Goodpasture syndrome is an autoimmune disorder which involves destruction of the glomerular and pulmonary alveolar basement membrane. The glomeruli are part of the filtering apparatus of the nephrons - the tiny units of the kidney. These are coiled loops of capillaries which filter out water and solutes from the blood passing through them. When the basement membrane is damaged by the autoantibodies formed in Goodpasture syndrome, glomerular cell proliferation occurs in response to cell-mediated immune responses, leading to the acute loss of renal function.
In Goodpasture syndrome, antibodies are produced against the body’s own tissue antigens. These then attack a type of collagen in the glomerular basement membrane (GBM) which leads to glomerulonephritis and acute renal failure.
The Autoantigen in Goodpasture Syndrome
Specifically, the autoantibodies target the NC1 domain of the alpha-3 chain of type IV collagen, which is part of three chains that twine together to form the basic unit of the collagen (IV) network which makes up the basement membrane. This type is found in only a few locations in the body, explaining why the disease is specific to these sites. The antigen itself is described as a cryptic antigen, which means it is not exposed to antibodies under normal circumstances.
The collagen alpha chains 3, 4 and 5 form a three-chain unit which joins another identical unit to form the α 345NC1 hexamer. This is the actual site of attack in Goodpasture syndrome. The hexamers form a characteristic network which are so arranged as to prevent the antibodies from coming into contact with the antigen. However, when there is a structural abnormality or damage to the GBM, the cryptic antigen is exposed. Exposure to various risk factors is most likely required to disrupt the network and reveal the antigen.
Causes of Goodpasture Syndrome
The causes of Goodpasture syndrome are not clearly understood, however we are able to name a number ofrisk factors for the development of this condition:
- Males have an eightfold increased risk for this condition
- Viral infections
- Smoking
- Use of hair dyes
- Hydrocarbon fumes
- Metal dust
- Certain drugs such as cocaine
- Presence of some HLA subtypes, especially HLA DRw2, DRB1 1501 AND DRB1 1502
- If one twin develops the syndrome it invariably manifests in the second twin
ANCA and Anti-GBM Disease
There is a consistently strong association between the presence of antineutrophil cytoplasmic antibodies (ANCA) and the occurrence of anti-GBM disease. Researchers have found the presence of ANCA at low levels for years or even decades before diagnosis of disease. This is followed by the onset of low levels of anti-GBM antibodies for up to 3 years before an acute rise. This heralded the development of anti-GBM disease by weeks to months.
This is taken as evidence that ANCA does contribute directly to the pathogenesis of Goodpasture syndrome. One school of thought suggests that these antibodies directly damage the basement membrane, thereby exposing the NC1 domain of the collagen type IV molecule. This triggers the production of anti-GBM antibody. The other is that ANCA suppresses the overactivity of proteolytic enzymes inside the target cell, to alter the level of α3(IV)NC1 antigen presentation, triggering the formation of anti-GBM antibodies.
The production of ANCA at a low but stable level occurs 3 years, on average, before the production of anti-GBM antibodies. this is, in turn, followed by clinical anti-GBM disease 3 or more years later. This may be evidence that chronic vasculitis is one cause of the disease.
The reason for the abrupt increase in anti-GBM antibodies is not clear, but current opinion is that multiple disruptive influences on the basement membrane expose the target antigen, provoking T-cell stimulation. This in turn triggers cell-mediated immune responses, with the migration of macrophages and monocytes into the affected area. The T-cells also activate B-cells to produce autoantibodies against the GBM antigen.
Interaction of Factors in Goodpasture Syndrome
Following a viral infection or hydrocarbon exposure, antigens in target tissues may be mistaken for foreign antigens and attacked, leading to tissue damage. This produces bleeding in the pulmonary alveoli and inflammatory proliferation of the glomeruli.
Thus viral antigens may mimic the GBM antigen (viral mimicry) leading to a rise in the already existing low levels of anti-GBM antibodies, leading to typical manifestations of Goodpasture syndrome. Similarly, trauma, medication-induced damage, and exposure to chemicals such as hydrocarbons and ANCA may all lead to damage to the basement membrane, which triggers anti-GBM antibodies and clinical disease. When there is renal infection coexisting with Goodpasture syndrome, the prognosis for renal injury is always worse, pointing to the importance of other factors interacting with the autoantibodies.
References
Further Reading