Tuesday, August 21, 2018

Concurrent cross‐reactivity of microbiota‐derived epitopes to both self and pathogens may underlie the ‘Hygiene hypothesis’

David Usharauli & Tirumalai Kamala


The current iteration of the ‘Hygiene hypothesis’ proposes precipitous decline in exposure to conserved microbial products and metabolites in individuals in developed countries undermines innate self‐nonself ‘training’ of immune system leading to allergy and autoimmunity. However, lack of innate ‘training’ alone fails to account for the antigen‐driven nature of these immunopathologies. Here, we advance an alternative, antigen‐specific interpretive framework, SPIRAL (Specific ImmunoRegulatory Algorithm), that predicts ‘loss’ of commensal microbiota‐derived epitopes cross‐reactive to both self and pathogens, rather than conserved microbial moieties or metabolites, underlies the ‘Hygiene hypothesis’. By mechanistically delineating how loss of selective microbiota in predisposed individuals could lead to corresponding ‘holes’ in the epitope‐specific Foxp3+regulatory T cell repertoire and subsequent selective immunopathologies, SPIRAL represents a novel interpretation of cross‐reactivity that could enable targeted discovery of microbiota species and their associated Treg epitopes ‘missing’ in the diseases ‘Hygiene hypothesis’ implicates, and provides a roadmap for a novel unified interpretation of self‐nonself discrimination and T helper phenotype selection.

Wednesday, August 1, 2018

Cross-reactivity between microbial-derived antigens and tumor neoantigens correlates with long-term survival

This is a very interesting paper published in Nature few months back. In this study the authors wanted to uncover immune correlates of long-term (>10 yrs) survival from pancreatic ductal adenocarcinoma that normally account for less than 2% of all patients. 

First they found that "patients with both the highest predicted neoantigen number and either the greatest CD3+CD8+, or polyclonal T-cell repertoire, but neither alone, exhibited the longest survival". It suggested that tumor neoantigen-derived epitope quality rather than simply quantity correlated with survival. 

More importantly, bioinformatics analysis of similarities (mimicry or cross-reactivity or poly-reactivity) and neoantigen fitness modelling between tumor neoatigens and microbial-derived antigens significantly stratified short- and long-term survivors independent of confounding factors and adjuvant chemotherapy. 

If these data will  hold true in other cancer settings, it will append how immunotherapy is applied to treat cancer patients. While this finding is potentially hugely important for immunotherapy, the authors tried not to make too big a statement about it (I would imagine it is a result of a typical reviewers conservatism), writing that "This hypothesis does not assume any associations between pre-existing antimicrobial immunity and survival, but rather aims to develop a strategy to identify candidate neoantigens based on defined immunogenic pathogen-derived epitopes" and in other place "Our results do not indicate causal associations of pre-existing microbial and anti-tumour immunity in LTSs [long-term survivors]. Instead, our data suggest that embedding microbial homology in the context of our neoantigen quality model can help to create an effective surrogate for immunogenic neoantigens." 

posted by David Usharauli