Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by pathogenic antinuclear autoantibodies, which are secreted by autoreactive plasma cells. Among novel plasma cell-depleting strategies, CD38 has been identified as promising target. The monoclonal anti-CD38 antibody daratumumab is approved for treatment of multiple myeloma and provided a therapeutically relevant depletion of plasma cells in patients with SLE ¹ .

Objectives: Beyond plasma cells, CD38 is widely expressed across innate and adaptive immune cells and additional cellular targets of anti-CD38 treatment, especially in patients with SLE, are largely unknown. Therefore, this study aimed to systematically characterize the expression of CD38 in peripheral blood leukocytes to identify potential target cells of CD38-directed therapies that may contribute to or limit therapeutic benefits in SLE.

Methods: We analyzed the expression of CD38 on peripheral blood leukocytes in two different cohorts, comprising a total of 56 SLE patients and 39 healthy controls, by flow and mass cytometry. CD38 expression levels across major immune cells were analyzed for changes between controls and SLE, as well as for correlation across immune cell lineages, and with clinical and serological disease parameters.

Results: We detected increased CD38 expression levels on circulating NK cells, plasmacytoid dendritic cells, CD4 ⁺ and CD8 ⁺ memory T cells, as well as IgD ^- CD27 ^- and marginal zone-like B cells in SLE compared to healthy controls. In myeloid and NK cells, CD38 expression was associated with an activated cellular phenotype, reflected by co-expression of molecules such as HLA-DR, CD11c or Syk. In the B cell compartment, IgA ^- plasmablasts and plasma cells expressed more CD38 than their IgA ⁺ counterparts. Also, HLA-DR ^high plasmablasts showed higher CD38 expression compared to HLA-DR ^low plasma cells. The strongest differences in CD38 expression between controls and SLE were found in CD8 ⁺ central and effector memory T cells. Additionally, we detected an expansion in CD38 ^high and CD38 ^int cells in the T cell memory compartment, with some patients showing distinctly increased expression values. We observed a high intra-individual correlation of CD38 expression across immune cell lineages, yet without correlation of CD38 expression levels with clinical activity (SLEDAI-2K), serological markers of SLE or the type I interferon surrogate marker CD169 (SIGLEC-1).

Conclusion: Our data indicate that not only pathogenic plasma cells are potential target cells of CD38-targeting antibodies. The highly dysregulated CD38 expression across innate and adaptive immune cells in SLE could be of pathophysiological importance with respect to the potential efficacy and side effects of such therapies. Since CD38 expression did not correlate with disease activity, it may be assumed that it is not a response protein solely induced and modulated by type I interferons. Nevertheless, our comprehensive characterization of CD38 expression in the immune system might have important implications for personalized approaches with emerging CD38-directed therapeutics.

REFERENCES:

[1]Ostendorf, L. et al. Targeting CD38 with Daratumumab in Refractory Systemic Lupus Erythematosus. N. Engl. J. Med. 383, 1149–1155 (2020).

Disclosure of Interests: None declared