Autoimmune Diseases of the Brain:

 

AGS

Innate immunity is the body's first line of defence against infection. Recognition of viral and bacterial nucleic acids activates innate immunity. Similar nucleic acids are also important triggers for autoimmunity in lupus and Rheumatoid Arthritis. Aicardi-Goutieres syndrome (AGS) is a genetic disorder which provides an important model for understanding the role of nucleic acids in autoimmunity. Our research goal is to study the cell biology and immunology of this condition to understand how this condition is caused, and apply these insights to common autoimmune diseases.

 

 

The AGS Genes

We have identified four genes for AGS (Nature Genetics 38:910 and Nature Genetics 38:917). These genes encode intracellular nucleases. The first three genes encode the Ribonuclease H2 complex, while the fourth encodes the TREX1 enzyme. Recently a fifth gene, SAMHD1 has been identified by the Yanick Crow's lab.

 

RNase H2

RNase H2 is a three unit complex containing a catalytic subunit A and two additional subunits (B&C). The enzyme degrades the RNA strand of RNA-DNA hybrids and can recognize ribonucleotides embedded in DNA. Its cellular functions however are not well defined. For instance, It may play a role in removing RNA primers during lagging strand DNA synthesis (Okazaki fragments), but experiments in yeast show that RNase H2 is not essential for this process.

 

Trex1

Trex1 is a 3'-5' DNA exonuclease which degrades single-stranded DNA, and is involved in Granzyme A induced single-stranded DNA apoptosis.

 

 

 

 

 

 

 

The Ribonuclease H2 complex

 

How do Mutant Nucleases Mimic Viral Infection?

Viral DNA/RNA is recognized by Toll-like receptors (TLR), and other innate immune sensors, activating innate immune signaling cascades. This results in the production of cytokines such as interferon alpha. High levels of interferon alpha in the brain cause white matter destruction and calcification, as is seen in congenital CMV/Rubella/HIV infections.

 

Our hypothesis is that mutations in the AGS nucleases (RNase H2 and TREX1), result in accumulation of nucleic acids within the cell, which inappropriately trigger innate immune signaling, resulting in the same white matter destruction and calcification seen in viral infections.

 

 

AGS mimics viral infection as a result of the accumulation of nucleic acids within the cell (1) that then trigger the same innate immune pathways as viral infection (2).

 

Current Work on RNaseH2

We want to establish why mutations in the AGS genes mimics CNS viral infections and autoimmunity. To do this, we plan to isolate the nucleic acids accumulating in patient cells (1), and show that these can trigger an innate immune response (2).

 

Aims

1. Investigate the normal cellular functions of RNase H2.
2. Determine the structural and cellular effects of disease-causing mutations on RNase H2 and identify the unprocessed RNA-DNA substrates present in AGS.
3. Establish and characterise a mouse model of AGS.
4. Investigate the roles of nucleic acids and Ribonuclease H2 in innate and adaptive immunity

 

Themes

• Disorders of Human Brain Size:
  Primary Microcephaly
  Primordial Dwarfism
  

• Autoimmune Disease of the Brain
  Aicardi Goutieres Syndrome
  

Other Links

Research Study Information
Laboratory Publications

 

 

Aicardi Goutieres Syndrome

Aicardi Goutieres syndrome (AGS) is a genetic disorder which resembles congenital infection of the brain.

 

It usually becomes apparent in the first few months of life. Children become irritable, feed poorly and then develop unusual (dystonic) postures, spasticity and fits. These neurological problems progress, resulting in profound physical and intellectual disability. Often there are other symptoms including enlarged liver and spleen, and intermittent fevers that also falsely suggest viral infection.

 

 

 

 

 

 

 

 

 

 

Identical Neuroimaging findings in AGS and Viral Infection.

 

CT scans of the brain showing identical changes in Aicardi Goutieres syndrome (left) and HIV infection acquired during pregnancy (right). The white areas in the centre of the brain are calcification of the basal ganglia. Similar changes can also occur after CMV and Rubella infections. ( Figure from Nat Genet 38,910).

 

Autoimmunity and AGS

There are clinical and immunological similarities between AGS and Systemic Lupus Erythematosis (SLE). A particularly striking similarity is the vasculitic skin lesions seen in AGS (upper figure). As with SLE, immunoglobulins and complement are deposited at the dermal-epidermal junction (lower figure). Also, recently, mutations in one of the AGS genes (TREX1) have also been found to cause chilblain lupus.

 

 

 

 

 

 

 

 

 

Am J Hum Genet. 2007 80(4):811

 

 

 

 

 

 

 

 

 

 

 

 

Nat Genet 38:917