without RUNX1 binding, PDCD1 dysregulation leads to loss of self-tolerance and to chronic lymphocyte hyperactivity that is characteristic of SLE.