Distinct dendritic cell subsets are associated with immune dysfunction and clinical severity in sickle cell anemia

Sickle cell anemia (SCA) is characterized by chronic hemolysis, vaso-occlusion, sustained inflammation, immune dysfunction, and increased susceptibility to infections. Molecules released upon hemolysis are recognized by innate immunity shaping adaptive immune responses. Although dendritic cells (DCs) are central to these processes, comprehensive characterization of their subsets and clinical relevance in SCA remains limited. Here, we performed an in-depth immunophenotypic analysis of circulating DC and monocyte subsets in SCA patients, integrating activation status, immunoregulatory molecules, T-cell phenotypes, systemic cytokines, and hematological and biochemical parameters. We identified distinct signatures across DC subsets. Activated type 2 conventional DCs (cDC2), inflammatory DCs (iDCs), and plasmacytoid DC (pDC) clusters were expanded in SCA, while type 1 cDCs (cDC1) were reduced. Activation of cDC2 and iDCs was associated with markers of disease severity, whereas activation of pDCs, transitional DCs (tDCs) and cDC1 correlated with less severe clinical profiles. Multiple DC subsets upregulated heme oxygenase-1 in SCA, indicating active heme metabolism. Activation and transferrin receptor expression by pDCs and tDCs correlated with IFN-γ and IL-17 production by T cells, and cDC1 frequency was associated with regulatory T-cell expansion. Collectively, our findings reveal distinct associations between DC and monocyte subsets, adaptive immune responses, and clinical severity in SCA, providing new insights into the immunopathogenesis of the disease.