Features of Goodpastures Syndrome Introduction Goodpastures syndrome, a rare autoimmune disease is characterized by anti-GBM (anti-glomerular basement membrane) antibodies attacking glomerular and alveolar basement membranes of the kidneys and lungs respectively. It was first reported by Dr. Ernest William Goodpasture in 1919 and first used by Stanton and Tange in 1957 in their case studies involving nine patients with the pulmonary-renal syndrome. [1, 2] Clinical Features à à The onset of this disease ranges from the ages of 20-30 and 60-70 especially in young men in their late twenties or in men and women over sixty years of age study. [3] The diagnostic techniques involved in detection of Goodpastures syndrome include i) urine analysis that detects kidney damage by presence of high number of red blood cells or protein in the urine sample ii) blood tests showing the presence of anti-GBM antibodies iii) x-rays that can show anomalies in lung anatomy or iv) biopsies that involve imaging of a kidney tissue sample to demonstrate glomeruli characterised by crescent-shaped structures and lines of antibodies attached to the GBM. [4] While Goodpastures syndrome constitutes the representation of clinical features like rapidly progressive glomerulonephritis (RPGN) and pulmonary hemorrhage from any cause, Goodpasture disease also includes the presence of anti-GBM antibodies in addition to the other characteristics. The term anti-GBM disease constitutes a patient with the typical autoantibodies, irrespective of clinical symptoms and characteristic features. [1,5] The clinical manifestations associated with Goodpastures syndrome include acute renal failure resulting from rapidly progressive glomerulonephritis along with pulmonary hemorrhage that might prove fatal. The symptoms in relation to it consist of bleeding of lungs, kidney failure, hematuria, proteinuria, general malaise, fatigue, and weight loss. [1,6,7,8,9] The exact etiology of this syndrome is not known however there seem to be genetic and environmental risk factors. The factors being i) exposure to organic solvents or hydrocarbons ii) smoking and drugs iii) infection iv) exposure to metal particulate matter v) lymphocyte-depletion therapy. [1,5,10] The characteristic pathology in individuals experiencing the Goodpastures Syndrome can be detected by immunofluorescence staining technique of the IgG on the GBM that shows smooth diffuse linear patterns. [11] Hemodialysis, plasma exchange, cyclophosphamide drugs and immunosuppressive agents like methylprednisolone pulse therapy or oral administration of prednisolone are possible treatments for Goodpastures syndrome. [12,13,14] Basic Cellular and Molecular Mechanisms The localization of immunoglobulin IgG deposits at sites of inflammation within the pulmonary and renal basement membranes shows Goodpastures syndrome (a form of the anti-GBM disease) to be an antibody-mediated autoimmune disease. The pathogenic role of these antibodies has been confirmed byà transplantation of circulating or kidney-eluted anti-GBM antibodies to Rhesus monkey or human kidney allografts that result in the development of the disease.à A type II hypersensitivity reaction occurs when antibodies are targeted against extracellular matrix (ECM) specific antigens. [15]à The hypersensitivity response affects all organs in the body of which collagen is a constituent but the alveolar and glomerular basement membranes are more prone to the effect. This discrepancy is a result of increased accessibility of epitopes (antigen molecules facilitating attachment to a matching antibody) linked to overexpression of ÃŽà ±3 collagen chains in the respective basement membranes allowing access and formation of antibodies. [16] While ÃŽà ±3NC1 antibodies are the most common in patients with Goodpastures syndrome, ÃŽà ±5NC1 antibodies are less prevalent. Sometimes antineutrophil cytoplasmic antibody [ANCA] can also be present. [5,17] The disorder develops antibodies that target ÃŽà ±3 chain of basement membrane collagen (type IV collagen) present in alveoli in lungs and in the glomeruli that form the filtering units of the kidneys within the nephrons. These structures contain the basement membrane with collagen as its essential component that differentiates the epithelia from the underlying tissue. The conformational epitopes of the Goodpasture antigen are localized within 2 regions in the carboxyl terminal, noncollagenous (NC1) domain of a type IV collagen chain, ÃŽà ±3(IV)NC1. [1, 5, 18]. Upon interaction of the anti-GBM antibodies with the conformational epitope of the GBM glycoproteins, the complement pathway of the immune system gets activated. This results in infiltration by polymorphonuclear leukocytes (PMNs) and monocytes. The severely damaged GBM induces reflux of fibrinogen into the Bowman space, fibrinogen polymerizes to fibrin through the proliferation of procoagulant factors from activated mono cytes, leading to a crescent formation.[19] Goodpastures syndrome is linked with specific HLA types. Both positive (HLA-DR15) and negative (HLA-DR7) associations are defined and being used to develop an understanding of antigen presentation, tolerance and autoimmunity. [20,21,22] Recent Developments Recent developments like the plasmapheresis technique, steroidal drugs, and immunosuppressive therapy have drastically ameliorated the course of the medical condition in comparison to yesteryears, in which Goodpasture syndrome was deemed fatal. [23] Zhao et al., demonstrate the significant role of ÃŽà ±5NC1-specific antibodies in pathogenesis of Goodpastures disease and also re-confirm ÃŽà ±345 collagen IV molecule as the original GP autoantigen. [17] The invention of a drug, now patented, with its active element containing boronà that constitutes inhibitors of arginase activity has claimed remedial effects in the pathological state of Goodpastures Syndrome. [24] A recently developed, patented prophylaxis for glomerulonephritis resulting from Goodpastures syndrome comprises of administration of a therapeutically effective amount of an IL-6 antibody that binds with or regulates the expression or activity of a mammalian IL-6 polypeptide. [25] Conclusions Goodpastures Syndrome is an autoimmune disease characterized by anti-GBM antibodies attacking glomerular and alveolar basement membranes. The innate immune response comprises of (i) cell death; (ii) polymorphonuclear cell releasing neutrophils, basophils, eosinophils, antigens and monocytes to infiltrate the glomerulus. The adaptive immune response triggers the classical pathway of complement activated by antigen-antibody complex formation, and type II hypersensitivity reaction. Here antigens are targeted against cell- specific and tissue specific antigens (chiefly the connective tissue). Unanswered Questions Currently, there is a lot of research focusing on deciphering the causative agents of the harmful antibodies that lead to the development of Goodpastures syndrome. Evidence from this research can lead to novel drug discovery, eventually leading to a potential definitive cure for Goodpastures syndrome. [17] The exact the genetic determinants that constitute the etiology of Goodpastures syndrome are yet to be found. Bibliography Salama AD, Pusey CD. Goodpasture syndrome and other antiglomerular basement membrane diseases. In: Gilbert SJ, Weiner DE, eds. National Kidney Foundations Primer on Kidney Diseases. 6th ed. Philadelphia, PA: Elsevier Saunders; 2014: chap 21. Benoit, F. L., D. B. Rulon, G. B. Theil, P. D. Doolan, and R. H. Watten. Goodpastures syndrome: a clinicopathologic entity. The American journal of medicine 37, no. 3 (1964): 424-444. Hudson B, Tryggvason K, Sundaramoorthy M, Neilson E. Alport syndrome, goodpasture syndrome, and type IV Collagen. New Engl J Med 2003; 348:2543-56. Fervenza, Fernando C. Goodpasture Syndrome | NIDDK National Institute of Diabetes and Digestive and Kidney Diseases. https://www.niddk.nih.gov/health-information/kidney-disease/glomerular-diseases/goodpasture-syndrome (accessed March 1, 2017). Phelps RG, Turner AN. Anti-glomerular basement membrane disease and Goodpasture disease. In: Johnson RJ, Feehally J, Floege J, eds. Comprehensive Clinical Nephrology. 5th ed. Philadelphia, PA: Elsevier Saunders; 2015: chap 24. Lahmer T, Heemann U. Anti-glomerular basement membrane antibody disease: a rare autoimmune disorder affecting the kidney and the lung. Autoimmun Rev 2012;12:169-73. Pedchenko V, Bondar O, Fogo AB, Vanacore R, Voziyan P, Kitching AR, et al. Molecular architecture of the Goodpasture autoantigen in anti-GBM nephritis. N Engl J Med2010;363:343-54. Salant David J. Goodpastures disease new secrets revealed. N Engl J Med 2010; 363:388-91. Dammacco F, Battaglia S, Gesualdo L, Racanelli V. Goodpastures disease: a report of ten cases and a review of the literature. Autoimmun Rev 2013;12:1101-8. Jones, Joanne L., Sara AJ Thompson, Priscilla Loh, Jessica L. Davies, Orla C. Tuohy, Allison J. Curry, Laura Azzopardi et al. Human autoimmunity after lymphocyte depletion is caused by homeostatic T-cell proliferation. Proceedings of the National Academy of Sciences 110, no. 50 (2013): 20200-20205. MD, Edward. Renal Pathology http://library.med.utah.edu/WebPath/RENAHTML/RENAL093.html (accessed March 1, 2017). Greco, Antonio, Maria Ida Rizzo, Armando De Virgilio, Andrea Gallo, Massimo Fusconi, Giulio Pagliuca, Salvatore Martellucci, Rosaria Turchetta, Lucia Longo, and Marco De Vincentiis. Goodpastures syndrome: a clinical update. Autoimmunity reviews 14, no. 3 (2015): 246-253. Bolton, W. Kline. Goodpastures syndrome. Kidney international 50, no. 5 (1996): 1753-1766. Johnson, John P., Walter Whitman, William A. Briggs, and Curtis B. Wilson. Plasmapheresis and immunosuppressive agents in anti-basement25] membrane antibody-induced Goodpastures syndrome. The American journal of medicine 64, no. 2 (1978): 354-359. Rutgers A, Meyers KEC, Canziani G, Kalluri R, Lin J, Madaio MP. High affinity of anti-GBM antibodies from Goodpasture and transplanted Alport patients to 3 (IV) NC1 collagen. Kidney Int. 2000;58:115-122. Kelly, Patrick T., and Edward F. Haponik. Goodpasture syndrome: molecular and clinical advances. Medicine 73, no. 4 (1994): 171-185. Zhao J, Cui Z, Yang R, et al. Anti-glomerular basement membrane autoantibodies against different target antigens are associated with disease severity. Kidney Int 2009; 76:1108. Borza, Dorin-Bogdan, Eric G. Neilson, and Billy G. Hudson. Pathogenesis of Goodpasture syndrome: a molecular perspective. In Seminars in nephrology, vol. 23, no. 6, pp. 522-531. WB Saunders, 2003. Morita, Takashi, Yasunosuke Suzuki, and Jacob Churg. Structure and development of the glomerular crescent. The American journal of pathology 72, no. 3 (1973): 349. Phelps, Richard G., and Andrew J. Rees. The HLA complex in Goodpastures disease: a model for analyzing susceptibility to autoimmunity. Kidney international 56, no. 5 (1999): 1638-1653. Phelps, Richard G., Victoria Jones, A. Neil Turner, and Andrew J. Rees. Properties of HLA class II molecules divergently associated with Goodpastures disease. International immunology 12, no. 8 (2000): 1135-1143. Turner AN, Rees AJ. Anti-glomerular basement membrane disease (Chapter 3.11). In: Cameron SDAM, Grunfeld JP, Kerr DNS, Ritz E, eds Oxford Textbook of Nephrology, 2nd edn. Oxford University Press, Oxford, 1997 Shah MK, Hugghins SY. Characteristics and outcomes of patients with Goodpastures syndrome. South Med J 2002;95:1411-8. Van Zandt, Michael, Adam Golebiowski, Min Koo Ji, Darren Whitehouse, Todd Ryder, and Raymond Paul Beckett. Inhibitors of arginase and their therapeutic applications. U.S. Patent 9,266,908, issued February 23, 2016. Marshall, Diane, and Stevan Shaw. Method for the treatment of glomerulonephritis by administering an IL-6 antibody. U.S. Patent 9,321,837, issued April 26, 2016.