Anti-GBM Antibody Disease

Updated: May 28, 2014
  • Author: Agnieszka Swiatecka-Urban, MD, FASN; Chief Editor: Craig B Langman, MD  more...
  • Print


Anti–glomerular basement membrane (anti-GBM) antibody disease is a rare autoimmune disorder in which circulating antibodies are directed against an antigen normally present in the GBM and alveolar basement membrane. The target antigen is the alpha-3 chain of type IV collagen. The resultant clinical syndrome encompasses a spectrum ranging from mild or no renal involvement to rapidly progressive glomerulonephritis. [1]

Many patients develop pulmonary hemorrhage, and most individuals have signs of a generalized systemic illness. The combination of glomerulonephritis and pulmonary hemorrhage is commonly referred to as Goodpasture syndrome. Pulmonary and/or renal manifestations can be encountered in various conditions, such as antineutrophilic cytoplasmic antibody (ANCA)–positive vasculitis and other autoimmune disorders. As a consequence, the identification of anti-GBM antibodies in the patient's serum or tissues is of paramount importance in the diagnosis of Goodpasture disease.

In this article, Goodpasture disease and anti-GBM disease are used synonymously and refer to the presence of anti-GBM antibodies in tissues (eg, kidney, lungs, or both), independent of clinical manifestations. Goodpasture syndrome refers to clinically evident glomerulonephritis, pulmonary hemorrhage, or both in a patient with Goodpasture disease.



Type IV collagen is a polymeric structure. The basic monomer of this network is a triple-helical molecule composed of 3 alpha chains (ie, alpha-3, alpha-4, and alpha-5). Each chain is characterized by a long collagenous domain interrupted by short noncollagenous sequences, a noncollagenous amino terminus, and a long noncollagenous domain (NC1) at the carboxyl terminus. The Goodpasture antigen is the carboxyl terminal, noncollagenous domain of the alpha-3 chain of type IV collagen (alpha-3[IV]NC1); it interacts with noncollagenous domains of the alpha-4 and alpha-5 chains to form the alpha-3.alpha-4.alpha-5(IV) triple helical molecule known as promoter, which, in turn, dimerizes to form a hexameric structure that is extensively crosslinked. Formation of the resilient alpha-3.alpha-4.alpha-5(IV) network is essential for the proper function of the basement membrane. [2]

Anti-GBM antibodies are almost exclusively of the immunoglobulin G (IgG) isotype. The principal targets for anti-GBM antibodies are two adjacent, conformational disulfide-bond–dependent regions in the NC1 domain of the alpha-3 chain of type IV collagen. These regions are called the Goodpasture epitopes. [3] The epitopes, designated EA and EB, are located in the NC1 domain at the amino acid residues 17-31 and 127-141, respectively. The anti-GBM antibodies can target the EA and EB epitope separately. The Goodpasture epitopes are structurally sequestered by the adjacent alpha-4(IV)NC1 and alpha-5(IV)NC1 molecules.

Investigation of the cryptic nature of the Goodpasture epitopes revealed 2 types of alpha-3.alpha-4.alpha-5(IV) hexamers: the autoantibody reactive M-hexamers and the autoantibody impenetrable D-hexamers. [4] The more abundant D-hexamers have dimer-reinforced crosslinks between NC1 domains that help to retain the cryptic nature of the Goodpasture epitopes, whereas the less abundant M-hexamers, composed of only monomeric subunits, allow epitope unmasking and antibody binding under inflammatory states. Thus, differences of the alpha-3(IV)NC1 monomer-dimer composition in the alveolar basement membrane observed between individuals may explain why some patients with Goodpasture syndrome do not develop pulmonary disease.

Differential susceptibility to anti-GBM disease in humans is strongly linked to class II major histocompatibility complex (MHC II). In addition, anti-GBM disease has a strong positive association with the human leukocyte antigen (HLA)–DR15 haplotype, particularly the DRB1*1501 allele, which is found in more that 80% of patients with anti-GBM disease. In contrast, strong dominant protection from the disease is associated with the expression of DRB1*0701, such that the risk of disease is the same in individuals inheriting DRB1*1501 and DRB1*0701 and in the general population.

The DRB1*0101 allele offers relatively weak protection. Exactly how the expression of the DR molecules determines differences in a person's susceptibility to anti-GBM disease is not well understood. The dominant protection is not due to inefficiency in the presentation of peptides because the DRB1*0101 and DRB1*0701 molecules bind the common human T-cell epitopes with higher affinity.

The T cells from patients with anti-GBM antibody disease recognize 2 epitopes located in regions that are highly susceptible to antigen processing by endosomal proteases; under normal conditions, these epitopes are destroyed by antigen-presenting cells before they are able to induce thymic deletion of potentially pathogenic T cells. The key candidate epitope in the pathogenesis of anti-GBM antibody disease overlaps with the EB region and binds with high affinity to the disease associated HLA-DRB1*1501 MHC II molecule. The key stimulatory candidate epitope has been mapped to a region that has the ability to stimulate Goodpasture T-cells to proliferate and secrete interferon (IFN)-gamma.

As with other autoimmune disease, incomplete central tolerance to alpha-3(IV)NC1 is thought to play a role in the anti-GBM antibody disease. Alpha-3(IV)NC1 is expressed in the thymus; however, CD4+ cells escape thymic deletion and participate in the anti-GBM antibody disease. Normal individuals have been shown to have low titers of antibodies to alpha-3(IV)NC1 and the alpha-3(IV)NC1 responsive naive T-cells. [5] Furthermore, low titers of antibodies to additional GBM components, particularly the NC1 domain of other collagen chains, are present in some anti-GBM sera. However, whether they represent an epiphenomena or whether they have a pathogenic importance remains unknown.

Delayed-type hypersensitivity–like cell mediated immunity may play a role in the pathogenesis of anti-GBM disease. Compelling experimental data suggest that T cells may have an indirect role in facilitating the anti-GBM antibody production by B cells and that they may also cause direct injury to the glomerulus and alveoli. In contrast, regulatory CD25+T-cells may attenuate the glomerular injury. [6] Some observations in humans strongly suggest that the T-cell–mediated mechanisms may play a similar role in human anti-GBM antibody disease. These observations demonstrate that the development of "self-immunoregulation" and the re-establishment of tolerance in the convalescent phase of the disease coincides with the emergence of the regulatory CD25+T-cells. Furthermore, depletion of regulatory CD25+T-cells from convalescent patients increases the number of Goodpasture antigen-specific IFN-gamma–producing cells.

The limited tissue involvement in anti-GBM disease results from the tissue-specific distribution of the alpha-3 chain of type IV collagen, the specificity of the anti-GBM antibodies, and the accessibility of the Goodpasture epitopes in the glomerular and alveolar capillaries. The alpha-3 chain of type IV collagen is expressed in the basement membranes of the glomerulus, alveoli, choroid plexus, eye, cochlea, and testis. The prevalence of renal involvement in anti-GBM antibody disease may result from the unique structure of the glomerular capillaries that allows circulating antibodies to access the GBM.

Other organs expressing the Goodpasture epitopes, with the exception of the lung, are not obviously affected, presumably because of the limited access of the anti-GBM antibodies to the basement membrane or because of other regulatory mechanisms. Pulmonary hemorrhage is associated with factors that affect the integrity of lung capillaries and allow the anti-GBM antibodies to contact the alveolar basement membrane. Examples of such factors are respiratory infections, smoking, or inhalation of toxins.




United States

Goodpasture disease is diagnosed in 1 per million persons each year. In adults, anti-GBM disease is responsible for approximately 5% of all cases of glomerulonephritis and is diagnosed in 1-2% of renal biopsy specimens. Anti-GBM glomerulonephritis accounts for 20% of all cases of rapidly progressive glomerulonephritis in adults and for less than 10% of such cases in children.


In untreated patients, the disease usually progresses to renal failure or death. Treated patients have a significant risk of morbidity and mortality from renal failure, pulmonary hemorrhage, or complications of treatment. With current therapy, more than 90% of patients survive the acute phase of the disease. However, the 2-year survival rate is less than 50%.

End-stage renal disease develops in 40-70% of patients who have nephritis mediated by anti-GBM antibodies and accounts for 10-15% of all cases of end-stage renal disease in the United States.


Anti-GBM antibody disease is reported in all racial groups but is primarily a disease of white populations. According to one review, 83% of cases in which race was identified occurred in whites.


The frequency distribution shows a male-female ratio of 3:2.


The disease can manifest in persons of any age. However, a bimodal distribution is noted, with the first peak at approximately age 30 years and a second peak at 60 years. The youngest reported patient with anti-GBM disease was an 11-month-old girl.