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Therapeutic implications of the anergic/postactivated status of B cells in systemic lupus erythematosus
Systemic lupus erythematosus (SLE) is characterised by numerous abnormalities in B lineage cells, including increased CD27++ plasmablasts/plasma cells, atypical CD27-IgD- B cells with increased CD95, spleen tyrosine kinase (Syk)++, CXCR5- and CXCR5+ subsets and anergic CD11c+Tbet+ age-associated B c...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425190/ https://www.ncbi.nlm.nih.gov/pubmed/32675278 http://dx.doi.org/10.1136/rmdopen-2020-001258 |
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author | Dörner, Thomas Szelinski, Franziska Lino, Andreia C Lipsky, Peter E |
author_facet | Dörner, Thomas Szelinski, Franziska Lino, Andreia C Lipsky, Peter E |
author_sort | Dörner, Thomas |
collection | PubMed |
description | Systemic lupus erythematosus (SLE) is characterised by numerous abnormalities in B lineage cells, including increased CD27++ plasmablasts/plasma cells, atypical CD27-IgD- B cells with increased CD95, spleen tyrosine kinase (Syk)++, CXCR5- and CXCR5+ subsets and anergic CD11c+Tbet+ age-associated B cells. Most findings, together with preclinical lupus models, support the concept of B cell hyperactivity in SLE. However, it remains largely unknown whether these specific B cell subsets have pathogenic consequences and whether they provide relevant therapeutic targets. Recent findings indicate a global distortion of B cell functional capability, in which the entire repertoire of naïve and memory B cells in SLE exhibits an anergic or postactivated (APA) functional phenotype. The APA status of SLE B cells has some similarities to the functional derangement of lupus T cells. APA B cells are characterised by reduced global cytokine production, diminished B cell receptor (BCR) signalling with decreased Syk and Bruton’s tyrosine kinase phosphorylation related to repeated in vivo BCR stimulation as well as hyporesponsiveness to toll-like receptor 9 engagement, but intact CD40 signalling. This APA status was related to constitutive co-localisation of CD22 linked to phosphatase SHP-1 and increased overall protein phosphatase activities. Notably, CD40 co-stimulation could revert this APA status and restore BCR signalling, downregulate protein tyrosine phosphatase transcription and promote B cell proliferation and differentiation. The APA status and their potential rescue by bystander help conveyed through CD40 stimulation not only provides insights into possible mechanisms of escape of autoreactive clones from negative selection but also into novel ways to target B cells therapeutically. |
format | Online Article Text |
id | pubmed-7425190 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-74251902020-08-24 Therapeutic implications of the anergic/postactivated status of B cells in systemic lupus erythematosus Dörner, Thomas Szelinski, Franziska Lino, Andreia C Lipsky, Peter E RMD Open Lupus Systemic lupus erythematosus (SLE) is characterised by numerous abnormalities in B lineage cells, including increased CD27++ plasmablasts/plasma cells, atypical CD27-IgD- B cells with increased CD95, spleen tyrosine kinase (Syk)++, CXCR5- and CXCR5+ subsets and anergic CD11c+Tbet+ age-associated B cells. Most findings, together with preclinical lupus models, support the concept of B cell hyperactivity in SLE. However, it remains largely unknown whether these specific B cell subsets have pathogenic consequences and whether they provide relevant therapeutic targets. Recent findings indicate a global distortion of B cell functional capability, in which the entire repertoire of naïve and memory B cells in SLE exhibits an anergic or postactivated (APA) functional phenotype. The APA status of SLE B cells has some similarities to the functional derangement of lupus T cells. APA B cells are characterised by reduced global cytokine production, diminished B cell receptor (BCR) signalling with decreased Syk and Bruton’s tyrosine kinase phosphorylation related to repeated in vivo BCR stimulation as well as hyporesponsiveness to toll-like receptor 9 engagement, but intact CD40 signalling. This APA status was related to constitutive co-localisation of CD22 linked to phosphatase SHP-1 and increased overall protein phosphatase activities. Notably, CD40 co-stimulation could revert this APA status and restore BCR signalling, downregulate protein tyrosine phosphatase transcription and promote B cell proliferation and differentiation. The APA status and their potential rescue by bystander help conveyed through CD40 stimulation not only provides insights into possible mechanisms of escape of autoreactive clones from negative selection but also into novel ways to target B cells therapeutically. BMJ Publishing Group 2020-07-15 /pmc/articles/PMC7425190/ /pubmed/32675278 http://dx.doi.org/10.1136/rmdopen-2020-001258 Text en © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/. |
spellingShingle | Lupus Dörner, Thomas Szelinski, Franziska Lino, Andreia C Lipsky, Peter E Therapeutic implications of the anergic/postactivated status of B cells in systemic lupus erythematosus |
title | Therapeutic implications of the anergic/postactivated status of B cells in systemic lupus erythematosus |
title_full | Therapeutic implications of the anergic/postactivated status of B cells in systemic lupus erythematosus |
title_fullStr | Therapeutic implications of the anergic/postactivated status of B cells in systemic lupus erythematosus |
title_full_unstemmed | Therapeutic implications of the anergic/postactivated status of B cells in systemic lupus erythematosus |
title_short | Therapeutic implications of the anergic/postactivated status of B cells in systemic lupus erythematosus |
title_sort | therapeutic implications of the anergic/postactivated status of b cells in systemic lupus erythematosus |
topic | Lupus |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425190/ https://www.ncbi.nlm.nih.gov/pubmed/32675278 http://dx.doi.org/10.1136/rmdopen-2020-001258 |
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