Distinct Epitopes for Anti–Glomerular Basement Membrane Alport Alloantibodies and Goodpasture Autoantibodies within the Noncollagenous Domain of α3(IV) Collagen

Abstract

Alport posttransplantation anti-glomerular basement membrane (GBM) nephritis is mediated by alloantibodies against the noncollagenous (NC1) domains of the ␣3␣4␣5(IV) collagen network, which is present in the GBM of the allograft but absent from Alport kidneys. The specificity of kidney-bound anti-GBM alloantibodies from a patient who had autosomal recessive Alport syndrome (ARAS) and developed posttransplantation nephritis was compared with that of Goodpasture autoantibodies from patients with autoimmune anti-GBM disease. Allograft-eluted alloantibodies reacted specifically with ␣3␣4␣5 NC1 hexamers, targeting their ␣3NC1 and ␣4NC1 subunits, and recognized a noncontiguous alloepitope formed jointly by the E A and E B regions of ␣3NC1 domain. In contrast, human Goodpasture autoantibodies recognized the separate E A and E B autoepitopes of ␣3NC1 but not the composite alloepitope. Molecular modeling of ␣3NC1 revealed that the alloepitope is more accessible within the NC1 hexamers than the partially sequestered Goodpasture autoepitopes. Overall, the specificity of alloantibodies indicated a selective lack of immune tolerance toward the ␣3 and ␣4(IV) collagen chains not expressed in patients with ARAS. Using COL4A3 knockout mice, a model of ARAS, it was shown further that acid-dissociated rather than native ␣3␣4␣5 NC1 hexamers elicited murine anti-GBM antibodies most closely resembling human ARAS alloantibodies. In contrast, ␣3NC1 monomers elicited Goodpasture-like murine antibodies, targeting the E A and E B autoepitopes. Thus, the identity of ␣3NC1 epitopes targeted by anti-GBM antibodies is strongly influenced by the molecular organization of the immunogen. These findings suggest that different isoforms of ␣3(IV) collagen may be implicated in the pathogenesis of ARAS posttransplantation anti-GBM nephritis and Goodpasture disease.

Mannose Receptor Expression and Function Define a New Population of Murine Dendritic Cells

“…24 and our own unpublished data), rheumatoid arthritis (collagen II, a major component of cartilage) (25), and Goodpasture's disease (collagen IV) (26). This correlation led us to consider that if the MR contributed to Ag presentation in vivo it could mediate the inappropriate presentation of its endogenous ligands to the acquired immune system.…”

Quaternary Epitopes of α345(IV) Collagen Initiate Alport Post-Transplant Anti-GBM Nephritis

“…8 For comparison, we used previously described Goodpasture sera. 28 Normal human sera (Innovative Research, Novi, MI) were used as negative controls. We also evaluated the presence of alloantibodies in archived serum samples from 12 transplanted X-linked Alport syndrome patients who did not develop APTN.…”

Basement membranes and human disease

“…Following kidney transplantation, the presence of "foreign" collagen IV chains can cause Alport's posttransplantation anti-GBM nephritis. In autosomal recessive Alport's syndrome the epitopes are located in the NC1 domains of Col4a3 or Col4a4 (Hudson et al 2003;Wang et al 2005) whilst X-linked patients develop alloantibodies targeting epitopes on COL4A5 (Brainwood et al 1998;Kang et al 2007). However in contrast to the cryptic Goodpasture epitopes, the epitopes are accessible in the NC1 hexamer indicating that separate mechanisms may exist (Kang et al 2007).…”