Computational Analysis of HLA-presentation of Non-synonymous Recipient Mismatches Indicates Effect on the Risk of Chronic Graft-vs.-Host Disease After Allogeneic HSCT

Genetic mismatches in protein coding genes between allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipient and donor can elicit an alloimmunity response via peptides presented by the recipient HLA receptors as minor histocompatibility antigens (mHAs). While the impact of individual mHAs on allo-HSCT outcome such as graft-vs.-host and graft-vs.-leukemia effects has been demonstrated, it is likely that established mHAs constitute only a small fraction of all immunogenic non-synonymous variants. In the present study, we have analyzed the genetic mismatching in 157 exome-sequenced sibling allo-HSCT pairs to evaluate the significance of polymorphic HLA class I associated peptides on clinical outcome. We applied computational mismatch estimation approaches based on experimentally verified HLA ligands available in public repositories, published mHAs, and predicted HLA-peptide affinites, and analyzed their associations with chronic graft-vs.-host disease (cGvHD) grades. We found that higher estimated recipient mismatching consistently increased the risk of severe cGvHD, suggesting that HLA-presented mismatching influences the likelihood of long-term complications in the patient. Furthermore, computational approaches focusing on estimation of HLA-presentation instead of all non-synonymous mismatches indiscriminately may be beneficial for analysis sensitivity and could help identify novel mHAs.Peer reviewe

The Critic as Quietist

Though a radical critic of capitalist society, Thorstein Veblen was a political quietist. His ideas of social evolution, cultural lag, and predatory power help to explain why. Veblen saw the need for deep-seated social change but despaired of its chances. He was in crucial ways a tragic writer, a radical realist who refused to yield to the temptations of political life. Veblen's quietism also helps to explain the hesitant, often unwelcome reception more ideologically minded scholars have given to his work. Attributing Veblen's quietism to timidity or confusion, they have frequently avoided coming to grips with his distinctions between theory and pragmatism, science and politics, which lie at the heart of his political refusal. Theory and science push toward reasonable explanations and accounts of things; pragmatic and predatory political actors apply “worldly wisdom” to the exploit of others. Scientists cannot change institutions; political actors cannot dispense with the operations of power. Veblen asks much of us: for he struggled to undrape the veils of power while puncturing false hopes in the prospects of democracy. His quietism situates itself within this awful contradiction. Above all, Veblen's work serves the purpose of reminding us that neither science nor democracy constitutes a self-evident ground for belief in the inherent reasonableness or justice of action per se. For these reasons alone, an acquaintance with his work should be part of any solidly grounded education in the possibilities and limits of democratic political life in a scientific age.</jats:p