Complementary Effects of Carbamylated and Citrullinated LL37 in Autoimmunity and Inflammation in Systemic Lupus Erythematosus

• Published in: International journal of molecular sciences Vol. 22; no. 4; p. 1650
• Main Authors: Lande, Roberto, Pietraforte, Immacolata, Mennella, Anna, Palazzo, Raffaella, Spinelli, Francesca Romana, Giannakakis, Konstantinos, Spadaro, Francesca, Falchi, Mario, Riccieri, Valeria, Stefanantoni, Katia, Conrad, Curdin, Alessandri, Cristiano, Conti, Fabrizio, Frasca, Loredana
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 06.02.2021; MDPI
• Subjects: Antibodies; Antigens; Antimicrobial agents; Arthritis; Autoantigens; Autoimmunity; Biopsy; Carbamylation; CD4 antigen; Chronic conditions; Citrulline; Dendritic cells; Deoxyribonucleic acid; Disease; DNA; Drb1 protein; Enzymes; Epitopes; Histocompatibility antigen HLA; Inflammation; Interferon; LL37; Lupus; Lymphocytes B; Lymphocytes T; Neutrophils; Nucleic acids; Peptides; Plasma cells; Post-translation; post-translational modifications (PTM); Psoriasis; Stimulators; Systemic lupus erythematosus; systemic lupus erythematosus (SLE); Translation; α-Interferon; post-translational modifications (PTM); systemic lupus erythematosus (SLE); LL37
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22041650

LL37 acts as T-cell/B-cell autoantigen in Systemic lupus erythematosus (SLE) and psoriatic disease. Moreover, when bound to "self" nucleic acids, LL37 acts as "danger signal," leading to type I interferon (IFN-I)/pro-inflammatory factors production. T-cell epitopes derived from citrullinated-LL37 act as better antigens than unmodified LL37 epitopes in SLE, at least in selected HLA-backgrounds, included the SLE-associated HLA-DRB1*1501/HLA-DRB5*0101 backgrounds. Remarkably, while "fully-citrullinated" LL37 acts as better T-cell-stimulator, it loses DNA-binding ability and the associated "adjuvant-like" properties. Since LL37 undergoes a further irreversible post-translational modification, carbamylation and antibodies to carbamylated self-proteins other than LL37 are present in SLE, here we addressed the involvement of carbamylated-LL37 in autoimmunity and inflammation in SLE. We detected carbamylated-LL37 in SLE-affected tissues. Most importantly, carbamylated-LL37-specific antibodies and CD4 T-cells circulate in SLE and both correlate with disease activity. In contrast to "fully citrullinated-LL37," "fully carbamylated-LL37" maintains both innate and adaptive immune-cells' stimulatory abilities: in complex with DNA, carbamylated-LL37 stimulates plasmacytoid dendritic cell IFN-α production and B-cell maturation into plasma cells. Thus, we report a further example of how different post-translational modifications of a self-antigen exert complementary effects that sustain autoimmunity and inflammation, respectively. These data also show that T/B-cell responses to carbamylated-LL37 represent novel SLE disease biomarkers.