Session Title: Systemic Lupus Erythematosus – Animal Models Poster
Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: CD73 is a surface nucleotidase that extends into the extracellular space where it generates adenosine from AMP. By regulating a cell’s “purinergic halo,” CD73 contributes to the maintenance of immune and vascular homeostasis. Although CD73 is known to be expressed on the surface of T cells, endothelial cells, and myeloid-lineage cells, it has yet to receive intensive study in the context of lupus.
Methods: In C57BL/6 Faslpr/lpr (B6.lpr) mice, we generated littermates of 3 genotypes: CD73+/+, CD73+/-, and CD73-/-. Autoantibody levels were measured at 16 and 32 weeks of age. At 32 weeks of age, splenocyte activation/polarization and endothelial function were also characterized. In parallel to the B6.lpr studies, we also assessed the role of CD73 in an inducible model of lupus. C57BL/6 mice with no lupus predisposition (CD73+/+, CD73+/-, and CD73-/-) received topical dosing of the TLR7/8 agonist R848 (resiquimod) three times weekly. Autoantibody levels were measured 4 and 8 weeks after the initiation of treatment.
Results: As compared with B6.lpr CD73+/+ mice, B6.lpr mice with CD73 deficiency (either partial or complete) demonstrated a greater than 2-fold increase in serum anti-double-stranded-DNA antibodies at both 16 and 32 weeks; this was despite no difference in total IgG levels between groups. Beyond antibodies, CD73-deficient B6.lpr mice demonstrated additional abnormalities in peripheral blood including relative lymphopenia (5-fold decrease), neutropenia (4-fold decrease), and elevated levels of cell-free DNA. In 32-week-old B6.lpr CD73+/+ mice, the majority of CD73-positive cells infiltrating spleens were either T cells (CD4+ and double-negative) or CD11b+Ly6C+ monocytes (likely myeloid-derived suppressor cells/MDSCs). In contrast, surface CD73 was not detected on CD8+ T cells or granulocytic MDSCs. Endothelial function was measured in the aortas of 32-week-old B6.lpr mice by ex vivo exposure of aortic rings to acetylcholine in a wire myography system. As compared with CD73+/+ mice, CD73 deficiency resulted in impaired vessel-wall relaxation consistent with decreased nitric oxide production and resultant endothelial dysfunction. In the R848-inducible model of lupus, anti-double-stranded-DNA antibody production was again potentiated by CD73 deficiency. Studies are now underway to comprehensively phenotype the spleens of both mouse models in order to understand the dominant CD73-expressing suppressive cell type in lupus.
Conclusion: These data reveal a protective role for CD73 in lupus autoimmunity and vascular disease, and are consistent with a model whereby a key suppressive cell type (either CD4+ regulatory T cells or monocytic MDSCs) wields CD73 and adenosine to suppress B cell function. These data also suggest that novel therapeutic strategies might harness purinergic signaling to limit the damage inflicted by lupus upon organs and blood vessels.
To cite this abstract in AMA style:Ali RA, Pearce NR, Yalavarthi S, Atkins KB, Gandhi AA, Kanthi Y, Knight JS. Ectonucleotidase CD73 Suppresses Autoantibody Production and Arterial Vasculopathy in Murine Lupus [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/ectonucleotidase-cd73-suppresses-autoantibody-production-and-arterial-vasculopathy-in-murine-lupus/. Accessed December 3, 2021.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/ectonucleotidase-cd73-suppresses-autoantibody-production-and-arterial-vasculopathy-in-murine-lupus/