Identification of C3d Complement Fragments in Lesional Tissues in ANCA‐Associated Vasculitis
13 affiliations
- 1Q32 Bio Inc Waltham Massachusetts
- 2Department of Pathology, Brigham and Women's Hospital Harvard Medical School Boston Massachusetts
- 3University of Colorado School of Medicine Aurora
- 4Department of Dermatology, Brigham and Women's Hospital Harvard Medical School Boston Massachusetts
- 5Department of Immunology and Inflammation Imperial College London United Kingdom
- 6University of South Florida Tampa
- 7Division of Rheumatology St. Joseph Healthcare Hamilton Ontario Canada
- 8Division of Rheumatology University of Utah Salt Lake City
- 9Division of Rheumatology Cleveland Clinic Cleveland Ohio
- 10Division of Rheumatology, Department of Medicine University of Pennsylvania Philadelphia
- 11Division of Epidemiology, Department of Biostatistics, Epidemiology, and Informatics University of Pennsylvania Philadelphia
- 12Veterans Administration Medical Center Boston Massachusetts
- 13Mount Sinai Hospital and University of Toronto Toronto Canada
Abstract
Objective: Antineutrophil cytoplasmic antibody–associated vasculitis (AAV) is typically described as “pauci‐immune” due to the absence or weak detection of Igs and complement activation within AAV tissue lesions. However, complement fragments have been recently reported in significant amounts in damaged tissue in AAV, notably in traps formed by neutrophil extravasation. This study aimed to characterize complement activation, in particular the long‐lasting fragment C3d, in affected tissue in AAV.
Methods: Biopsies from patients with AAV (kidney, n = 40; lung, n = 5; sinus, n = 2; and skin, n = 3), IgA nephropathy (IgAN; kidney, n = 29), C3 glomerulonephritis (C3G; kidney, n = 9), lupus nephritis (LN; kidney, n = 30), and cutaneous leukocytoclastic vasculitis (skin, n = 41) were stained using a novel anti‐C3d monoclonal antibody (3d8b), and, in some instances, a commercially available anti‐C3c polyclonal antibody.
Results: Both semiquantitative scoring and digital quantification revealed moderate glomerular staining in AAV and IgAN and higher signal in C3G and LN. A distinct C3c/C3d glomerular staining pattern was seen in AAV and IgAN with more deposition in mesangium than capillaries. C3G and LN exhibited more homogenous deposition. Three of seven biopsies that tested negative for C3 by routine diagnostic immunostaining were positive for C3d. C3d deposition was also detected in extra‐glomerular small vessels in the kidney, in superficial dermal vasculature in leukocytoclastic vasculitis, and in lung and sinus lesional tissues in AAV.
Conclusion: Immunostaining for complement fragments, particularly C3d, reveals evidence of complement activation in multiple tissues in AAV, including biopsies deemed negative by routine C3 staining. These data indicate that glomerulonephritis in AAV is less pauci‐immune than previously appreciated.
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BibTeX
@article{galand2026identification,
title = {{Identification of C3d Complement Fragments in Lesional Tissues in ANCA‐Associated Vasculitis}},
author = {Claire Galand and Fei Liu and Katherine A. Vernon and Ravi Vats and Christine Lian and V. Michael Holers and Michael Woodbury and H. Terence Cook and David Cuthbertson and Nader Khalidi and Curry Koening and Carol A. Langford and Carol A. McAlear and Paul A. Monach and Christian Pagnoux and Jason A. Campagna and Stefan Wawersik and Shelia Violette and Peter A. Merkel and for the Vasculitis Clinical Research Consortium},
journal = {ACR Open Rheumatology},
year = {2026},
month = nov,
doi = {10.1002/acr2.90164},
url = {https://doi.org/10.1002/acr2.90164},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Identification of C3d Complement Fragments in Lesional Tissues in ANCA‐Associated Vasculitis
AU - Claire Galand
AU - Fei Liu
AU - Katherine A. Vernon
AU - Ravi Vats
AU - Christine Lian
AU - V. Michael Holers
AU - Michael Woodbury
AU - H. Terence Cook
AU - David Cuthbertson
AU - Nader Khalidi
AU - Curry Koening
AU - Carol A. Langford
AU - Carol A. McAlear
AU - Paul A. Monach
AU - Christian Pagnoux
AU - Jason A. Campagna
AU - Stefan Wawersik
AU - Shelia Violette
AU - Peter A. Merkel
AU - for the Vasculitis Clinical Research Consortium
PY - 2026
DA - 2026/11/03
JO - ACR Open Rheumatology
DO - 10.1002/acr2.90164
UR - https://doi.org/10.1002/acr2.90164
AB - Objective: Antineutrophil cytoplasmic antibody–associated vasculitis (AAV) is typically described as “pauci‐immune” due to the absence or weak detection of Igs and complement activation within AAV tissue lesions. However, complement fragments have been recently reported in significant amounts in damaged tissue in AAV, notably in traps formed by neutrophil extravasation. This study aimed to characterize complement activation, in particular the long‐lasting fragment C3d, in affected tissue in AAV. Methods: Biopsies from patients with AAV (kidney, n = 40; lung, n = 5; sinus, n = 2; and skin, n = 3), IgA nephropathy (IgAN; kidney, n = 29), C3 glomerulonephritis (C3G; kidney, n = 9), lupus nephritis (LN; kidney, n = 30), and cutaneous leukocytoclastic vasculitis (skin, n = 41) were stained using a novel anti‐C3d monoclonal antibody (3d8b), and, in some instances, a commercially available anti‐C3c polyclonal antibody. Results: Both semiquantitative scoring and digital quantification revealed moderate glomerular staining in AAV and IgAN and higher signal in C3G and LN. A distinct C3c/C3d glomerular staining pattern was seen in AAV and IgAN with more deposition in mesangium than capillaries. C3G and LN exhibited more homogenous deposition. Three of seven biopsies that tested negative for C3 by routine diagnostic immunostaining were positive for C3d. C3d deposition was also detected in extra‐glomerular small vessels in the kidney, in superficial dermal vasculature in leukocytoclastic vasculitis, and in lung and sinus lesional tissues in AAV. Conclusion: Immunostaining for complement fragments, particularly C3d, reveals evidence of complement activation in multiple tissues in AAV, including biopsies deemed negative by routine C3 staining. These data indicate that glomerulonephritis in AAV is less pauci‐immune than previously appreciated.
SN - 2578-5745
ER -