Tuesday, March 20, 2018

IL-33 is a natural target of allergen proteases

IL-33 is a member of IL-1 family and requires proteolytic cleavage to form active form. It has already been linked to allergy manifestation. Now, new study in nature immunology expands on earlier observations to show that full-length non-active IL-33 (IL-33FL) is a natural target of group of allergens with proteases activity.

In general, many known allergens display protease activity such as from fungi, mites, pollens, insects. Co-incubation of IL-33FL with such allergen proteases in presence of innate lymphoid cells type II (ILC2) generated biologically-active smaller fragments and release of type II cytokines.

IL-33FL is an intra-nuclear proto-chemokine found in epithelial and endothelial cells. So, how allergens get access to it? It requires cell damage to release IL-33FL extra-cellularly. However, it is not clear if any allergen proteases can damage cells. At least one such allergen from fungus, Alternaria alternata (A. alternata) can damage cell and then cleave IL-33FL.

Similar effects were seen in vivo using IL-33KO mice. In these mice, recruitment of eosinophils, a readout for IL-33-driven allergic response, were only observed when injected with pre-incubated IL-33FL and A. alternata mixture.

In summary, these results suggest that allergen from A. alternata with protease activity can damage cells to release IL-33FL and cleave it into biologically-active shorter peptides. However, this study did not show that other allergens can deliver similar double punch. Also, it is not clear how this innate mechanism translates to adaptive immune system to generate allergen-specific T cell and antibody responses.

posted by David Usharauli

Thursday, March 15, 2018

Reduced CTLA-4 signaling predisposes to Th2 driven gastric tumorigenesis

Anti-CTLA4 antibodies such as Yervoy, has been used in clinical practice to treat solid tumors. It supposed to work either by augmenting and revitalizing effector T cells function directly or indirectly through temporal silencing of inhibitory Foxp3+ Treg population or both. However, new study from Journal of Experimental Medicine showed that at least in [genetically predisposed] mice reduced CTLA-4 signaling by itself could cause Th2 driven tumorigenic transformation of stomach epithelial tissue.

For this study the authors created transgenic CTLA4 shRNA knockdown (CTLA4KD) mice on the BALB/c × C57BL/6 (B6) mixed genetic background. This they did because it appears that BALB/c but not B6 mice were susceptible developing gastric tumors in this model. CTLA4KD mice showed gastric epithelial transformation by 20w of age. Similarly, month long treatment of newborn BALB/c mice with anti-CTLA4 antibody also led to gastric epithelial transformation.

This tumorigenic transformation was CD4 T cell dependent and effector T cells from CTLA4KD but not from WT mice could mediate it. It indicated that changes in effector T cell composition and functionality were driving de novo inflammatory tumorigenesis.

Interestingly, gastric epithelial transformation were happening even in germ-free CTLA4KD mice lacking microbiota. However, since these mice also harbor increased numbers of inflammatory T cells, in all subsets analyzed such as Th1, Th2, Th17, and independent of microbiota it could indicate that T cells could be responding to antigens from food or environment.

Finally, elimination of canonical T helper cytokines showed that surprisingly neither IFN-γ nor IL-17 but IL-4 deficiency could abolish gastric epithelial transformation under conditions of reduced CTLA-4 activity.

In summary, this study suggests that inherited or clinically-induced reduction of CTLA-4 signaling in predisposed individuals could paradoxically lead to inflammatory tumorigenesis driven by type II immunity.

posted by David Usharauli

Saturday, March 10, 2018

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