Histone‐Specific CD4+ T Cell Plasticity in Active and Quiescent Systemic Lupus Erythematosus

• Published in: Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2024-05, Vol.76 (5), p.739-750
• Main Authors: Ramirez, Giuseppe A., Tassi, Elena, Noviello, Maddalena, Mazzi, Benedetta A., Moroni, Luca, Citterio, Lorena, Zagato, Laura, Tombetti, Enrico, Doglio, Matteo, Baldissera, Elena M., Bozzolo, Enrica P., Bonini, Chiara, Dagna, Lorenzo, Manfredi, Angelo A.
• Format: Article
• Language: English
• Subjects: Adult; Antibodies; Antibodies, Antinuclear - immunology; Antigens; Arteritis; Autoantibodies; Autoantibodies - immunology; Autoimmune diseases; Bioinformatics; Blood; Blood levels; Case-Control Studies; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; Cell differentiation; Chronic conditions; Differentiation (biology); Drb1 protein; Effector cells; Female; Flow cytometry; Helper cells; Histocompatibility antigen HLA; Histones; Histones - immunology; Histones - metabolism; HLA-DRB1 Chains - genetics; HLA-DRB1 Chains - immunology; Humans; Immunological memory; Immunoregulation; Immunosuppressive agents; Lupus; Lupus Erythematosus, Systemic - immunology; Lymphocytes; Lymphocytes T; Male; Memory cells; Middle Aged; Peptides; Precision medicine; Remission; Serology; Systemic lupus erythematosus; Takayasu's disease; Th1 Cells - immunology
• ISSN: 2326-5191; 2326-5205
• DOI: 10.1002/art.42778

Objective The aim of this study was to assess whether circulating histone‐specific T cells represent tools for precision medicine in systemic lupus erythematosus (SLE). Methods Seroprevalence of autoantibodies and HLA‐DR beta (DRB) 1 profile were assessed among 185 patients with SLE and combined with bioinformatics and literature evidence to identify HLA–peptide autoepitope couples for ex vivo detection of antigen‐specific T cells through flow cytometry. T cell differentiation and polarization was investigated in patients with SLE, patients with Takayasu arteritis, and healthy controls carrying HLA‐DRB1*03:01 and/or HLA‐DRB1*11:01. SLE Disease Activity Index 2000 and Lupus Low Disease Activity State were used to estimate disease activity and remission. Results Histone‐specific CD4+ T cells were selectively detected in patients with SLE. Among patients with a history of anti‐DNA antibodies, 77% had detectable histone‐specific T cells, whereas 50% had lymphocytes releasing cytokines or upregulating activation markers after in vitro challenge with histone peptide antigens. Histone‐specific regulatory and effector T helper (Th) 1‐, Th2‐, and atypical Th1/Th17 (Th1*)‐polarized cells were significantly more abundant in patients with SLE with quiescent disease. In contrast, total Th1‐, Th2‐, and Th1*‐polarized and regulatory T cells were similarly represented between patients and controls or patients with SLE with active versus quiescent disease. Histone‐specific effector memory T cells accumulated in the blood of patients with quiescent SLE, whereas total effector memory T cell counts did not change. Immunosuppressants were associated with expanded CD4+ histone‐specific naive T (TN) and terminally differentiated T cells. Conclusion Histone‐specific T cells are selectively detected in patients with SLE, and their concentration in the blood varies with disease activity, suggesting that they represent innovative tools for patient stratification and therapy.