TY - JOUR
T1 - Identification and characterization of circulating immune complexes in IgA nephropathy
AU - Matsumoto, Yasuyuki
AU - Aryal, Rajindra P.
AU - Heimburg-Molinaro, Jamie
AU - Park, Simon S.
AU - Wever, Walter J.
AU - Lehoux, Sylvain
AU - Stavenhagen, Kathrin
AU - van Wijk, Joanna A. E.
AU - van Die, Irma
AU - Chapman, Arlene B.
AU - Chaikof, Elliot L.
AU - Cummings, Richard D.
N1 - Funding Information: This work was supported by the National Institute of Health, grants R01DK080876, P41GM103694, and R24GM137763 (to R.D.C.). Publisher Copyright: Copyright © 2022 The Authors, some rights reserved.
PY - 2022/10/28
Y1 - 2022/10/28
N2 - The underlying pathology of immunoglobulin A (IgA) nephropathy (IgAN), the most common glomerulonephritis worldwide, is driven by the deposition of immune complexes containing galactose-deficient IgA1 [Tn(+)IgA1] in the glomerular mesangium. Here, we report that novel anti-Tn circulating immune complexes (anti-Tn CICs) contain predominantly IgM, representing large macromolecular complexes of ~1.2 megadaltons to several megadalton sizes together with Tn(+)IgA1 and some IgG. These complexes are significantly elevated in sera of patients with IgAN, which contains higher levels of complement C3, compared to healthy individuals. Anti-Tn CICs are bioactive and induce specific proliferation of human renal mesangial cells. We found that these anti-Tn CICs can be dissociated with small glycomimetic compounds, which mimic the Tn antigen of Tn(+)IgA1, releasing IgA1 from anti-Tn CICs. This glycomimetic compound can also significantly inhibit the proliferative activity of anti-Tn CICs of patients with IgAN. These findings could enhance both the diagnosis of IgAN and its treatment, as specific drug treatments are now unavailable.
AB - The underlying pathology of immunoglobulin A (IgA) nephropathy (IgAN), the most common glomerulonephritis worldwide, is driven by the deposition of immune complexes containing galactose-deficient IgA1 [Tn(+)IgA1] in the glomerular mesangium. Here, we report that novel anti-Tn circulating immune complexes (anti-Tn CICs) contain predominantly IgM, representing large macromolecular complexes of ~1.2 megadaltons to several megadalton sizes together with Tn(+)IgA1 and some IgG. These complexes are significantly elevated in sera of patients with IgAN, which contains higher levels of complement C3, compared to healthy individuals. Anti-Tn CICs are bioactive and induce specific proliferation of human renal mesangial cells. We found that these anti-Tn CICs can be dissociated with small glycomimetic compounds, which mimic the Tn antigen of Tn(+)IgA1, releasing IgA1 from anti-Tn CICs. This glycomimetic compound can also significantly inhibit the proliferative activity of anti-Tn CICs of patients with IgAN. These findings could enhance both the diagnosis of IgAN and its treatment, as specific drug treatments are now unavailable.
UR - http://www.scopus.com/inward/record.url?scp=85141003795&partnerID=8YFLogxK
U2 - https://doi.org/10.1126/sciadv.abm8783
DO - https://doi.org/10.1126/sciadv.abm8783
M3 - Article
C2 - 36306365
SN - 2375-2548
VL - 8
SP - eabm8783
JO - Science advances
JF - Science advances
IS - 43
M1 - eabm8783
ER -