Fc alpha 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 pre valent form of glomerulonephritis worldwide, involves circulating macromole cular IgA1 complexes. However, the molecular mechanism(s) of the disease re main poorly understood. We report here the presence of circulating soluble Fc alpha R (CD89)-IgA complexes in patients with IgAN. Soluble CD89 was ide ntified as a glycoprotein with a 24-kD backbone that corresponds to the exp ected size of CD89 extracellular domains. To demonstrate their pathogenic r ole, 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 ISA deposition, glomerular and interstitial mac rophage infiltration, mesangial matrix expansion, hematuria, and mild prote inuria. The molecular mechanism was shown to involve soluble CD89 released after interaction with IgA. This release was independent of CD89 associatio n with the FcR gamma chain. The disease was induced in recombination activa ting gene (RAG)2(-/-) mice by injection of serum from Tg mice, and in sever e combined immunodeficiency (SCID)-Tg mice by injection of patients' IgA. D epletion of soluble CD89 from serum abolished this effect. These results re veal the key role of soluble CD89 in the pathogenesis of IgAN and provide a n in vivo model that will be useful for developing new treatments.