Aetiopathogenesis
Possible implication of intermolecular epitope spreading in the production of anti-glomerular basement membrane antibody in anti-neutrophil cytoplasmic antibody-associated vasculitis
Y. Nishibata1, M. Nonokawa2, Y. Tamura3, R. Higashi4, K. Suzuki5, H. Hayashi6, S. Masuda7, D. Nakazawa8, S. Tanaka9, U. Tomaru10, A. Ishizu11
- Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.
- Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.
- Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.
- Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.
- Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.
- Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.
- Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.
- Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
- Center for Cause of Death Investigation, Faculty of Medicine, Hokkaido University, Sapporo, Japan.
- Department of Pathology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
- Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan. aishizu@med.hokudai.ac.jp
CER14947
2022 Vol.40, N°4
PI 0691, PF 0704
Aetiopathogenesis
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PMID: 35200124 [PubMed]
Received: 30/06/2021
Accepted : 25/10/2021
In Press: 04/02/2022
Published: 04/05/2022
Abstract
OBJECTIVES:
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is sometimes complicated by anti-glomerular basement membrane (GBM) disease. Proteases, including elastase, released from neutrophils activated by ANCA are implicated in the pathogenesis of AAV. Epitopes of anti-GBM antibody exist in the α3-subunit non-collagenous (NC1) domain of collagen type IV [Col (IV)]. This region, called α3(IV)NC1, is structurally cryptic. This study aimed to determine the production mechanism of anti-GBM antibody in AAV.
METHODS:
We first examined whether α3(IV)NC1 could be revealed by the digestion of formalin-fixed, paraffin-embedded (FFPE) normal kidney sections and Col (IV) by proteases, including neutrophil elastase, using immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA). Next, the reveal of α3(IV)NC1 and the infiltration of CD11c+ macrophages in the affected kidneys were evaluated by IHC and immunofluorescent staining using FFPE sections. Finally, the production of anti-GBM antibody in AAV rats was determined by ELISA.
RESULTS:
α3(IV)NC1 was revealed by the digestion of FFPE normal kidney sections and Col (IV) by proteases. Although the reveal of α3(IV)NC1 was observed in sclerotic glomeruli regardless of causative diseases, CD11c+ macrophages near α3(IV)NC1 were characteristics of AAV. Anti-GBM antibody was produced subsequent to ANCA in some AAV rats. IHC demonstrated the reveal of α3(IV)NC1 in affected renal tissues and the infiltration of CD11c+ macrophages around the sites.
CONCLUSIONS:
The collective findings suggest that, in AAV, proteases released from neutrophils activated by ANCA digest Col (IV) and result in the reveal of α3(IV)NC1, CD11c+ macrophages present GBM epitopes, and then the host’s immune system produce anti-GBM antibody.
