4.7 Article

Profound inhibition of CD73-dependent formation of anti-inflammatory adenosine in B cells of SLE patients

期刊

EBIOMEDICINE
卷 73, 期 -, 页码 -

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ELSEVIER
DOI: 10.1016/j.ebiom.2021.103616

关键词

Purines; Metabolism; Autoimmune disease; CD38; CD39

资金

  1. German Research Council (DFG) [236177352, 323627809]
  2. Cardiovascular Research Institute Duesseldorf (CARID)
  3. Research Committee of the Medical Faculty of the Heinrich-Heine-University DuEurosseldorf [2018-12]
  4. Hiller Research Foundation

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This study identified a new pathomechanism for SLE, in which inactivation of CD73 on B cells results in reduced production of anti-inflammatory adenosine, leading to immune cell activation. The inactivation of CD73 was not due to genetic variation but may be related to posttranslational modification.
Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that leads to a breakdown of tolerance to self-antigens resulting in inflammation and organ damage. The anti-inflammatory activity of CD73-derived adenosine is well documented, however, its role in SLE pathogenesis is unknown. Methods: Human peripheral blood immune cells were obtained from adult SLE patients (SLE) and healthy controls (HC). Expression and activity of purinergic ectoenzymes were assessed by qRT-PCR, flow cytometry and HPLC. Genes encoding purinergic ectoenzymes in SLE patients were analysed with targeted DNA sequencing. Findings: Among circulating immune cells (both in HC and SLE), CD73 was most highly expressed on B cells, which was mirrored by high enzymatic activity only in HC. CD73 protein molecular weight was unchanged in SLE, however, the enzymatic activity of CD73 on SLE B cells was almost fully abolished. Accordingly, AMP accumulated in cultured SLE B cells. A similar discrepancy between protein expression and enzymatic activity was observed for NAD-degrading CD38 on SLE B cells. No differences were found in the rate of extracellular ATP degradation and expression of CD39, CD203a/c, and CD157. DNA sequencing identified no coding var-iants in CD73 in SLE patients. Interpretation: We describe a new pathomechanism for SLE, by which inactivation of CD73 on B cells produ-ces less anti-inflammatory adenosine, resulting in immune cell activation. CD73 inactivation was not due to genetic variation but may be related to posttranslational modification. (C) 2021 Published by Elsevier B.V.

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