Necroptosis in spontaneously-mutated hematopoietic cells induces autoimmune bone marrow failure in mice Journal Article

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Authors: Xin, J.; Breslin, P; Wei, W.; Li, J; Gutierrez, R.; Cannova, J.; Ni, A.; Ng, G.; Schmidt, R; Chen, H; Parini, V.; Kuo, P. C.; Kini, A. R.; Stiff, P; Zhu, J.; Zhang, J
Article Title: Necroptosis in spontaneously-mutated hematopoietic cells induces autoimmune bone marrow failure in mice
Abstract: Acquired aplastic anemia is an autoimmune-mediated bone marrow failure syndrome. The mechanism by which such an autoimmune reaction is initiated is unknown. Whether and how the genetic lesions detected in patients cause autoimmune bone marrow failure have not yet been determined. We found that mice with spontaneous deletion of the TGFbeta-activated kinase-1 gene in a small subset of hematopoietic cells developed bone marrow failure which resembled the clinical manifestations of acquired aplastic anemia patients. Bone marrow failure in such mice could be reversed by depletion of CD4+ T lymphocytes or blocked by knockout of interferon-gamma, suggesting a Th1 cell-mediated autoimmune mechanism. The onset and progression of bone marrow failure in such mice were significantly accelerated by the inactivation of tumor necrosis factor-alpha signaling. Tumor necrosis factor-alpha restricts autoimmune bone marrow failure by inhibiting type-1 T cell responses and maintaining the function of myeloid-derived suppressor cells. Furthermore, we determined that necroptosis among a small subset of mutant hematopoietic cells is the cause of autoimmune bone marrow failure because such bone marrow failure can be prevented by deletion of receptor interacting protein kinase-3. Our study suggests a novel mechanism to explain the pathogenesis of autoimmune bone marrow failure.
Journal Title: Haematologica
ISSN: 1592-8721; 0390-6078
Publisher: Ferrata Storti Foundation  
Journal Place: Italy
Date Published: 2016
Language: ENG
DOI/URL:

haematol.2016.151514
Notes: LR: 20160916; CI: Copyright (c) 2016; JID: 0417435; OTO: NOTNLM; 2016/06/27 [received]; 2016/09/12 [accepted]; aheadofprint