title: ALS patients' regulatory T lymphocytes are dysfunctional, and correlate with disease progression rate and severity.
abstract: Neuroinflammation is a pathological hallmark of ALS in both transgenic rodent models and patients, and is characterized by proinflammatory T lymphocytes and activated macrophages/microglia. In ALS mouse models, decreased regulatory T lymphocytes (Tregs) exacerbate the neuroinflammatory process, leading to accelerated motoneuron death and shortened survival; passive transfer of Tregs suppresses the neuroinflammation and prolongs survival. Treg numbers and FOXP3 expression are also decreased in rapidly progressing ALS patients. A key question is whether the marked neuroinflammation in ALS can be attributed to the impaired suppressive function of ALS Tregs in addition to their decreased numbers. To address this question, T lymphocyte proliferation assays were performed. Compared with control Tregs, ALS Tregs were less effective in suppressing responder T lymphocyte proliferation. Although both slowly and rapidly progressing ALS patients had dysfunctional Tregs, the greater the clinically assessed disease burden or the more rapidly progressing the patient, the greater the Treg dysfunction. Epigenetically, the percentage methylation of the Treg-specific demethylated region was greater in ALS Tregs. After in vitro expansion, ALS Tregs regained suppressive abilities to the levels of control Tregs, suggesting that autologous passive transfer of expanded Tregs might offer a novel cellular therapy to slow disease progression.
authors.affiliation: Peggy and Gary Edwards ALS Laboratory, Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Beers
authors.affiliation: Peggy and Gary Edwards ALS Laboratory, Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Weihua
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Peggy and Gary Edwards ALS Laboratory, Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Jinghong
authors.initials: J
authors.lastname: Wang
authors.affiliation: Peggy and Gary Edwards ALS Laboratory, Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Xiujun
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Peggy and Gary Edwards ALS Laboratory, Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Shixiang
authors.initials: S
authors.lastname: Wen
authors.affiliation: Department of Surgery, University of Florida, Gainesville, Florida, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Neal
authors.affiliation: Peggy and Gary Edwards ALS Laboratory, Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Thonhoff
authors.affiliation: Department of Stem Cell Transplant and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Abdullah S
authors.initials: AS
authors.lastname: Alsuliman
authors.affiliation: Department of Stem Cell Transplant and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Shpall
authors.affiliation: Department of Stem Cell Transplant and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Katy
authors.initials: K
authors.lastname: Rezvani
authors.affiliation: Peggy and Gary Edwards ALS Laboratory, Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Research Institute, Houston Methodist Hospital, Houston, Texas, USA.
authors.forename: Stanley H
authors.initials: SH
authors.lastname: Appel
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000276:immunology* / Q000473:pathology*; D000818:Animals; D030801:Animals, Genetically Modified; D004195:Disease Models, Animal; D018450:Disease Progression; D051858:Forkhead Transcription Factors / Q000235:genetics; D006801:Humans; D051379:Mice; D012720:Severity of Illness Index; D000072105:Superoxide Dismutase-1 / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C000606291:Sod1 protein, mouse; D000072105:Superoxide Dismutase-1