Factor H polymorphism elevates granzyme B and impairs complement inhibition in human and mouse models
Abstract
The complement factor H (CFH) Y402H polymorphism is a leading genetic risk factor for age-related macular degeneration (AMD). Here, we identify extracellular granzyme B (GzmB) as a crucial mediator connecting complement dysregulation to structural pathology. In non-AMD human donor eyes, the high-risk CFH genotype was associated with increased GzmB-positive choroidal mast cells, membrane attack complex deposition, and distinct vitronectin redistribution. Using in vitro human retinal pigment epithelium (RPE) cells, we demonstrate that complement fragment C5a triggers GzmB secretion and zonula occludens-1 disruption. RNA sequencing of GzmB-stimulated RPE cells confirmed transcriptomic signatures of barrier dysfunction and cellular stress. Furthermore, GzmB-deficient mice displayed preserved choroidal vitronectin compared with wild-type controls, supporting a role for GzmB in cleaving this terminal complement inhibitor. These findings delineate a pathogenic C5a-GzmB pathway compromising extracellular matrix integrity, implicating extracellular GzmB as a critical downstream mediator linking genetic risk to early AMD onset.
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BibTeX
@article{chakravarthy2026factor,
title = {{Factor H polymorphism elevates granzyme B and impairs complement inhibition in human and mouse models}},
author = {Harshini Chakravarthy and Jeanne Xi and Hyung-Suk Yoo and Andrew Buss and Boaz Li and Robert Bell and Anne Haegert and Stephane Le Bihan and David J. Granville and Joanne A. Matsubara},
journal = {iScience},
year = {2026},
month = oct,
doi = {10.1016/j.isci.2026.117957},
url = {https://www.cell.com/iscience/fulltext/S2589-0042(26)03340-7},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Factor H polymorphism elevates granzyme B and impairs complement inhibition in human and mouse models
AU - Harshini Chakravarthy
AU - Jeanne Xi
AU - Hyung-Suk Yoo
AU - Andrew Buss
AU - Boaz Li
AU - Robert Bell
AU - Anne Haegert
AU - Stephane Le Bihan
AU - David J. Granville
AU - Joanne A. Matsubara
PY - 2026
DA - 2026/10/19
JO - iScience
DO - 10.1016/j.isci.2026.117957
UR - https://www.cell.com/iscience/fulltext/S2589-0042(26)03340-7
AB - The complement factor H (CFH) Y402H polymorphism is a leading genetic risk factor for age-related macular degeneration (AMD). Here, we identify extracellular granzyme B (GzmB) as a crucial mediator connecting complement dysregulation to structural pathology. In non-AMD human donor eyes, the high-risk CFH genotype was associated with increased GzmB-positive choroidal mast cells, membrane attack complex deposition, and distinct vitronectin redistribution. Using in vitro human retinal pigment epithelium (RPE) cells, we demonstrate that complement fragment C5a triggers GzmB secretion and zonula occludens-1 disruption. RNA sequencing of GzmB-stimulated RPE cells confirmed transcriptomic signatures of barrier dysfunction and cellular stress. Furthermore, GzmB-deficient mice displayed preserved choroidal vitronectin compared with wild-type controls, supporting a role for GzmB in cleaving this terminal complement inhibitor. These findings delineate a pathogenic C5a-GzmB pathway compromising extracellular matrix integrity, implicating extracellular GzmB as a critical downstream mediator linking genetic risk to early AMD onset.
SN - 2589-0042
ER -