Approximately 0.05% of the population of the Western world 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 has remained unknown. Now, Prokunina et al. report in Nature Genetics an association between programmed cell death gene 1 ( PDCD1 ) and SLE. Importantly, they also propose how a particular sequence variant of PDCD1 might contribute to the aetiology of this disease.

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, also known as PD1, that belongs to the CD28 family and is known to regulate peripheral self-tolerance of T and B cells. Moreover, Pdcd1−/− mice suffer from SLE-like symptoms.

By sequencing PDCD1 in five healthy, unrelated individuals and in five patients with SLE from a Nordic population, the authors discovered seven single-nucleotide polymorphisms (SNPs) in this gene, three of which constitute a disease-associated haplotype that can account for all of the genetic linkage seen in the original population sample. These SNPs were then genotyped in five sets of families of different ethnic origin. The results were clear — only one SNP, which is found in an enhancer-like region in intron 4 of PDCD1, was associated consistently 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, a member of the Runt-related family of transcription factors. Using an electrophoretic mobility-shift assay, the authors confirmed that RUNX1 binds this sequence and that binding is abolished by the sequence change that is associated with the SNP.

The authors propose that binding of RUNX1 to wild-type PDCD1 modulates its transcription and ensures its correct expression. As PDCD1 contains an immunoreceptor tyrosine-based inhibitory motif (ITIM), it might be involved in preserving self-tolerance by inhibiting autoreactive cells. It remains to be confirmed whether, in the absence of RUNX1 binding, dysregulation of PDCD1 leads to loss of self-tolerance and to the chronic lymphocyte hyperactivity that is characteristic of SLE.