Microbiota-derived peptide and autoimmune heart inflammation: a tale of missing data

Papers published in journal Science supposed to undergo thorough high-level vetting process. However, to err is human. Both reviewers and editors are humans and hence they frequently err, for the annoyance of scientists and for the joy of postdocs doing journal clubs.  

Here is an example of a paper that squeezed through the cracks of the Science vetting process. It claims that peptides derived from certain commensal microbiota species cross-react with heart muscle protein, MYH6, causing autoimmune heart inflammation. It has a great Figure 1 showing that MYH6-specific TCR transgenic mice on a germ-free background, lacking microbiota, is protected from heart autoimmunity.

Furthermore, they showed that the re-introduction of microbiota into germ-free makes these mice susceptible to heart inflammation similar to microbiota+ mice.

The authors then tried to identify the microbiota species that contribute to this inflammatory condition. An in silico search identified cross-reactive β-galactosidase (β-gal) mimic peptides in Bacteroides thetaiotaomicron (B. theta) and B. faecis with high similarity to MYH6.

The authors even introduced into germ-free TCR transgenic mice Bacteroides thetaiotaomicron (B. theta) lacking the β-gal. Up to now, it feels that the authors have checked all the boxes necessary for high-quality research. But then for some reason, they do not show survival data comparing Bacteroides thetaiotaomicron (B. theta) with and without the β-gal gene as in figure 1. They just showed how a lack of β-gal Bacteroides thetaiotaomicron modifies MYH6-T cells accumulation in the heart tissue.

So, why the authors don't show survival data of germ-free MYH6 TCR transgenic mice colonized with Bacteroides thetaiotaomicron -/+ β-gal gene? Isn't it the most important result for their hypothesis? Where were reviewers and editors looking?

posted by David Usharauli

Melanoma dendritic cell vaccine is safe but is it effective?

Few days ago journal Science has published yet another study describing procedures how to identify tumor (melanoma)-specific immunogenic neo-antigens through exome-sequencing and combining peptide binding in silico and in vitro peptide recognition analysis. 

There is no doubt that cancerous tissue can yield multiple neo-antigens derived from non-synonymous mutations. Hypothetically and practically (as this new study and others as well have shown), immune system can and is able to detect these minute differences in the mutated proteins. It appears that by combining current in silico algorithms such as NETMHC-3.4 with epitope presentation assays (in vitro assays) provide quite accurate list of potential immunogenic tumor peptides.

The authors in this new paper, for example, were able to identify and confirm in a complementary in vitro assays (T2 cell peptide binding assay and tandem minigene constructs expression assay in DM6 cell line) the presence of several neo-antigens in melanoma tissue derived from 3 patients.

Re-injection of CD40L+TLR ligand matured, melanoma-peptide pulsed autologous dendritic cells back into patients yielded antigen-specific CD8 T cells expansion.

This was a small Phase I clinical study to determine the safety of the DCs vaccine. Since science fundamentals are strong behind this trial (especially considering the authors focus on IL-12p70 producing DCs as a source of cellular vaccine), the results were expected. Of note, these 3 patients were treated with ipilimumab (humanized α-CTLA4 antibody) prior to the experiments described in this paper. It is not clear how this could have skewed the [positive] outcome of DC vaccine here. Anyway, successful tumor treatment would require simultaneous approach from several directions (DC vaccine, checkpoint inhibitors, small drug tyrosine inhibitors).

David Usharauli