Excerpt from Goodpasture Syndrome

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Background

Goodpasture syndrome is an eponym used to describe the triad of diffuse pulmonary hemorrhage, glomerulonephritis, and circulating anti–glomerular basement membrane (anti-GBM) antibodies.

Goodpasture first described the disorder in 1919. He reported a case of pulmonary hemorrhage and glomerulonephritis during an influenza epidemic. In 1955, Parkin described 3 cases of lung hemorrhage and nephritis that occurred in the absence of arteritis. In 1958, Stanton and Tang reported a series of young men with pulmonary hemorrhage and glomerulonephritis, similar to Goodpasture's original description. The discovery of anti-GBM antibodies in 1967 led to the understanding of the pathogenesis of Goodpasture syndrome.

Goodpasture disease is a term used to describe glomerulonephritis and the presence of circulating anti-GBM antibodies, without pulmonary hemorrhage. Anti-GBM disease, a better term, should be used to refer to either of the 2 distinct clinical manifestations of this disorder.

Pathophysiology

Anti-GBM disease is an autoimmune disorder. The autoantibodies mediate the tissue injury by binding to their reactive epitopes in the basement membranes. This is a classic type II reaction in the Gell and Coombs classification of antigen-antibody reactions. This binding of antibodies can be visualized as the linear deposition of immunoglobulin along the glomerular basement membrane and, less commonly, the alveolar basement membranes, by direct immunofluorescent techniques.

In the 1950s, Krakower and Greenspun identified GBM as the antigen. Later, Lerner, Glassock, and Dixon subsequently confirmed that the antibodies taken from the diseased kidneys produced nephritis in experimental animals.

The principle component of the basement membrane is type IV collagen, which acts as a support structure and is composed of building blocks that are linked end-to-end. The building blocks are composed of 3 alpha subunits of collagen, which form a triple helix. Type IV collagen can be expressed as 6 different chains, alpha1 to alpha6. The alpha chain itself has 3 structural domains, as follows: (1) 7-S domain at the amino terminus; (2) a triple helix of 3 alpha chains, which ends at the carboxyl terminus; and (3) a noncollagenous domain. The classic triple helix is composed of 2 alpha1 chains and 1 alpha2 chain. The Goodpasture antigen has been localized to the carboxyl terminus of the noncollagenous domain of the alpha3 chain of type IV collagen. The antibodies are directed against a 28-kd monomeric subunit present within the noncollagenous domain.

The anti-GBM antibody can usually be found in serum. In some patients, this antibody also reacts with the pulmonary alveolar basement membrane and causes alveolar hemorrhage. The basement membranes are complex structures that support layers of endothelium and epithelium. The circulating anti-GBM antibodies react with an epitope contained within the basement membranes. Although basement membranes are ubiquitous, only the alveolar and glomerular basement membranes are affected clinically. The preferential binding to the alveolar and glomerular basement membranes appears to be caused by greater accessibility of epitopes and greater expansion of alpha3 collagen units. Furthermore, the alpha3 collagen chains of glomerular and basement membranes are structurally integrated in such a way that they become more accessible to the circulating antibodies.

Under normal conditions, the alveolar endothelium is a barrier to the anti–basement membrane antibodies. However, with increased vascular permeability, antibody binding to the basement membrane occurs in the alveoli. Therefore, for the deposition of antibody, an additional nonspecific lung injury that increases alveolar-capillary permeability is required. These factors include increased capillary hydrostatic pressure, high concentrations of inspired oxygen, bacteremia, endotoxemia, exposure to volatile hydrocarbons, upper respiratory infections, and tobacco smoking.

Strong evidence exists that genetics play an important role. Patients with specific human leukocyte antigen (HLA) types are more susceptible to disease and may have a worse prognosis. Patients with Goodpasture disease have an increased incidence of HLA-DR2 compared to control populations. The association is caused by an excess of the haplotype bearing DR-W 15. In addition, HLA-B7 is found more frequently and is associated with more severe anti-GBM nephritis. The exact role of these genetic findings in the pathogeneses of disease is not clear.

Sophisticated immunologic and molecular techniques have shown that immune response against Goodpasture autoantigen and syntheses of autoantibodies depend not only on the association of antigen with HLA molecules but also on how fragments of the antigen are handled by antigen-processing cells, such as B lymphocytes, monocytes and macrophages, and dendritic cells. Recent reports have shown that presentation of Goodpasture autoantigen to CD4 T lymphocytes, which is strongly associated with HLA-DR 15 alloantigen, is largely dependent on the ability of antigen antigenic epitopes to be processed and is less clearly dependent on the binding affinity to the DR-15 molecule.

Frequency

United States

Anti-GBM disease is an uncommon disorder; approximately 1-2% of all cases of rapidly progressive glomerulonephritis are secondary to this disorder.

International

In 1984, the incidence in England was 0.5 cases per million people per year, occurring over a 4-year period. This disorder, compared to Wegener granulomatosis, which has an incidence of approximately 0.5 cases per 100,000 people, is rare.

Mortality/Morbidity

In the past, the disease was almost universally fatal. Currently, the mortality rate is approximately 10%. However, most patients who survive progress to end-stage renal disease (ESRD).

Race

Anti-GBM disease occurs more commonly in white people than in black people, but it also may be more common in certain ethnic groups, such as the Maoris of New Zealand.

Sex

Incidence shows a male predominance, with the male-to-female ratio reported as 2-9:1.

Age

Distribution is bimodal. Young men present with a pulmonary-renal syndrome at ages 20 and 30 years, and elderly women (ie, aged 60-70 y) present primarily with glomerulonephritis.

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