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Major pathogenic steps in human lupus can be effectively suppressed by nucleosomal histone peptide epitope-induced regulatory immunity.
- Source :
-
Clinical immunology (Orlando, Fla.) [Clin Immunol] 2013 Dec; Vol. 149 (3), pp. 365-78. Date of Electronic Publication: 2013 Aug 23. - Publication Year :
- 2013
-
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.<br /> (© 2013.)
- Subjects :
- Adult
Anti-Inflammatory Agents pharmacology
Antigens, CD genetics
Antigens, CD immunology
Autoantibodies biosynthesis
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
Humans
Lupus Erythematosus, Systemic genetics
Lupus Erythematosus, Systemic pathology
Lymphocyte Activation
Male
Middle Aged
Nucleosomes chemistry
Nucleosomes immunology
Peptides immunology
Primary Cell Culture
Protein Serine-Threonine Kinases genetics
Protein Serine-Threonine Kinases immunology
Receptor, Transforming Growth Factor-beta Type I
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
T-Lymphocytes, Regulatory immunology
T-Lymphocytes, Regulatory pathology
Transforming Growth Factor beta genetics
Transforming Growth Factor beta immunology
Autoimmunity drug effects
CD8-Positive T-Lymphocytes drug effects
Histones immunology
Lupus Erythematosus, Systemic immunology
Peptides pharmacology
T-Lymphocytes, Regulatory drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1521-7035
- Volume :
- 149
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Clinical immunology (Orlando, Fla.)
- Publication Type :
- Academic Journal
- Accession number :
- 24211843
- Full Text :
- https://doi.org/10.1016/j.clim.2013.08.008