Increased complement activation and high levels of C3d are important in the pathogenesis of alpha-1 antitrypsin deficiency (AATD), according to a new study published in the journal Biomedicines.

The study showed the effect of C3d, the final degradation product of the third component of complement C3, on circulating neutrophils and its impact on endothelial cell wound repair. The findings provide a potential mechanism of why wound healing is disturbed in patients with AATD, the authors said.

The team led by Emer P. Reeves, PhD, collected blood from 88 patients with AATD and chronic obstructive pulmonary disease (COPD), 10 patients with COPD but no AATD, and 40 healthy controls.


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The researchers then challenged the neutrophils from each set of blood with C3d and assessed their degranulations, a sign of their activations. When C3d bound to CR3 receptors, primary, secondary, and tertiary granule releases were triggered, CXCL8 secretion was increased, and cell migration was decreased.

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They also observed that the levels of C3d were increased in the plasma and on the membranes of neutrophils obtained from patients with AATD compared to that obtained from healthy controls, as were plasma levels of bactericidal-permeability-increasing-protein, myeloperoxidase, and lactoferrin.

“In summary, AATD patients had increased C3d in plasma and on neutrophil membranes and, together with neutrophil-released granule enzymes, reduced endothelial cell migration and wound healing,” the researchers wrote and added that this could have implications for AATD-related vasculitis.

AATD is a complex disease affecting many biological processes which can cause a plethora of problems from a high risk of emphysema, COPD, and vasculitis, to wound-healing impairments. It is caused by mutations in the SERPINA1 gene, which disrupt the normal production of the AAT protein.

Reference

Fee LT, Gogoi D, O’Brien ME, et al. C3d elicits neutrophil degranulation and decreases endothelial cell migration, with implications for patients with alpha-1 antitrypsin deficiency. Biomedicines. 2021;16;9(12):1925. doi:10.3390/biomedicines9121925