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Stem cell biology

Reduced red blood cell surface level of Factor H as a mechanism underlying paroxysmal nocturnal hemoglobinuria

Leukemia volume 35, pages 1176–1187 (2021)Cite this article

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Abstract

The absence of the cell-surface complement inhibitors CD55 and CD59 is considered the mechanism underlying the complement-mediated destruction of affected red blood cells (RBCs) in paroxysmal nocturnal hemoglobinuria (PNH) patients, but Factor H (FH), a fluid-phase complement inhibitor, has also been proposed to be involved. However, the status of FH on the PNH patient RBC surface is unclear and its precise role in PNH pathogenesis remains to be further defined. In this study, we identified significantly lower levels of surface-bound FH on the affected CD59− RBCs than on the unaffected CD59+ RBCs. Although this reduction in surface-bound FH on PNH RBCs was accompanied by decreased surface sialic acid levels, the enzymatic removal of sialic acids from these RBCs did not significantly affect the levels of surface-bound FH. We further observed higher surface levels of FH on the C3b/iC3b/C3dhigh RBCs than on C3b/iC3b/C3dlow RBCs within the affected PNH RBCs of patients treated with eculizumab. Finally, we determined that enhanced surface levels of FH on CD55/CD59-deficient RBCs from mice and PNH patients protected against complement-mediated hemolysis. Taken together, our results suggest that a reduced surface level of FH is another important mechanism underlying the pathogenesis of PNH.

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Fig. 1: PNH RBCs exhibit reduced levels of surface FH.
Fig. 2: PNH RBCs exhibit reduced surface levels of sialic acids.
Fig. 3: Enzymatic desialylation does not affect surface FH levels on PNH and normal RBCs.
Fig. 4: Correlation between the surface levels of FH and C3b/iC3b/C3d on RBCs of PNH patients under anti-C5 treatments.
Fig. 5: Augmentation of surface FH levels on RBCs from CD55/CD59 double-KO mice protects against complement-mediated hemolysis.
Fig. 6: Augmentation of surface FH levels on human PNH RBCs protects against complement-mediated hemolysis.

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Acknowledgements

This project is supported in part by NIH grants DK103581 (FL), EY031087 (FL) and HL135795 (JM).

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Authors and Affiliations

  1. Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    Lingjun Zhang, Jin Y. Chen & Feng Lin

  2. Translational Hematology and Oncology Research Department, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA

    Cassandra Kerr & Jaroslaw P. Maciejewski

  3. Department of Pathology, Case Western Reserve University, Cleveland, OH, USA

    Brian A. Cobb

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  1. Lingjun Zhang
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Contributions

LZ and JC did the experiments, analyzed the data, and edited the paper; CK collected and organized the patient samples, BC and JM discussed the results and edited the paper; FL designed the experiments, interpret the results, and wrote the paper.

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Correspondence to Feng Lin.

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Zhang, L., Chen, J.Y., Kerr, C. et al. Reduced red blood cell surface level of Factor H as a mechanism underlying paroxysmal nocturnal hemoglobinuria. Leukemia 35, 1176–1187 (2021). https://doi.org/10.1038/s41375-020-1008-5

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