Interestingly, one of the examples was in clarifying the concept of immunogenicity and referenced this beautiful article by @pradeu and Carosella that was new to me https://www.pnas.org/content/103/47/17858?ijkey=1116e668dcb13921f941348643c7e24848458b72&keytype2=tf_ipsecsha … "On the definition of a criterion of immunogenicity" 2/n
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wherein they criticize the self/non-self paradigm (and language) of immunology.pic.twitter.com/SIcDqxXlBz
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Specifically, they point out that it's not the *endogenous* vs *exogenous* origin of an antigen that is critical, but rather the *shape* of the antigen that matters. But wait, isn't this obvious (in 2020)? Yes! It is... and yet 3/npic.twitter.com/4mXjI2qTrR
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We still use the self/non-self language even though it is no longer factually correct and is even more conceptually wrong. Why do we do this? Perhaps because the idea of self/non-self is seductively simple. 4/n
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An example: In the field of T cell immunogenicity in cancer we have focused tremendous effort on characterizing MHC bound neoantigens which differ from their wild-type counterparts by only a single amino acid. 5/n
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Partially we do this because we have reasonably good computational tools to predict whether peptides will bind to an MHC molecule and reasonably reliable assays to test immunogenicity. 6/n
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But what we are also doing is relying on the crutch of "self" vs "non-self." Indeed, a short wild type ("self") peptide vs. a short mutated ("non-self") peptide is about the simplest example of self vs. non-self you can find. 7/n
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Isn't there a little bit of hubris in believing that we can explain outcomes in oncology on the basis of this small set of differences compared to the massive number of total differences between a cancer cell and a non-cancer cell? 8/n
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The MHC bound peptides are just a few shapes on the surface of the cell. In pursuit of simplicity, we have ignored the broader question of what makes a tumor recognizable to the immune system: which is a function of the hundreds to thousands of alterations in cancer cells. 9/n
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I freely admit to at times focusing far more attention on the narrow, tractable question of which mutations lead to immunogenic epitopes than on the broader question of what makes a cell immunogenic overall. 10/n
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The authors of the "criterion of immunogenicity" article propose a completely different conceptual framework for immunogenicity that is based on discontinuities in the normal pattern of antigens encountered by the immune system. 11/n
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I don't want to get into the weeds about the model they propose. Instead, I just want to remind myself (and anyone reading) that the language we use to describe our experiments and the conceptual frameworks we use to interpret data can be as limiting as they are helpful. 12/n
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