Oral Presentation Australasian Society for Immunology Annual Scientific Meeting 2014

Apics deficiency reveals a role for lncRNA in dendritic cell function and autoimmune disease (#122)

Edward P F Chu 1 2 , Michelle P Ashton 1 2 , Colleen Elso 1 , Leanne Mackin 1 , Sharon Ford 3 , Natalie Payne 4 , May Alsayb 1 2 , Helen Thomas 1 , Stuart Mannering 1 , Tom Kay 1 , Tony Papenfuss 5 , Richard Kitching 3 , Claude Bernard 4 , Grant Morahan 6 , Ken Shortman 5 7 , Meredith O'Keeffe 7 , Tom Brodnicki 1
  1. St. Vincent's Institute, Fitzroy, VIC, Australia
  2. Department of Medicine, University of Melbourne, Parkville, Victoria, Australia
  3. Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia
  4. Australian Regenerative Medicine Institute, Monash University, Clayton, Victoria, Australia
  5. The Walter and Eliza Hall Institute, Parkville, Victoria, Australia
  6. The Western Australian Institute of Medical Research, Perth, Western Australia, Australia
  7. Burnet Institute, Melbourne, Victoria, Australia

The original belief that genes are predominantly protein coding has been disproven with the relatively recent discovery of new classes of regulatory non-coding RNAs. One such class of non-coding RNAs is the long non-coding RNAs (lncRNAs). Recent cell-based studies have demonstrated the potential for lncRNAs to regulate innate immune responses, however, their effect upon immune tolerance in vivo has not been characterised. We have identified a novel gene for which sequence variation is associated with autoimmune diabetes in the nonobese diabetic (NOD) mouse strain. Bioinformatics and expression analyses indicate this gene encodes a lncRNA that is induced by toll-like receptor (TLR) activation and localizes to the nucleus and cytoplasm of dendritic cells.  Moreover, sequence variation for this gene is associated with altered TLR-mediated cytokine production. Hence this gene was named Apics for Attenuator of Pattern recognition receptor-Induced Cytokine Secretion. To further investigate the function of this lncRNA, we established a C57BL/6 (B6) knockout mouse strain for Apics and found that Apics-deficient dendritic cells exhibit enhanced TLR-mediated cytokine production. Apics-deficient mice also demonstrate increased susceptibility to induced models of autoimmune disease. Our study suggests that lncRNAs, such as Apics, can serve as TLR-inducible repressors that attenuate the magnitude of innate immune responses to reduce the risk for developing autoimmune disease.