Goodpasture Syndrome- A Condition affecting One in every Million

Priasha Dutta, Amity University Kolkata, West Bengal

A very rare and life-threatening autoimmune disease, Goodpasture syndrome (GPS) was discovered in 1919 by Dr. Ernest Goodpasture when he reported a case of bleeding in the lungs and glomerulonephritis during an influenza epidemic. Its rate of occurrence is 1 out of 1 million per year. This disorder causes the build-up of autoantibodies in the basement membrane of kidneys and lungs that leads to pulmonary hemorrhage, kidney failure, and glomerulonephritis. Thus, it is also referred to as anti-glomerular basement membrane (anti-GBM) disease. 

Cause 

GPS does not have much clarity about its cause. A strong association has been shown between GPS and the human leukocyte antigen (HLA) system. This system helps in human immunity by determining the difference between self and non-self antigens. HLA-DR15 is one such HLA located in about 88% of people affected by GPS. The high prevalence of these alleles within the diagnosed individuals shows a potential genetic predisposition for this disease. However, some alleles involved with the HLA system are common among unaffected populations, suggesting that there are additional factors are involved in the development of GPS. A study released in 2016 investigated spatial and temporal clustering of cases, implying that the presence of environmental factors may contribute to initiating the disease. 

Certain environmental factors or exposure to tobacco smoke and powdered drugs, chloroform fumes, metallic dust, high-oxygen environments, bacteremia, etc. are some probable causes. Antilymphocyte therapies (especially with monoclonal antibodies) can trigger specific respiratory infections which, in turn, provokes the immune system. Exposure to dry cleaning chemicals and the weed killer brand “Paraquat” has also proven to be activators. Some pre-existing damage to the alveolar lining can allow the increased permeability that further eases the access for autoantibodies. Binding can then occur on the epitopes on the self-antigens of membranous subunits, further activating cascade reactions that result in injury to the lining. 

Pathophysiology 

GPS is caused by anomalous plasma cell production of anti-GBM antibodies which belong under the class of IgG antibodies. Their major target is the non-collagen domain of the alpha-3 chain of type 4 collagen, usually found in the basal membranes of alveolar and glomerular capillaries. This molecule contains two epitopes, EA and EB, where antibodies bind and allow T-cell recognition to initiate a humoral immune response. This is also called the self-antigen, which triggers the autoimmune response in GPS after antibody binding starts. Specific binding of antibodies to the alveolar basement membrane is enabled by the epitopes on self-antigens and the arrangement of collagen chains, thus allowing easy access to the traveling antibodies.

In a healthy individual, the alveolar endothelium provides a protective barrier so that the anti-GBM antibodies are unable to bind to the epitopes. But because of its increased permeability (from either increased capillary hydrostatic pressure or environmental factors like smoking, hydrocarbon exposure, or an alveolar infection), antibodies can more efficiently bind to the epitope units present in the collagen domains of the basement membrane. This binding activates the cascade of reactions that lead to the death of the cells. Damage to the collagenous structure in the alveolar basement membrane destroys the surrounding alveolar capillaries, causing mass hemorrhage into the alveolar space. Hemoptysis and anemia may develop later. Gradually, oxygenation for blood that was traveling throughout the pulmonary circulation can no longer occur. This can lead to alveolar collapse, resulting in hypoxemia. In more severe cases, the result is respiratory failure and death.

Diagnosis and Symptoms

Diagnosis of Goodpasture syndrome involves the results from serology tests for the detection of anti-GBM autoantibodies. Renal biopsy and chest X-ray give indications of the damages to the kidneys and lungs respectively. Other tests, such as respiratory function testing and bronchoscopy but may be used to show signs of hemorrhage in the lungs. The disease can progress rapidly and be fatal if identification and subsequent treatment are delayed. Correct results must therefore be quickly obtained to guarantee the best possible outcome for the affected person.

The most significant symptom of GPS is coughing up specks to large volumes of blood as a result of alveolar or pulmonary hemorrhage leading to hemoptysis. Around 80%-90% of patients present with rapidly advancing glomerulonephritis. Dyspnea, chest pain, hematuria, and proteinuria are experienced by the most affected individuals. Approximately 60%-80% of patients with GPS develop both pulmonary and renal disease. 

Treatment

Treatment for GPS comprises of three goals: swift removal of autoantibodies from circulation, prevention of any further autoantibody production, and removal of other potentially harmful agents that are produced from the initial immune response. Several treatment options usually target the anti-GBM antibodies that destroy the alveolar and glomerular basement membrane. Starting therapy despite a negative result for anti-GBM antibodies is still important, as delay can lead to the progression of the disease. Further severe stages may require dialysis and organ transplantation. Following are the two measures of treatment for GPS-

1. Plasmapheresis- The function of plasmapheresis is to remove unwanted toxins like the anti-GBM antibodies from the blood, thus reducing the risk of an autoimmune response in the alveoli. In this procedure, blood is removed from the patient and the plasma is separated from the cellular elements. Donated human plasma is replaced in the patient’s infected plasma. Then the blood with the donated plasma is transfused back into the patient. If a bleeding risk occurs after pulmonary hemorrhage or renal biopsy in patients, fresh frozen plasma is added to keep coagulation at normal levels. Plasma exchanges of around four liters for 2-3 weeks are performed daily till anti-GBM antibodies are not detected anymore.
2. Immunoadsorption- Often accompanying the process of plasmapheresis, immunoadsorption is another method of serum-antibody removal. Apart from GPS, it is used for several autoimmune diseases that involve antibody-mediated rejection. Immunoadsorption is an ideal therapy in GPS due to its high-affinity binding of different IgG antibodies and redundancy of fresh plasma. With this technique, more than 98% of IgG can be cleared after numerous sessions.
3. Immunosuppression- The prevention of ongoing anti-GBM antibody production is achieved by using immunosuppression drugs such as corticosteroids. It can also prevent rebound hypersynthesis of antibodies after plasmapheresis ends. Reduction of the body’s immune response decreases the activity of circulating antibodies, including the anti-GBM antibodies. This helps to lower the possibility of autoantibody-induced destruction of the basement membranous structure in the glomeruli and alveoli. However, the reduction in the body’s ability to produce an immune response increases the possibility of contracting viral and bacterial infections. There are also many side effects of this treatment, including interstitial pneumonitis, erythrocyte aplasia, and thrombocytopenia can occur. Thus, the consumption and dosage of immunosuppressive drugs must be planned and monitored carefully. 

Despite its rarity, Goodpasture syndrome has become increasingly better understood over the years. Except for fatal cases, effective patient management is usually achieved. Alternate methods of treatment are being researched and undergoing trials to improve therapy efficacy. Research in the type IV collagen family, the main target of the antibodies, is also being conducted for the further molecular understanding of the pathogenesis and progression. Soon, we may see significant changes to approaching disease management and improving patient recovery.

Also read: Microbial community fitness boost: Adaptive laboratory evolution

References :

1. Shield, J. (2021). Goodpasture syndrome: An investigation of disease process, diagnosis, treatment, and contribution to intrapulmonary hemorrhage. Butler Journal of Undergraduate Research, 7(1). https://digitalcommons.butler.edu/bjur/vol7/iss1/16  
2. Betsy, J., Anuradha, P., Jayakrishnan, S., & Ajith, B. (2019). “Goodpasture’s syndrome: An autoimmune conformational disease.” Journal of Pharmaceutical Research Asia, 9(3), 172–176. https://doi.org/0.5958/2231-5691.2019.00027.3
3. Canney, M., O’Hara, P., McEvoy, C., Medani, S., Connaughton, D., & Little, M. (2016). “Spatial and temporal clustering of anti-glomerular basement membrane disease.” Clinical Journal of the American Society of Nephrology, 8(11), 1392–1399. https://doi.org/10.2215/CJN.13591215
4. Chung, J. (2019). Goodpasture syndrome (anti-basement membrane antibody disease). In C. Walker (Ed.), Muller’s imaging of the chest e-book: Expert radiology series (2nd ed., pp. 606–611). https://wwwclinicalkey-com-au.ezproxy.library.uq.edu.au/#!/content/book/3-s2.0-B9780323462259000471

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