Complementary Effects of Carbamylated and Citrullinated LL37 in Autoimmunity and Inflammation in Systemic Lupus Erythematosus
Open Access
- 6 February 2021
- journal article
- research article
- Published by MDPI AG in International Journal of Molecular Sciences
- Vol. 22 (4), 1650
- https://doi.org/10.3390/ijms22041650
Abstract
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.Funding Information
- National Psoriasis Foundation (Translational Grant 2019-2021)
- Ricerca Finalizzata (CO-2018)
This publication has 39 references indexed in Scilit:
- The genetic contribution of HLA‐DRB5*01:01 to systemic lupus erythematosus in ThailandInternational Journal of Immunogenetics, 2012
- Neutrophils Activate Plasmacytoid Dendritic Cells by Releasing Self-DNA–Peptide Complexes in Systemic Lupus ErythematosusScience Translational Medicine, 2011
- Carbamylation-Dependent Activation of T Cells: A Novel Mechanism in the Pathogenesis of Autoimmune ArthritisThe Journal of Immunology, 2010
- Complement in human diseases: Lessons from complement deficienciesMolecular Immunology, 2009
- Self-RNA–antimicrobial peptide complexes activate human dendritic cells through TLR7 and TLR8The Journal of Experimental Medicine, 2009
- Functional recombinant MHC class II molecules and high-throughput peptide-binding assaysImmunome Research, 2009
- Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptideNature, 2007
- Molecular Analysis of TCR and Peptide/MHC Interaction Using P18-I10-Derived Peptides with a Single d-Amino Acid SubstitutionBiophysical Journal, 2007
- Cathelicidins, multifunctional peptides of the innate immunityJournal of Leukocyte Biology, 2003
- Interferon and Granulopoiesis Signatures in Systemic Lupus Erythematosus BloodThe Journal of Experimental Medicine, 2003