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 TGFβ-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-γ, 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-α signaling. Tumor necrosis factor-α 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.
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA neuroimmune@gmail.com jzhang@luc.edu.|Research and Development Service, Hines VA Hospital, Hines, IL, USA.|Department of Molecular Pharmacology and Therapeutics, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: Junping
authors.initials: J
authors.lastname: Xin
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.|Department of Biology, Loyola University Chicago, IL, USA.|Department of Molecular/Cellular Physiology, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Breslin
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Department of Biology, College of Life and Environment Science, Shanghai Normal University, P.R. of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: Gutierrez
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Cannova
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: Allen
authors.initials: A
authors.lastname: Ni
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Ng
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Schmidt
authors.affiliation: Department of Pathology, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Pathology, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: Vamsi
authors.initials: V
authors.lastname: Parini
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Kuo
authors.affiliation: Department of Pathology, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: Ameet R
authors.initials: AR
authors.lastname: Kini
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Stiff
authors.affiliation: State Key Laboratory for Medical Genomics and Shanghai Institute of Hematology and Collaborative Innovation Center of Hematology, Rui-Jin Hospital; Shanghai Jiao-Tong University School of Medicine, P.R. of China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, USA neuroimmune@gmail.com jzhang@luc.edu.|Department of Pathology, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: Jiwang
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000741:Anemia, Aplastic / Q000209:etiology / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D015551:Autoimmunity; D015415:Biomarkers; D001853:Bone Marrow / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D001854:Bone Marrow Cells / Q000276:immunology* / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006410:Hematopoiesis / Q000235:genetics / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000172:deficiency; D008213:Lymphocyte Activation; D020930:MAP Kinase Kinase Kinases / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009336:Necrosis / Q000235:genetics / Q000276:immunology; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000172:deficiency; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D015415:Biomarkers; D007371:Interferon-gamma; D020930:MAP Kinase Kinase Kinases; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C485615:Ripk3 protein, mouse