The lectin and alternative pathways both play a role in promoting inflammation and vaso-occlusion in sickle cell disease, according to a new study published in Translational Research. Inhibiting complement activation via these 2 pathways could therefore prevent vaso-occlusive crises in patients with sickle cell disease.
The markers of complement activation are high in patients with sickle cell disease and increase further when a vaso-occlusive crisis occurs.
However, scientists do not fully understand what drives complement activation in sickle cell disease. They do know, however, that ischemia-reperfusion and heme released from hemoglobin during ongoing hemolysis can activate the lectin and alternative pathways, respectively.
Here, a team of researchers led by Gregory M. Vercellotti, MD, FACP, from the Division of Hematology, Oncology, and Transplantation, Department of Medicine at University of Minnesota in Minneapolis further investigated the role of these 2 pathways in sickle cell disease using a mouse model.
Read more about vaso-occlusive crisis and other symptoms of sickle cell disease
The researchers treated the mice with monoclonal antibodies that inhibited either mannose-binding lectin-associated serine protease (MASP)-2 or MASP-3 and then challenged the animals with hypoxia-reoxygenation or hemoglobin.
They found that the antibody treatment markedly reduced Bb fragments (an enzymatic component of the alternative pathway), C4d, and C5a in the plasma of the animals as well as the deposition of complement proteins in the liver, kidneys, and lungs.
Moreover, the hepatic inflammation markers nuclear factor kappa B (NF-ĸB) phospho-p65, vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), and E-selectin were also significantly reduced, which is consistent with complement inhibition.
Finally, antibody treatment significantly inhibited vaso-occlusion induced by hypoxia-reoxygenation or hemoglobin.
The researchers concluded that blocking the lectin or alternative pathway may help prevent or treat vaso-occlusive crises in patients with sickle cell disease.
Belcher JD, Nguyen J, Chen C, et al. MASP-2 and MASP-3 inhibitors block complement activation, inflammation, and microvascular stasis in a murine model of vaso-occlusion in sickle cell disease. Transl Res. Published online July 22, 2022. doi:10.1016/j.trsl.2022.06.018