title: Defining a new biomarker for the autoimmune component of Multiple Sclerosis: Th40 cells.
abstract: Multiple Sclerosis (MS) is a chronic inflammatory, neurodegenerative disease. Diagnosis is very difficult requiring defined symptoms and multiple CNS imaging. A complicating issue is that almost all symptoms are not disease specific for MS. Autoimmunity is evident, yet the only immune-related diagnostic tool is cerebral-spinal fluid examination for oligoclonal bands. This study addresses the impact of Th40 cells, a pathogenic effector subset of helper T cells, in MS. MS patients including relapsing/remitting MS, secondary progressive MS and primary progressive MS were examined for Th40 cell levels in peripheral blood and, similar to our findings in autoimmune type 1 diabetes, the levels were significantly (p<0.0001) elevated compared to controls including healthy non-autoimmune subjects and another non-autoimmune chronic disease. Classically identified Tregs were at levels equivalent to non-autoimmune controls but the Th40/Treg ratio still predicted autoimmunity. The cohort displayed a wide range of HLA haplotypes including the GWAS identified predictive HLA-DRB1*1501 (DR2). However half the subjects did not carry DR2 and regardless of HLA haplotype, Th40 cells were expanded during disease. In RRMS Th40 cells demonstrated a limited TCR clonality. Mechanistically, Th40 cells demonstrated a wide array of response to CNS associated self-antigens that was dependent upon HLA haplotype. Th40 cells were predominantly memory phenotype producing IL-17 and IFNγ with a significant portion producing both inflammatory cytokines simultaneously suggesting an intermediary between Th1 and Th17 phenotypes.
authors.affiliation: Webb-Waring Center and Department of Medicine, University of Colorado Denver Anschutz Medical Campus, 12850 East Montview Blvd., Aurora, CO 80045, United States.
authors.forename: Dan M
authors.initials: DM
authors.lastname: Waid
authors.affiliation: Department of Neurology, University of Colorado Denver Anschutz Medical Campus, 12850 East Montview Blvd., Aurora, CO 80045, United States.
authors.forename: Teri
authors.initials: T
authors.lastname: Schreiner
authors.affiliation: Webb-Waring Center and Department of Medicine, University of Colorado Denver Anschutz Medical Campus, 12850 East Montview Blvd., Aurora, CO 80045, United States.
authors.forename: Gisela
authors.initials: G
authors.lastname: Vaitaitis
authors.affiliation: Webb-Waring Center and Department of Medicine, University of Colorado Denver Anschutz Medical Campus, 12850 East Montview Blvd., Aurora, CO 80045, United States.
authors.forename: Jessica R
authors.initials: JR
authors.lastname: Carter
authors.affiliation: Department of Neurology, University of Colorado Denver Anschutz Medical Campus, 12850 East Montview Blvd., Aurora, CO 80045, United States.
authors.forename: John R
authors.initials: JR
authors.lastname: Corboy
authors.affiliation: Webb-Waring Center and Department of Medicine, University of Colorado Denver Anschutz Medical Campus, 12850 East Montview Blvd., Aurora, CO 80045, United States. Electronic address: David.Wagner@ucdenver.edu.
authors.forename: David H
authors.initials: DH
authors.lastname: Wagner
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015551:Autoimmunity / Q000235:genetics / Q000276:immunology; D015415:Biomarkers / Q000097:blood; D019013:CD40 Antigens / Q000276:immunology*; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D006684:HLA-DR Antigens / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood / Q000235:genetics / Q000276:immunology*; D010641:Phenotype; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D019013:CD40 Antigens; D006684:HLA-DR Antigens
keywords: Autoimmunity; Diagnosis; Multiple Sclerosis; Th40 cells