Rare Diseases

Research indentifying and analysing Mendelian variants of lupus

Overview

Autoimmune diseases are a major cause of morbidity and mortality in the UK; and the autoimmune state, where the person’s immune system turns on itself, remains a scientific mystery.

Systemic lupus erythematosus (SLE) is a form of autoimmunity characterised by the production of antibodies against self nucleic acids, and a dysregulation of proteins. Studies have suggested that common genetic variants explain only a proportion of the hereditary risk for SLE. This leaves the possibility that rare genetic variants might account for an important part of this unexplained heritability.

Problem

The aim of our work is to understand the disturbance in immune system function underlying lupus through identifying subtypes, also called ‘extreme phenotypes’, of the disease. The fact that these conditions result from single gene defects makes understanding the disturbance of immune function relatively easy to study.

Our interest in lupus derives from our studies of Aicardi-Goutières syndrome (AGS). AGS and congenital viral infection are both associated with an increased production of interferon alpha (IFN-alpha). Furthermore, a disturbance of IFN-alpha homeostasis is considered central to the pathogenesis of lupus. In keeping with this, some children with AGS develop an early-onset form of lupus.

What we have achieved to date

Our researchers have already had many successes in their research investigating SLE. In 2006, our researchers 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 a subtype of SLE, called familial chilblain lupus (FCL).

In addition to this in 2009 we described the AGS5 gene SAMHD1 as a regulator of the innate immune response. More recently still, we showed that mutations in SAMHD1 can, like TREX1, cause FCL.

We know that nucleases TREX1 and RNASEH2 are involved in removing ‘waste’ cellular nucleic acid species, a failure of this process triggers the innate immune response that is more normally induced by viral nucleic acid. These studies have defined a novel cell-intrinsic mechanism for the initiation of autoimmunity. 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.

What we aim to achieve

Our on-going work aims to define the pathway from AGS / FCL gene mutation(s) through nucleic acid accumulation to stimulation of the immune system. We hope that this will lead to earlier diagnosis and provide molecular targets for the development of therapeutic interventions. This means the definition of genetic subtypes of lupus will allow for therapies to be tailored according to disease subtype.

As an extension of our work on AGS and FCL, we recently identified the causative gene, ACP5 – encoding tartrate resistant acid phosphatase (TRAP), responsible for the immuno-osseus dysplasia spondyloenchondrodysplasia, in which affected individuals are at very high risk of multiple autoimmune phenotypes including SLE. This work immediately implicates TRAP to have a, previously unrecognised, role in IFN-alpha metabolism and lupus, suggesting that a better understanding of this interesting axis of immune regulation may lead to new therapeutic opportunities in autoimmunity.