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Circulating immune-complexes and complement activation through the classical pathway in
Tadasu Kojima1, Dan Inoue1, Takeaki Wajima2
1Department of Nephrology and Blood Purification, Kidney Disease Center, Tokyo Medical University Hachioji Medical Center, Hachioji, Japan.
Insights
This study suggests immune-complexes activate the classical complement pathway in myeloperoxidase-ANCA-associated glomerulonephritis (MPO-AAGN). High-affinity antibodies and elevated C5a/C5b-9 indicate classical pathway involvement in MPO-AAGN pathogenesis.
Area of Science:
- Nephrology
- Immunology
- Complement System Biology
Background:
- Anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (AAGN) is a severe kidney disease.
- Complement system activation is implicated in AAGN, but the specific pathway remains unclear.
Purpose of the Study:
- To investigate the role of complement activation pathways in myeloperoxidase (MPO)-AAGN.
- To determine the relationship between ANCA affinity, circulating immune-complexes (CICs), and complement activation in MPO-AAGN.
Main Methods:
- Retrospective analysis of 20 MPO-AAGN patients.
- Assessed serum CICs, C5a, C5b-9, and classical pathway activation.
- Evaluated ANCA affinity and complement component deposition in renal tissue via immunofluorescence.
Main Results:
- Circulating immune-complexes (CICs) were detected in 65% of patients, all with high-affinity ANCAs.
- Elevated serum C5a and C5b-9 levels correlated positively with CIC levels.
- Glomerular deposition of C4d, C5, and C5b-9 was observed, with minimal alternative pathway component deposition.
Conclusions:
- Results indicate immune-complex-induced complement activation via the classical pathway contributes to MPO-AAGN pathogenesis.
- High-affinity ANCAs and CICs are associated with classical pathway activation in MPO-AAGN.
Background:
Anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (AAGN) is the fulminant glomerular diseases with poor renal prognosis. Activation of the complement system has recently been reported in the pathogenesis of AAGN, but it remains to be clarified as to which complement pathway is mainly involved.
Methods:
20 patients with myeloperoxidase (MPO)-AAGN were retrospectively evaluated. Using serum samples, circulating immune-complexes (CICs) were assessed by the monoclonal rheumatoid factor assay, and C5a and C5b-9 were assessed by ELISA. Complement activation through the classical pathway was further evaluated by the WIESLAB® Complement System Classical Pathway kit. The affinities of ANCAs were evaluated by a competitive inhibition method using ELISA, and were classified into the high, and low-affinity group. Deposition of complement components, such as C3, C5, C4d, C5b-9, factor Bb, mannan-binding lectin serine peptidase (MASP)-1, MASP-2, and mannose/mannan-binding lectin (MBL), in frozen renal sections were analyzed by immunofluorescence staining.
Results:
CICs were found to be positive in 65% of the patients. All CIC-positive patients belonged to the high-affinity group. Furthermore, serum C5a and C5b-9 were significantly increased in MPO-AAGN patients, and these levels positively correlated with CIC levels. A significant negative correlation was also found between levels of WIESLAB® classical pathway kit and CICs. By immunofluorescence staining, glomerular deposition of C4d, C5, and C5b-9 were observed in similar distributions in MPO-AAGN patients, whereas the deposition of MASP-1, MASP-2, MBL, and factor Bb were minimal.
Conclusions:
These results suggest the involvement of immune-complex induced complement activation through the classical pathway in the pathogenesis of MPO-AAGN.
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