Translocation of a specific gut pathobiont, Enterococcus gallinarum, exacerbate autoimmune phenotype

A new study in journal Science suggests that a specific gut pathobiont, Enterococcus gallinarum, could exacerbate autoimmune phenotype in predisposed mouse strain. This autoimmune phenotype in mice are thought to represent mouse version of human systemic lupus erythematosus (SLE).

SLE is associated with genetic polymorphism linked to excessive signaling of RNA sensing Toll-like receptor 7 (TLR7) and type I interferons (IFNs). In the specific pathogen-free (NZW × BXSB)F1 hybrid mouse, responses to endogenous retrovirus glycoprotein 70 (ERV gp70) via TLR7 signaling leads to progressive autoimmune response by pathogenic anti-phospholipid [β2-glycoprotein I (β2GPI)] and anti–double-stranded DNA (dsDNA) antibodies.

The authors observed that certain antibiotic treatment significantly improved survival of (NZW × BXSB)F1 hybrid mice.

Further experiments showed that there was bacterial translocation from gut tissue into portal veins and livers in these mice that could be reduced by antibiotic treatment.

16S rRNA sequencing and species-specific PCR consistently revealed Enterococcus gallinarum (E. gallinarum) in the feces, small intestine and liver of (NZW× BXSB)F1 mice. Monocolonzation of germ-free mice with E. gallinarum (EG, here) revealed that it could specifically drive Th17 response, unlike E. faecalis or B. thetaiotaomicron.

Moreover, E. gallinarum could specifically drive  ERV gp70 expression in the liver cells,

and augment anti-nucleic acid antibody response.

Finally, the authors showed that liver tissues from human SLE patients harbored E. gallinarum.

In summary, this study proposes the following patho-mechanism of SLE: when residing in predisposed individuals E. gallinarum causes degradation of gut barrier function, then translocates internally, activates Th17 pathway and initiates "innate" autoimmune phenotype by activating expression of retroviral genes and amplifying endogenous nucleic acid detection system that breaks tolerance checkpoints and leads to auto-antibody formation, Ab-Ag complex deposition in tissues and inflammatory disease exaggeration. The authors proposed antibiotic treatment could provide relieves in certain SLE patients.

However, there are few unanswered questions in this study: first of all, it is clear that E. gallinarum does not induce autoimmunity by itself. Second, If Th17 activity is relevant for E. gallinarum action, then it would have been more valuable for the authors to compare E. gallinarum to segmented filamentous bacteria (SFB) a known inducer of Th17 response in the gut tissue.

posted by David Usharauli

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.  

For example, few days ago journal Cell published study showing that mice deficient for DNAse1L3, an enzyme capable of degrading extracellular chromatin associated DNA, develop systemic lupus erythematosus (SLE)-like condition.

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