title: Regulatory T-lymphocytes mediate amyotrophic lateral sclerosis progression and survival.
abstract: In amyotrophic lateral sclerosis (ALS) mice, regulatory T-lymphocytes (Tregs) are neuroprotective, slowing disease progression. To address whether Tregs and FoxP3, a transcription factor required for Treg function, similarly influence progression rates of ALS patients, T-lymphocytes from patients were assessed by flow cytometry. Both numbers of Tregs and their FoxP3 protein expressions were reduced in rapidly progressing ALS patients and inversely correlated with progression rates. The mRNA levels of FoxP3, TGF-β, IL4 and Gata3, a Th2 transcription factor, were reduced in rapidly progressing patients and inversely correlated with progression rates. Both FoxP3 and Gata3 were accurate indicators of progression rates. No differences in IL10, Tbx21, a Th1 transcription factor or IFN-γ expression were found between slow and rapidly progressing patients. A 3.5-year prospective study with a second larger cohort revealed that early reduced FoxP3 levels were indicative of progression rates at collection and predictive of future rapid progression and attenuated survival. Collectively, these data suggest that Tregs and Th2 lymphocytes influence disease progression rates. Importantly, early reduced FoxP3 levels could be used to identify rapidly progressing patients.
authors.affiliation: Department of Neurology, The Methodist Hospital Research Institute, Houston, TX, USA. jhenkel@tmhs.org
authors.forename: Jenny S
authors.initials: JS
authors.lastname: Henkel
authors.forename: David R
authors.initials: DR
authors.lastname: Beers
authors.forename: Shixiang
authors.initials: S
authors.lastname: Wen
authors.forename: Andreana L
authors.initials: AL
authors.lastname: Rivera
authors.forename: Karen M
authors.initials: KM
authors.lastname: Toennis
authors.forename: Joan E
authors.initials: JE
authors.lastname: Appel
authors.forename: Weihua
authors.initials: W
authors.lastname: Zhao
authors.forename: Dan H
authors.initials: DH
authors.lastname: Moore
authors.forename: Suzanne Z
authors.initials: SZ
authors.lastname: Powell
authors.forename: Stanley H
authors.initials: SH
authors.lastname: Appel
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D016022:Case-Control Studies; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008875:Middle Aged; D011446:Prospective Studies; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; C508598:IL4 protein, human; D018836:Inflammation Mediators; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D015847:Interleukin-4