Major pathogenic steps in human lupus can be effectively suppressed by nucleosomal histone peptide epitope-induced regulatory immunity

• Published in: Clinical immunology (Orlando, Fla.) Vol. 149; no. 3; pp. 365 - 378
• Main Authors: Zhang, Li, Bertucci, Anne M., Ramsey-Goldman, Rosalind, Harsha-Strong, Elizabeth Randall, Burt, Richard K., Datta, Syamal K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2013
• Subjects: Adult; Allergy and Immunology; Anti-Inflammatory Agents - pharmacology; Antigens, CD - genetics; Antigens, CD - immunology; Autoantibodies - biosynthesis; Autoimmunity; Autoimmunity - drug effects; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - pathology; Epitopes; Female; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - immunology; Gene Expression Regulation; Histones - chemistry; Histones - immunology; Human; Humans; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - pathology; Lymphocyte Activation; Male; Middle Aged; Nucleosomes - chemistry; Nucleosomes - immunology; Peptide epitopes; Peptides - immunology; Peptides - pharmacology; Primary Cell Culture; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - immunology; Receptors, Transforming Growth Factor beta - genetics; Receptors, Transforming Growth Factor beta - immunology; Signal Transduction; Smad2 Protein - genetics; Smad2 Protein - immunology; Smad3 Protein - genetics; Smad3 Protein - immunology; Systemic lupus erythematosus; T cells; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - pathology; Tolerance; Transforming Growth Factor beta - genetics; Transforming Growth Factor beta - immunology; Human; Autoimmunity; TSA; iTreg; RAPA; H; 1,25(OH)2D3; Tolerance; T cells; SLE; RA; Peptide epitopes; Systemic lupus erythematosus; DEX; HCQ; APG; ODN; LAP; HSCT; 1,25-dihydroxyvitamin D3; systemic lupus erythematosus; hydroxychloroquine; Apigenin; hematopoietic stem cell transplantation; Trichostatin A; induced regulatory T cells; dexamethasone; 1,25(OH) 2D 3; Rapamycin; oligonucleotide; latency associated peptide; retinoic acid; histone; 1,25(OH)D
• ISSN: 1521-6616; 1521-7035; 1521-7035
• DOI: 10.1016/j.clim.2013.08.008

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+CD25highFoxP3+ or CD4+CD45RA+FoxP3low 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. •Immunoregulatory effects of nucleosomal histone peptide epitopes in humans revealed•Histone peptide epitopes induce Treg cells in healthy humans and lupus patients.•Peptide epitope-induced human Treg are TGFβ−dependent and express TGFβ-LAP.•Peptides inhibit autoantibody production in human lupus by additional mechanisms.•Peptide-induced Treg suppress type I interferon gene expression in human lupus.