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Pathogenesis and diagnosis of anti-GBM antibody (Goodpasture's) disease

Authors
Charles D Pusey, MD
Raghu Kalluri, MD, PhD
Section Editors
Richard J Glassock, MD, MACP
Fernando C Fervenza, MD, PhD
Deputy Editor
Albert Q Lam, MD

INTRODUCTION

Anti-GBM antibody disease is a disorder in which circulating antibodies are directed against an antigen intrinsic to the glomerular basement membrane (GBM), thereby resulting in acute or rapidly progressive glomerulonephritis that is typically associated with crescent formation [1]. Goodpasture's syndrome and Goodpasture's disease are often used synonymously to refer to anti-GBM antibody-mediated disease, which typically presents with the syndrome of glomerulonephritis and pulmonary hemorrhage, but may present with glomerulonephritis alone. However, some use the term Goodpasture's syndrome for the clinical constellation of glomerulonephritis and pulmonary hemorrhage, regardless of the underlying pathogenesis [1]. The term Goodpasture's disease is often reserved for those patients with glomerulonephritis, pulmonary hemorrhage, and anti-GBM antibodies.

The pathogenesis, clinical presentation, and diagnosis of anti-GBM disease will be reviewed here. The treatment of this disorder, and other renal conditions associated with pulmonary hemorrhage, are discussed separately. (See "Treatment of anti-GBM antibody (Goodpasture's) disease" and "Differential diagnosis and evaluation of glomerular disease", section on 'Acute glomerulonephritis and pulmonary hemorrhage'.)

The differential diagnosis of glomerular disease and the approach to the patient with suspected kidney disease are discussed in detail elsewhere. (See "Differential diagnosis and evaluation of glomerular disease" and "Diagnostic approach to the patient with subacute kidney injury in an outpatient setting".)

PATHOGENESIS

There is short-lived production of circulating autoantibodies, which are directed against an antigen intrinsic to the glomerular basement membrane (GBM), in response to an unknown inciting stimulus [2]. The development of anti-GBM antibodies may precede the onset of clinical signs and symptoms by many months [3]. The principal target for the anti-GBM antibodies (which are typically IgG 1 and 3 but sometimes IgA or IgM) is the NC1 domain of the alpha-3 chain of type IV collagen (alpha-3(IV) chain), one of six genetically distinct gene products found in basement membrane collagen [4,5]. The specific conformational epitopes are localized to the globular NC1 domain of the alpha-3(IV) (and alpha-5) chain [6-8]. These antibodies represent about one percent of the circulating IgG in these patients. Anti-GBM antibodies may also be directed against other alpha chains [9]. Antibodies eluted from the kidneys of patients with Goodpasture's disease were shown to bind most strongly to alpha-3(IV) NC, but the majority also recognized alpha-5(IV) and, to a lesser extent, alpha-4(IV). The kidney bound antibodies recognized the EA and EB epitopes in alpha-3(IV), and the EA epitope in alpha-5(IV). They did not bind native cross-linked alpha-3, 4, 5 hexamers until they were dissociated [10].

The cDNA for the alpha-3(IV) chain was cloned and its chromosomal location identified (q35-37 region of the long arm of chromosome 2) [11,12]. Cells transfected with the alpha-3(IV) chain cDNA make the protein that binds anti-GBM antibodies, thereby proving that the alpha-3(IV) chain is the target antigen in this disorder [13,14].

          

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Literature review current through: Nov 2016. | This topic last updated: Wed Jan 13 00:00:00 GMT+00:00 2016.
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