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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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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915858/
https://www.ncbi.nlm.nih.gov/pubmed/33562078
http://dx.doi.org/10.3390/ijms22041650
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author 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
author_facet 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
author_sort Lande, Roberto
collection PubMed
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.
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spelling pubmed-79158582021-03-01 Complementary Effects of Carbamylated and Citrullinated LL37 in Autoimmunity and Inflammation in Systemic Lupus Erythematosus 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 Int J Mol Sci Article 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. MDPI 2021-02-06 /pmc/articles/PMC7915858/ /pubmed/33562078 http://dx.doi.org/10.3390/ijms22041650 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
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
Complementary Effects of Carbamylated and Citrullinated LL37 in Autoimmunity and Inflammation in Systemic Lupus Erythematosus
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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915858/
https://www.ncbi.nlm.nih.gov/pubmed/33562078
http://dx.doi.org/10.3390/ijms22041650
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