Wednesday, June 15, 2016

Mutation in DNAse1L3 triggers systemic lupus erythematosus (SLE)-like condition in mice

Autoimmune disease, as word implies, is an immune response directed to self. Traditionally we used to think that autoimmune diseases arise as a result of failure of adaptive immune system (T and B cells) to distinguish between self and nonself antigens. However, as with many inherited immunodeficiencies, frequently we see that inherited innate genetic mutations play pivotal part in autoimmune phenotypes as well.  

DNAse1L3, a homologue to DNAse1, contains a short, positively charged C-terminal peptide that allows it to uniquely digest DNA chromatin in microparticles released from apoptotic cells.

Mice deficient for DNAse1L3 develop anti-dsDNA Ab response and Ab deposition in the kidney glomeruli [clinical feature of SLE in humans].

Unlike other genetic DNA/RNA housekeeping mutations (Trex1-/-, DNase-II-/-, RNase H2B-/- ) phenotype of DNAse1L3-KO mice was independent of STING activity (but was dependent on MyD88, though was not clear how or why).

In summary, This study revealed that DCs/Mac derived secreted DNAse1L3 is intimately involved in digestion of apoptotic microparticle associated DNA and in prevention of anti-DNA antibody formation (of note, one of the authors is a co-founder and consultant of Resolve Therapeutics, which develops soluble nucleases for therapeutic purposes).

David Usharauli


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