title: Major pathogenic steps in human lupus can be effectively suppressed by nucleosomal histone peptide epitope-induced regulatory immunity.
abstract: Low-dose tolerance therapy with nucleosomal histone peptide epitopes blocks lupus disease in mouse models, but effect in humans is unknown. Herein, we found that CD4(+)CD25(high)FoxP3(+) or CD4(+)CD45RA(+)FoxP3(low) T-cells, and CD8(+)CD25(+)FoxP3(+) T-cells were all induced durably in PBMCs from inactive lupus patients and healthy subjects by the histone peptide/s themselves, but in active lupus, dexamethasone or hydroxychloroquine unmasked Treg-induction by the peptides. The peptide-induced Treg depended on TGFβ/ALK-5/pSmad 2/3 signaling, and they expressed TGF-β precursor LAP. Lupus patients' sera did not inhibit Treg induction. The peptide epitope-induced T cells markedly suppressed type I IFN related gene expression in lupus PBMC. Finally, the peptide epitopes suppressed pathogenic autoantibody production by PBMC from active lupus patients to baseline levels by additional mechanisms besides Treg induction, and as potently as anti-IL6 antibody. Thus, low-dose histone peptide epitopes block pathogenic autoimmune response in human lupus by multiple mechanisms to restore a stable immunoregulatory state.
authors.affiliation: Divisions of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Anne M
authors.initials: AM
authors.lastname: Bertucci
authors.forename: Rosalind
authors.initials: R
authors.lastname: Ramsey-Goldman
authors.forename: Elizabeth Randall
authors.initials: ER
authors.lastname: Harsha-Strong
authors.forename: Richard K
authors.initials: RK
authors.lastname: Burt
authors.forename: Syamal K
authors.initials: SK
authors.lastname: Datta
mesh_terms: D000328:Adult; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis; D015551:Autoimmunity / Q000187:drug effects*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D000939:Epitopes; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D006657:Histones / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D009707:Nucleosomes / Q000737:chemistry / Q000276:immunology; D010455:Peptides / Q000276:immunology / Q000494:pharmacology*; D061251:Primary Cell Culture; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics / Q000276:immunology; D051900:Smad3 Protein / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; D015703:Antigens, CD; D001323:Autoantibodies; D000939:Epitopes; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006657:Histones; D009707:Nucleosomes; D010455:Peptides; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse
keywords: 1,25(OH)(2)D(3); 1,25-dihydroxyvitamin D3; APG; Apigenin; Autoimmunity; DEX; H; HCQ; HSCT; Human; LAP; ODN; Peptide epitopes; RA; RAPA; Rapamycin; SLE; Systemic lupus erythematosus; T cells; TSA; Tolerance; Trichostatin A; dexamethasone; hematopoietic stem cell transplantation; histone; hydroxychloroquine; iTreg; induced regulatory T cells; latency associated peptide; oligonucleotide.; retinoic acid; systemic lupus erythematosus