Aicardi-Goutières syndrome (AGS) is a genetically-determined brain disease closely mimicing the sequelae of congenital infection. AGS and congenital viral infection are both associated with an increased production of interferon alpha (IFN-a). Furthermore, a disturbance of IFN-a homeostasis is considered central to the pathogenesis of the autoimmune disorder systemic lupus erythematosus (SLE). In keeping with this, some children with AGS develop an early-onset form of SLE.
In 2006 we reported that recessive mutations in any of the genes encoding the 3´- 5´ exonuclease TREX1 (AGS1) or the three non-allelic components of the RNASEH2 endonuclease complex (AGS2, 3 and 4) result in AGS. We further showed, in 2007, that heterozygous TREX1 mutations cause both a dominant form of AGS and a cutaneous subtype of SLE, called familial chilblain lupus. And in 2009 we described the AGS5 gene SAMHD1 as a regulator of the innate immune response.
The nucleases TREX1 and RNASEH2 are involved in removing ‘waste’ cellular nucleic acid species, a failure of this process resulting in triggering of the innate immune response that is more normally induced by viral nucleic acid. This understanding defines a novel cell-intrinsic mechanism for the initiation of autoimmunity by interferon-stimulatory nucleic acid, and offers an elegant mechanistic explanation for the phenotypic overlap of AGS with congenital infection and SLE. That is, in the absence of TREX1 or RNASEH2 activity, endogenous nucleic acids accumulate and are sensed as viral or ‘non-self’, leading to the induction of an IFN-alpha mediated immune response.
Our ongoing work aims to define the pathway from gene mutation through nucleic acid accumulation to stimulation of the immune system. Considering the natural history of AGS, ‘windows of opportunity’ for the treatment of this devastating disease exist and it is realistic to expect that advances in our understanding of the mechanisms underlying the phenotype will lead to earlier diagnosis, and provide molecular targets for the development of therapeutic interventions. We are pursuing these aims through a large international EU funded project (www.nimbl.eu).
Furthermore, the above studies have prompted us to consider the identification and analysis of single-gene disorders predisposing to the development of SLE as a tractable approach to understanding the pathogenesis of lupus; such ‘experiments of nature’ representing the equivalent of genetically engineered animal models of disease – in the human context. As further proof of principle then, we have recently identified the causative gene for the immuno-osseus dysplasia spondyloenchondrodysplasia, in which affected individuals are at very high risk of multiple autoimmune phenotypes including lupus.
Not only can ‘extreme phenotypes’ provide direct insights into disease pathogenesis, experience of certain ‘common / complex’ diseases already shows that molecular lesions in Mendelian-variant associated genes can sometimes explain a significant proportion of the related common disease phenotype (and go unrecognised in genome-wide association studies). All of this leaves us to speculate on how much ‘complexity’ in lupus might equate to Mendelian genetic heterogeneity; a question we are planning to answer using the new sequencing technologies.
Dr Gillian Rice - Senior Postdoc employed by the University of Manchester
Dr Paul Kasher - Postdoc funded through the European Union FP7 NIMBL project
Dr Catherine Morrissey - Postdoc funded through the European Leukodystrophy Association
Dr Beverley Nicholas - Postdoc funded (half-time) through the European Union FP7 NIMBL project
Dr Massimiliano Zampini - Postdoc funded through the European Union FP7 NIMBL project
Dr Gabbie Forte - Research Technician funded through the European Union FP7 NIMBL project
Dr Dr Emma Jenkinson - Postdoc funded through the Great Ormond Street Children's Charity
Dr Jonathan Dickerson - Postdoc funded (half-time) through the European Union FP7 NIMBL project
Dr Imran Tabasum - Postdoc funded through the Alliance for Lupus Research
Dr Tracy Briggs - Wellcome Trust Clinical Training Fellow
Mr Marcin Szynkiewicz - Research Technician funded through the European Union FP7 NIMBL project
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