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Identification and characterization of circulating immune complexes in IgA nephropathy
Yasuyuki Matsumoto1, Rajindra P Aryal1, Jamie Heimburg-Molinaro1
1Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Science Advances
|October 28, 2022
Summary
Novel anti-galactose-deficient IgA1 immune complexes (anti-Tn CICs) are elevated in IgA nephropathy (IgAN) patients. These bioactive complexes, containing IgM and Tn(+)IgA1, can be dissociated and their activity inhibited by glycomimetic compounds.
Area of Science:
- Nephrology
- Immunology
- Glycobiology
Background:
- Immunoglobulin A (IgA) nephropathy (IgAN) is the most common glomerulonephritis globally.
- Pathology involves immune complex deposition of galactose-deficient IgA1 [Tn(+)IgA1] in the glomeruli.
- Current treatment options for IgAN are limited, highlighting the need for new therapeutic strategies.
Purpose of the Study:
- To characterize novel circulating immune complexes (CICs) in IgA nephropathy patients.
- To investigate the composition, bioactivity, and potential therapeutic targeting of these novel CICs.
Main Methods:
- Characterization of anti-Tn CICs composition using size-exclusion chromatography and mass spectrometry.
- Quantification of anti-Tn CICs and complement C3 levels in patient and healthy individual sera.
- Assessment of anti-Tn CICs bioactivity on human renal mesangial cell proliferation.
- In vitro testing of glycomimetic compounds for dissociation and inhibition of anti-Tn CICs.
Main Results:
- Novel anti-Tn CICs, predominantly IgM with Tn(+)IgA1 and some IgG, were identified.
- These large macromolecular complexes (~1.2 to several megadaltons) were significantly elevated in IgAN patients.
- Elevated levels of complement C3 were observed in association with anti-Tn CICs in IgAN sera.
- Anti-Tn CICs demonstrated bioactivity, inducing human renal mesangial cell proliferation.
- Glycomimetic compounds successfully dissociated anti-Tn CICs and inhibited their proliferative activity.
Conclusions:
- The study identified novel, bioactive anti-Tn CICs as a key component in IgA nephropathy pathogenesis.
- These findings suggest that anti-Tn CICs could serve as a diagnostic biomarker for IgAN.
- Glycomimetic compounds show promise as a potential therapeutic strategy for IgAN by targeting these immune complexes.
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