Complementary Effects of Carbamylated and Citrullinated LL37 in Autoimmunity and Inflammation in Systemic Lupus Erythematosus
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 ac...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/4/1650 |
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| author | Roberto Lande Immacolata Pietraforte Anna Mennella Raffaella Palazzo Francesca Romana Spinelli Konstantinos Giannakakis Francesca Spadaro Mario Falchi Valeria Riccieri Katia Stefanantoni Curdin Conrad Cristiano Alessandri Fabrizio Conti Loredana Frasca |
| author_facet | Roberto Lande Immacolata Pietraforte Anna Mennella Raffaella Palazzo Francesca Romana Spinelli Konstantinos Giannakakis Francesca Spadaro Mario Falchi Valeria Riccieri Katia Stefanantoni Curdin Conrad Cristiano Alessandri Fabrizio Conti Loredana Frasca |
| author_sort | Roberto Lande |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T05:21:24Z |
| format | Article |
| id | doaj.art-9a420d58abbb432c92e69ffeae8f672a |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T05:21:24Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-9a420d58abbb432c92e69ffeae8f672a2023-12-03T12:40:05ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-02-01224165010.3390/ijms22041650Complementary Effects of Carbamylated and Citrullinated LL37 in Autoimmunity and Inflammation in Systemic Lupus ErythematosusRoberto Lande0Immacolata Pietraforte1Anna Mennella2Raffaella Palazzo3Francesca Romana Spinelli4Konstantinos Giannakakis5Francesca Spadaro6Mario Falchi7Valeria Riccieri8Katia Stefanantoni9Curdin Conrad10Cristiano Alessandri11Fabrizio Conti12Loredana Frasca13Pharmacological Research and Experimental Therapy Unit, National Centre for Pre-Clinical and Clinical Drug Research and Evaluation, Istituto Superiore di Sanità, 00161 Rome, ItalyDepartment of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, ItalyPharmacological Research and Experimental Therapy Unit, National Centre for Pre-Clinical and Clinical Drug Research and Evaluation, Istituto Superiore di Sanità, 00161 Rome, ItalyPharmacological Research and Experimental Therapy Unit, National Centre for Pre-Clinical and Clinical Drug Research and Evaluation, Istituto Superiore di Sanità, 00161 Rome, ItalyDepartment of Clinical and Internistic Sciences, Anesthesiology and Cardiovascular Sciences, University Sapienza, 00161 Rome, ItalyDepartment of Pathology, University Sapienza, 00161 Rome, ItalyConfocal Microscopy UNIT, Core Facilities, Istituto Superiore di Sanità, 00161 Rome, ItalyNational AIDS Center, Istituto Superiore di Sanità, 00161 Rome, ItalyDepartment of Clinical and Internistic Sciences, Anesthesiology and Cardiovascular Sciences, University Sapienza, 00161 Rome, ItalyDepartment of Clinical and Internistic Sciences, Anesthesiology and Cardiovascular Sciences, University Sapienza, 00161 Rome, ItalyDepartment of Dermatology, University Hospital CHUV, 1011 Lausanne, SwitzerlandDepartment of Clinical and Internistic Sciences, Anesthesiology and Cardiovascular Sciences, University Sapienza, 00161 Rome, ItalyDepartment of Clinical and Internistic Sciences, Anesthesiology and Cardiovascular Sciences, University Sapienza, 00161 Rome, ItalyPharmacological Research and Experimental Therapy Unit, National Centre for Pre-Clinical and Clinical Drug Research and Evaluation, Istituto Superiore di Sanità, 00161 Rome, ItalyLL37 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.https://www.mdpi.com/1422-0067/22/4/1650LL37post-translational modifications (PTM)systemic lupus erythematosus (SLE) |
| spellingShingle | Roberto Lande Immacolata Pietraforte Anna Mennella Raffaella Palazzo Francesca Romana Spinelli Konstantinos Giannakakis Francesca Spadaro Mario Falchi Valeria Riccieri Katia Stefanantoni Curdin Conrad Cristiano Alessandri Fabrizio Conti Loredana Frasca Complementary Effects of Carbamylated and Citrullinated LL37 in Autoimmunity and Inflammation in Systemic Lupus Erythematosus International Journal of Molecular Sciences LL37 post-translational modifications (PTM) systemic lupus erythematosus (SLE) |
| title | Complementary Effects of Carbamylated and Citrullinated LL37 in Autoimmunity and Inflammation in Systemic Lupus Erythematosus |
| title_full | Complementary Effects of Carbamylated and Citrullinated LL37 in Autoimmunity and Inflammation in Systemic Lupus Erythematosus |
| title_fullStr | Complementary Effects of Carbamylated and Citrullinated LL37 in Autoimmunity and Inflammation in Systemic Lupus Erythematosus |
| title_full_unstemmed | Complementary Effects of Carbamylated and Citrullinated LL37 in Autoimmunity and Inflammation in Systemic Lupus Erythematosus |
| title_short | Complementary Effects of Carbamylated and Citrullinated LL37 in Autoimmunity and Inflammation in Systemic Lupus Erythematosus |
| title_sort | complementary effects of carbamylated and citrullinated ll37 in autoimmunity and inflammation in systemic lupus erythematosus |
| topic | LL37 post-translational modifications (PTM) systemic lupus erythematosus (SLE) |
| url | https://www.mdpi.com/1422-0067/22/4/1650 |
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