Thursday, September 24, 2015

Cytosolic DNA sensor cGAS controls systemic autoimmunity to self-DNA

Type 1 IFN system (IFN-α, IFN-β, etc) is a complex and powerful immuno-regulatory circuit that show both anti-viral (or general pro-inflammatory) or anti-inflammatory activity. Similar to IL-12p70, type I IFNs were shown to prime naive T cells for anti-tumor activity. Very few cytokines have such direct priming effect on naive T cells. 

However, it was not clear how tumors were detected by IFN circuit. Later, cytosolic DNA sensor cGAS and its adaptor molecule STING were discovered and implicated in tumor DNA sensing and T cell priming via IFN circuit.

Unlike viral or bacterial DNA, self-DNA are not ordinarily accessible to cGAS in the cytoplasm. But in disease state when there is an excess of self-DNA, cytoplasmic cGAS could become activated and mistakenly initiate "anti-viral" cascade to self-DNA leading to debilitating immunopathology.

This is a story told by two recent papers, one published in Journal of Immunology and another in PNAS. In these papers, the authors showed that mice knockout for self-DNA degradation enzymes (Trex1-/- or DNase-II-/-) succumb to immunopathology, but could be rescued by absence of cGAS (or STING).     

Both papers showed very similar results so I will going to mix them in my analysis. In brief, the authors showed that immunopathology in mice deficient for Trex1 (an exonuclease that degrades cytosolic DNA) could be completely reversed by absence of DNA sensor cGAS.

Mechanistically, Trex1-/-cGAS-/- double knockout mice showed reduced level of auto-antibodies, comparable to WT mice (immunoblots against heart Ag are shown).

Similarly, peripheral immunopathology in [DNase-II-/- mice] that lack another cytosolic DNA degradation enzyme DNase-II could be completely rescued by simultaneous absence of cGAS.

In summary, these two studies clearly support the hypothesis that abnormal sensing of endogenous self-DNA by cGAS is a major priming step leading to immunopathology in diseases such as systemic lupus erythematosus (SLE), Aicardi-Goutieres syndrome, familial chilblain lupus, retinal vasculopathy and cerebral leukodystrophy.

In general, I agree that modulation of cGAS-STING pathway will provide enormous benefits in both tumor therapy and systemic autoimmunity.

David Usharauli

No comments:

Post a Comment