Anti-GBM Antibody 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. ^[3]

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. ^[4] 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. ^[5] 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. ^[6] 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. ^[7] 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.

Clustering of new anti-GBM disease cases has been reported since the identification of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). ^[8]  A study reported a 68% increase (P = .026) in anti-GBM disease among the biopsied patients with acute kidney injury/rapidly progressive renal failure compared with the pre-COVID-19 cohort. ^[9]  The exact mechanism by which SARS-CoV-2 triggers anti-GBM antibody disease is unknown. It has been hypothesized that the infection of respiratory cells by the virus leads to inflammation and complement activation, and endothelial injury. Subsequently, unmasking of the previously sequestered epitopes on the alveolar basement membrane leads to formation of autoantigens that stimulate plasma cells to secrete autoantibodies responsible for the development of anti-GBM disease. Anti-GBM disease becomes clinically apparent days to weeks after the acute SARS-CoV-2 infection.

Anti-GBM disease is an autoimmune condition of known pathogenesis but unclear etiology. However, several factors play a permissive role in disease initiation.

• Respiratory infections (eg, influenza) or inhaled toxins (eg, hydrocarbons, gasoline vapors, hypercarbic oxygen, tobacco, hairspray) may trigger pulmonary involvement.

• Factors associated with renal manifestations are renal injury from ischemia, membranous glomerulonephritis, and, possibly, extracorporeal shock-wave lithotripsy. Only 3 cases of anti-GBM disease occurring after lithotripsy have been described, although several million procedures have been performed. Therefore, the number of cases is too small to establish a causative association. However, consider testing for anti-GBM antibodies when patients have declining renal function after lithotripsy.

• Individuals with Alport syndrome lack the Goodpasture epitopes. The transplantation of a kidney from a healthy donor to a patient with an Alport syndrome introduces the Goodpasture epitopes as neoantigens. Approximately 50% of kidney recipients with Alport syndrome develop anti-GBM antibodies; only a few of these patients have graft failure because of anti-GBM disease.

• In a review of 118 male patients with the X-linked dominant form of Alport syndrome, anti-GBM glomerulonephritis developed in only 3 (2.5%). ^[10]  All had a large deletion in the COLA4A5 gene. Sixteen other patients with a large rearrangement in COLA4A5 and 32 with a small mutation that was expected to produce a truncated alpha-5 (type IV collagen) protein lacking the NC1 domain did not develop anti-GBM glomerulonephritis in the graft.

• In some patients, the anti-GBM antibody has immunoblotting characteristics different from those of patients with the primary form of Goodpasture syndrome. These characteristics may result from differences in antigenic expression caused by the interaction of the various alpha chains in the basement membrane. This difference also may explain why the clinical expression of the disease is milder in patients with Alport syndrome than in those with the primary form of Goodpasture syndrome. The low incidence of the syndrome and its mild clinical manifestations make renal transplantation the treatment of choice for patients with Alport syndrome who have end-stage renal disease.

• Anti-GBM antibody disease has a strong positive association with the HLA-DR15 haplotype, particularly the DRB1*1501 allele, which is found in more that 80% of patients with anti-GBM antibody disease. Furthermore, a strong dominant protection from the disease is associated with the expression of DRB1*0701 such that individuals inheriting DRB1*1501 and DRB1*0701 have no higher risk of disease than does the general population. The DRB1*01 allele offers relatively weak protection.

United States statistics

Goodpasture disease is diagnosed in 1-1.5 per million persons each year. ^[11]  It is less common in children, accounting for less than 10% of such cases.

Race-, sex-, and age-related demographics

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.

The prognosis is poor but not uniform. Without treatment, 90% of patients progress to dialysis or die, and only 10% improve. With current therapies, improvement occurs in 50%. Patients who survive the first year with normal renal function have a good long-term prognosis, though late relapses can occur. Several clinical, laboratory, and histologic features have prognostic relevance independent of the type of therapy.

Chronic disease (weeks vs days), a need for dialysis, a serum creatinine level of more than 5 mg/dL, and crescent formation in 50-75% of the glomeruli at the time of diagnosis are associated with a poor outcome. Other histologic findings, including fibrous crescents, widespread necrosis, and tubulointerstitial changes, indicate advanced disease and a high likelihood of progression to renal failure.

Anti-GBM disease is usually non-relapsing. Patients who are antineutrophilic cytoplasmic antibody (ANCA) positive and who have a clinical course resembling that of vasculitis tend to respond well to treatment and recover renal function despite an increased frequency of vasculitic relapses. Those patients may require maintenance immunosuppressive therapy to prevent relapses. ^[12]  

Although untreated disease has a poor prognosis, the use of plasmapheresis, corticosteroids, and cyclophosphamide is effective in treating lung hemorrhage and preserving kidney function. ^[13]

Morbidity/mortality

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.

Complications

Complications of renal failure include hyperkalemia, pulmonary edema, hypertension, and seizures.

Complications of pulmonary hemorrhage include hemorrhagic shock and respiratory failure.

Complications of immunosuppressive medications include infection, avascular bone necrosis, and bone marrow suppression.

Complications of plasmapheresis include infection, bleeding, hypocalcemia, and immunoglobulin deficiency.

Complications of renal transplantation include a recurrence rate of linear immunoglobulin G (IgG) staining in the graft as high as 50%. However, most patients remain asymptomatic, probably because of inhibition of autoantibody production with routine posttransplantational immunosuppression. The risk of graft loss due to recurrent anti-GBM disease is low.

Patients should seek prompt medical attention if symptoms of recurrent renal and/or pulmonary involvement, including cough, bloody sputum, oliguria, discoloration of urine, or edema, develop.

Patients should be informed about their long-term prognosis and the risks of treatment.

Patients should be made aware of known risk factors such as exposure to influenza, cigarette smoke, and inhaled toxins.