Recurrent Goodpasture’s disease secondary to a monoclonal IgA1-κ antibody autoreactive with the α1/α2 chains of type IV collagen (original) (raw)
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American Journal of Kidney Diseases the Official Journal of the National Kidney Foundation, 2005
Goodpasture's disease is characterized by crescentic glomerulonephritis and lung hemorrhage in the presence of anti-glomerular basement membrane (anti-GBM) antibodies. This disease usually is mediated by IgG autoantibodies directed against the noncollagenous domain of the alpha3(IV) collagen chain, the Goodpasture autoantigen. In rare cases, anti-GBM antibodies of IgA or IgM class are involved, but their specificity has not been determined, and their target antigen remains unknown. The authors present the case of a 62-year-old man with anti-GBM disease mediated by a monoclonal IgA-kappa antibody, which progressed to end-stage renal disease despite intensive immunosuppression. The patient underwent living-related kidney transplantation, but lung hemorrhage and crescentic glomerulonephritis recurred, causing the loss of the allograft 2 years later. Indirect immunofluorescence found the presence of circulating IgA antibodies reactive with a basement membrane component, identified by enzyme-linked immunoabsorbent assay and Western blot as the alpha1/alpha2(IV) collagen chains. Sensitivity to digestion with collagenase indicated that IgA bound to epitopes located in the collagenous domain. This is the first case of recurrent Goodpasture's disease secondary to an autoreactive IgA antibody. The specificity of an IgA antibody implicated in the pathogenesis of anti-GBM disease has been investigated for the first time, identifying the alpha1/alpha2(IV) collagen chains as a novel target for nephritogenic antibodies.
Antigenic Heterogeneity of IgA Anti-GBM Disease: New Renal Targets of IgA Autoantibodies
American Journal of Kidney Diseases, 2008
Anti-glomerular basement membrane (anti-GBM) disease is an aggressive form of glomerulonephritis, usually mediated by immunoglobulin G (IgG) autoantibodies to the noncollagenous (NC1) domain of ␣3(IV) collagen. Less is known about the target antigen(s) in patients with atypical anti-GBM disease involving IgA autoantibodies. We report a new case of IgA anti-GBM disease in a patient with a history of proliferative lupus nephritis who presented with increasing creatinine levels, proteinuria, and hematuria, but no clinical or serological evidence of lupus recurrence. Renal biopsy showed focal and segmental necrotizing glomerulonephritis with strong linear capillary loop IgA staining by means of immunofluorescence. Serological test results were negative for IgG or IgA autoantibodies against the ␣3NC1 domain. By means of immunoblotting, IgA from patient serum bound to 38-to 48-kd antigens collagenasesolubilized from human GBM, but not to purified NC1 domains of GBM collagen IV. The target of patient's IgA autoantibodies thus was identified as a novel GBM antigen, distinct from the ␣3NC1 domain or other known targets of anti-GBM IgA autoantibodies. Clinical resolution was attained by means of conventional treatment with steroids and cyclophosphamide. The diversity of antigens recognized by anti-GBM IgA autoantibodies highlights the importance of renal biopsy for the reliable diagnosis of this rare condition because conventional serological immunoassays likely would yield false-negative results. Am J Kidney Dis 52:761-765.
Kidney International, 2000
property likely contributes to both the fulminant nature of High affinity of anti-GBM antibodies from Goodpasture and this disease and its resistance to therapy, because persistent transplanted Alport patients to ␣3(IV)NC1 collagen. glomerular Ab deposition has the potential to produce continu-Background. Anti-glomerular basement membrane (anti-GBM) antibody-mediated diseases are characterized by rapidly ous inflammation, despite removal of circulating Abs and adeprogressive glomerulonephritis (RPGN) that often results in quate immunosuppression. irreversible loss of renal function and renal failure. Although many factors contribute to the fulminant nature and treatment resistance of this disease, we questioned whether high affinity Spontaneous production and deposition of anti-GBM autoantibody-␣3(IV) collagen interactions lead to persistent antibody deposition, thereby perpetuating inflammation. To antibodies characterize anti-GBM antibody-mediated address this hypothesis, the binding kinetics of human antidiseases. The disease spectrum includes patients with GBM antibodies (Ab) to ␣3(IV)NC1 were evaluated using an glomerulonephritis and pulmonary hemorrhage [Goodoptical biosensor interaction analysis. pasture syndrome (GS)], rapidly progressive glomerulo-Methods. Polyclonal anti-GBM Abs were purified by ␣3(IV)NC1 affinity chromatography from the sera of patients nephritis (RPGN) without clinical evidence of lung with anti-GBM AB-mediated diseases, including individuals involvement (type I), and isolated pulmonary hemorwith Goodpasture syndrome (GS), idiopathic RPGN (N ϭ 7), rhage [1, 2]. The mortality in patients with GS is high and Alport syndrome (AL) following kidney transplantation (11%), and 40 to 70% of patients with anti-GBM anti-(N ϭ 4). The affinity-binding characteristics of the autoantibodbody-mediated nephritis develop end-stage renal disease ies were determined using a biosensor analysis system, with immobilized bovine ␣3(IV)NC1 dimers. [3-6]. Of potential pathogenic relevance, anti-GBM anti-Results. All of the autoantibody preparations bound to bodies are frequently produced in patients with Alport's ␣3(IV)NC1, whereas none bound to ␣1(IV)NC1 (control). syndrome following renal transplantation, and a signifi-Purified, normal serum IgG did not bind to either antigen. cant fraction of these patients develops crescentic glo-Estimated dissociation constants (K d) for the purified autoantibodies were 1.39E-04 Ϯ 7.30E-05 s-l (GS) and 8.90E-05 Ϯ merulonephritis that results in the loss of graft function 2.80E-05 s-l (AL). Their estimated association constants (K a) [7, 8]. were 2.67Eϩ04 Ϯ 1.8Eϩ04 (M-ls-l) and 2.76Eϩ04 Ϯ 1.70Eϩ04 In the spontaneous form of the disease, the factors (M-ls-l) for GS and AL patients, respectively. By comparison leading to autoantibody production are unclear, howwith other Ab interactions, these Abs demonstrated high affinever, exposure of "hidden" basement membrane antiity, with relatively high on (binding) rates and slow off (dissociation) rates. gens and molecular mimicry have been postulated to be Conclusions. The results suggest that anti-GBM Abs bind involved in disease induction [9]. Nevertheless, it has rapidly and remain tightly bound to the GBM in vivo. This been conclusively demonstrated that the NC1 domain of ␣3 chain of type IV collagen [␣3(IV)NC1] is the major autoantigenic target [9-12].
Clinical kidney journal, 2012
Goodpasture's (GP) disease is usually mediated by IgG autoantibodies. We describe a case of IgA-mediated GP, in a patient presenting with isolated rapidly progressive glomerulonephritis. The diagnosis was established on kidney biopsy, since routine enzyme-linked immunosorbent assay (ELISA) targeted at IgG circulating autoantibodies failed to detect the nephritogenic antibodies. Immunofluorescence microscopy showed intense linear deposition of IgA along the glomerular capillary walls. An elevated titre (1:80) of circulating IgA anti-glomerular basement membrane (GBM) antibodies was retrospectively demonstrated by indirect fluorescence. Despite immunosuppressive regimen, the disease progressed to end-stage renal failure (ESRF). Transplantation was not associated with recurrence in the kidney graft. We reviewed the 11 previously reported cases of IgA-mediated GP.
Journal of the American Society of Nephrology, 2005
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.
2005
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.
Mesangial IgA deposits indicate pathogenesis of anti-glomerular basement membrane disease
Molecular medicine reports, 2012
Anti-glomerular basement membrane (anti-GBM) disease is characterized by crescentic glomerulonephritis with immunoglobulin G (IgG) autoantibodies to the non-collagenous (NC1) domain of α3(IV) collagen presenting along the GBM. The patient clinically manifests with rapidly progressive glomerulonephritis (RPGN) with pulmonary hemorrhage (Goodpasture syndrome). In rare cases, other immunocomplexes of IgA or IgM are involved, but their specificities have not been determined. We report a rare case of a 31-year-old female who was diagnosed as having anti-GBM disease with extensive IgA deposits in the mesangium. This patient presented heavy hematuria, proteinuria with increasing creatinine, but no lung hemorrhage. Renal biopsy showed crescentic glomerulonephritis (type Ⅰ) with strong IgA (3+) as lump and branch shape. Therapies with pulse methylprednisolone, plasmapheresis and cyclophosphamide administration were less effective. This case is different from the present type Ⅰ crescentic glo...