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

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.

Automated summary

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.