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. 2022 Jan 28;12:830172. doi: 10.3389/fimmu.2021.830172

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Copyright © 2022 Colden, Kumar, Munkhbileg and Babushok

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Potential mechanisms of immune-escape by the PNH cells. (A) A schematic diagram illustrating the hypothesis of immunoselection of GPI (-) cells by NK cells. Normal GPI (+) cells express NKG2D ligands ULBPs and MICA/B, and activate NK cells (left), whereas the lack of ULBPs on GPI (-) PNH cells leads to an impaired NK activation (right). (B) A schematic diagram illustrating the immunoselection of GPI (-) cells by CD1d-restricted immune attack against GPI. CD1d-restricted, GPI-specific NKT cells target GPI molecule presented by CD1d and attack GPI (+) normal HSPCs (left) but not the GPI (-) PNH HSPC (right). (C) A schematic diagram illustrating the hypothesis of immune selection of GPI (-) cells by CD4⁺ lymphocyte-mediated attack. GPI (-) cell may have the reduced ability to activate autoreactive CD4⁺ T lymphocytes due to missing GPI-anchored co-stimulatory molecules (top diagram). Alternatively, GPI (-) PNH cells may have reduced MHC class II presentation of hypothetical autoantigens compared to GPI (+) normal cells, and survive CD4⁺ T cell mediated immune attack due to their reduced recognition (bottom diagram). (D) A schematic diagram illustrating the hypothesis of immune selection of GPI (-) cells by CD8⁺ lymphocyte-mediated attack. GPI (-) cell may have the reduced ability to activate autoreactive CD4⁺ T lymphocytes due to missing GPI-anchored co-stimulatory molecules (left diagram). Alternatively, GPI (-) PNH cells may have reduced MHC class I presentation of hypothetical autoantigens compared to GPI (+) normal cells, and survive CD8⁺ T cell mediated immune attack due to their reduced recognition (right diagram).