Fcalpha receptor (CD89) mediates the development of immunoglobulin A (IgA) nephropathy (Berger's disease). Evidence for pathogenic soluble receptor-Iga complexes in patients and CD89 transgenic mice.
The pathogenesis of immunoglobulin A (IgA) nephropathy (IgAN), the most prevalent form of glomerulonephritis worldwide, involves circulating macromolecular IgA1 complexes. However, the molecular mechanism(s) of the disease remain poorly understood. We report here the presence of circulating soluble FcalphaR (CD89)-IgA complexes in patients with IgAN. Soluble CD89 was identified as a glycoprotein with a 24-kD backbone that corresponds to the expected size of CD89 extracellular domains. To demonstrate their pathogenic role, we generated transgenic (Tg) mice expressing human CD89 on macrophage/monocytes, as no CD89 homologue is found in mice. These mice spontaneously developed massive mesangial IgA deposition, glomerular and interstitial macrophage infiltration, mesangial matrix expansion, hematuria, and mild proteinuria. The molecular mechanism was shown to involve soluble CD89 released after interaction with IgA. This release was independent of CD89 association with the FcRgamma chain. The disease was induced in recombination activating gene (RAG)2(-/-) mice by injection of serum from Tg mice, and in severe combined immunodeficiency (SCID)-Tg mice by injection of patients' IgA. Depletion of soluble CD89 from serum abolished this effect. These results reveal the key role of soluble CD89 in the pathogenesis of IgAN and provide an in vivo model that will be useful for developing new treatments.
Launay
P
P
Institut National de la Santé et de la Recherche Médicale U25, Necker Hospital, Paris 75743, France.
Grossetête
B
B
Arcos-Fajardo
M
M
Gaudin
E
E
Torres
S P
SP
Beaudoin
L
L
Patey-Mariaud de Serre
N
N
Lehuen
A
A
Monteiro
R C
RC
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D005260:Female; D005922:Glomerulonephritis, IGA / Q000276:immunology* / Q000473:pathology; D006417:Hematuria / Q000276:immunology; D006801:Humans; D007070:Immunoglobulin A / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D009687:Nuclear Proteins; D011961:Receptors, Fc / Q000235:genetics / Q000276:immunology*; D012995:Solubility
D015703:Antigens, CD; D004268:DNA-Binding Proteins; C036832:Fc(alpha) receptor; D007070:Immunoglobulin A; D009687:Nuclear Proteins; C499311:RAG2 protein, human; C499308:Rag2 protein, mouse; D011961:Receptors, Fc; C064655:V(D)J recombination activating protein 2