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Clustering of anti-GBM disease: clues to an environmental trigger? Dr Stephen P McAdoo & Prof Charles D Pusey Renal and Vascular Inflammation Section, Department of Medicine, Imperial College London, London UK; Vasculitis Clinic, Hammersmith Hospital, Imperial College Healthcare National Health Service Trust, London UK. Correspondence: Dr Stephen P. McAdoo, Renal and Vascular Inflammation Section, Department of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W112 0NN. Email: [email protected] Running Title: Clustering of anti-GBM disease Keywords: Anti-GBM disease; Goodpasture’s syndrome; ANCA; epidemiology and outcomes Words: 1604; References: 28 Disclosures: The authors declare no financial conflicts of interest related to this work. Acknowledgements: SPM is in receipt of a National Institute for Health Research (NIHR) Clinical Lectureship. We acknowledge support of the Imperial NIHR Biomedical Research Centre. The classical paradigm of autoimmune disease pathogenesis describes the role of an environmental insult, to a genetically predisposed individual, that results in miscommunication between the innate and adaptive immune systems, breakdown of tolerance, and the recognition of self-antigens as the target of a damaging immunological response. This paradigm is perhaps best exemplified by the interaction of HLA genotype and smoking, in the development of autoantibodies to citrullinated peptides and the onset of rheumatoid arthritis1. It is assumed that similar pathogenic mechanisms are involved in other autoimmune diseases, though few are so well delineated as in this example. In anti-GBM disease, the components of the aberrant adaptive immune response that are involved in disease pathogenesis are clearly described, such as pathogenic auto-antibodies, directed to a well-defined auto-antigen, supported by a population of auto-reactive T cells2,3. The putative environmental triggers, however, and how they interact with the known genetic determinants of disease susceptibility, to initiate this aberrant response, are not fully understood. These genetic determinants of anti-GBM disease are increasingly well described. Whilst there has not been an undirected genetic survey, such as a genome wide association study, perhaps reflecting the overall rarity of anti-GBM disease, targeted genetic analysis has been informative. Polymorphisms in certain non-HLA genes, such as those encoding Fcγ receptors, are associated with disease susceptibility4,5, consistent with the contribution of pathogenic autoantibodies in mediating organ damage, whereas polymorphisms in COL4A, the gene encoding the target auto-antigen, have been excluded from playing a significant role6. Better characterised are the HLA associations of anti-GBM disease, with 80% of patients inheriting an HLA-DR2 haplotype. Genotyping studies have identified a hierarchy of associations with particular DRB1 alleles: DRB1*1501, DRB1*03 and DRB1*04 are positively associated with disease, whereas DRB1*01 and DRB1*07 appear to confer a dominantnegative protective effect7. These susceptibility alleles, however, are associated with other autoimmune diseases (such as multiple sclerosis and Sjogren’s syndrome) and they are common in most populations, whilst anti-GBM disease remains exceptionally rare, highlighting the importance of other factors, including environmental exposures, in the development of this specific condition. Previous reports of ‘clustering’ or ‘outbreaks’ of anti-GBM disease8, and of seasonal variations in disease incidence9, support a role for environmental factors, such as infection, in triggering disease onset, though they are limited to anecdotal observation. The report of Canney and colleagues in this edition of CJASN is the first to assess geographical or temporal clustering using formal statistical methods, in a national cohort of patients10. In this well-designed study, the authors have systematically identified all anti-GBM disease cases in Ireland over an 11 year period by screening results from referral immunology laboratories and interrogating a national renal histopathology database. This has allowed them to define, for the first time, a national incidence rate for this rare condition. This rate is higher than previous estimates in other European populations, which, as discussed by the authors, most likely reflects the methodological inadequacies of previous studies that were prone to ascertainment bias and the inability to accurately define at-risk populations. It might also reflect the moderate over-representation of the DR2 haplotype and DRB1 risk alleles in the Irish population11, or perhaps a genuine increase in the frequency of antiGBM disease in recent years compared to historical cohorts. The study, in addition, has employed variable-window scan-statistic and Bayesian spatial modelling methods to identify both temporal and geographical clustering of cases, respectively. These formal statistical methods confirm the prior anecdotal experience of many other authors. Notably, some differences in disease phenotype were observed in the two clusters. It is striking, for example, that the temporal cluster had a very high prevalence of positivity for anti-neutrophil cytoplasm antibodies (ANCA), found in over 70% of patients, particularly in view of the strict diagnostic criteria used by the investigators that excluded patients who had overt clinical features of vasculitis. Double-positivity for ANCA and anti-GBM antibodies is a well-recognised phenomenon, with previous studies estimating that approximately 30% of patients with anti-GBM disease have a concurrent ANCA12, consistent with overall prevalence reported in the entire Irish cohort. That the temporal cluster had an overrepresentation of ANCA suggests that a different disease mechanism may be acting in these patients, or as the authors suggest, that the disease may present variably in different sub-populations. This is perhaps in keeping with other recent reports that have identified ‘atypical’ presentations of anti-GBM disease, such as those associated with IgG4 anti-GBM antibodies13, or with what might be termed ‘idiopathic linear immunoglobulin deposition’14, and illustrates the challenges in reliably characterising the full phenotypic spectrum of a very rare disorder. Of greater significance, the identification of these disease clusters also supports a role for an environmental trigger in anti-GBM disease. A number of such environmental triggers have been suggested previously. Perhaps best known is the association of cigarette smoking with the development of lung haemorrhage15. Inhalation of hydrocarbons has also been associated with anti-GBM disease16, and an interesting report of identical twins who both developed anti-GBM disease following hydrocarbon exposure supports a link between genetics and environmental factors17. It is hypothesised that localised airway inflammation induced by smoking or inhaled hydrocarbons may disrupt the architecture of the alveolar basement membrane, revealing usually sequestered epitopes in type IV collagen, and thus permitting access to pathogenic autoantibodies. Whether these factors have a role in the initiation of the autoimmune response per se, however, is not so clear. A similar process of ‘conformational transition’ of the auto-antigen within the kidney has been suggested to account for the association of anti-GBM disease with other glomerular lesions (such as ANCA-associated glomerulonephritis and membranous nephropathy) and lithotripsy for renal stones, that may disrupt the quaternary structure of glomerular basement membrane18. These associations with smoking and other specific diseases, however, are not likely to account for the clustering of diseases that has been confirmed in this study. Some of the early series reported a seasonal variation in disease incidence, with peaks in spring and early summer which, in the absence of any reported association with atopy, suggest an infectious trigger9. It is of historical interest that Ernest Goodpasture’s original description of glomerulonephritis associated with alveolar haemorrhage was in the context of the influenza outbreak of 1919, though it is not clear whether his patient had genuine anti-GBM disease19. There are somewhat more recent reports of disease outbreaks associated with influenza virus, such a series of four cases presenting during an influenza A2 epidemic in the early 1970s, though in these cases confirmatory virologic or serologic evidence of infection was not demonstrated20. There are a small number of additional, isolated cases where influenza infection was serologically confirmed, reported in the same era21,22. Other specific infectious associations with antiGBM disease, however, have not been reported, and the precise mechanisms via which infection might initiate disease are not defined. It is conceivable that non-specific inflammation at the time of respiratory or systemic infection may result in the release of sequestered epitopes in the lung or kidney, akin to the mechanisms implicated for smoking in the induction of disease. Alternatively, T or B lymphocytes that are auto-reactive to GBM antigens (the presence of which are confirmed in healthy individuals23-25) may undergo ‘bystander activation’ at the time of intercurrent infection, thus initiating anti-GBM disease. More specific molecular mechanisms may also be at work, and observations in a commoner form of crescentic glomerulonephritis - that associated with ANCA - may be informative. A variant ANCA type, directed against LAMP2, a human protein that bears a high degree of homology to FimH, a protein expressed in fimbriated gram negative bacilli, has been identified in human patients with AAV, and is purported to arise via a process of molecular mimicry following bacterial infection 26. It has also been shown that certain Staphylococcus aureus peptides bear high homology to complementary PR3, and it is thus suggested that anti-PR3 antibodies may arise via a process of idiotype-anti-idiotype interactions following Staphylococcal infection27. Whilst there are no specific mechanisms suggested for the infectious induction of anti-GBM antibodies, it is notable that comparable idiotype-anti-idiotype interactions have recently been described in the induction of experimental anti-GBM disease in a rodent model28. The authors of the present study do not comment on the potential infective, occupational or other environmental exposures that may have initiated disease in their cohort, and exploring these features in more detail may be informative in the future. In addition, analysis of concurrent patterns of infectious disease, such as influenza, in the general population during the study period might be considered. It may also be of interest to determine the pattern of disease in the adjacent six counties of Northern Ireland, particularly in view of the shared border with the spatial cohort of cases they have described in Donegal, as this may identify additional cases in the same region, and further opportunity to identify shared exposures in a larger cohort of cases. This study is notable for being the first to accurately determine the frequency of anti-GBM disease in any country, and the authors are to be commended on their collaborative approach, that enabled capture of systematically identified and strictly defined cases at a national level, and their thoughtful use of statistical methodology to identify disease clusters over time and by geographical region. The challenge now is to determine how these data can be utilised to identify putative environmental factors that trigger disease and may account for these clusters, and how these factors interact with known (or yet to be identified) genetic determinants to initiate disease. This might then allow the development of early detection, preventative or more targeted treatment strategies for this rare but potentially devastating condition, and other comparable renal and autoimmune disorders with a presumed environmental trigger. References 1. Mahdi H, Fisher BA, Kallberg H, et al. Specific interaction between genotype, smoking and autoimmunity to citrullinated alpha-enolase in the etiology of rheumatoid arthritis. Nat Genet. 2009;41(12):1319-1324. 2. Pusey CD. Anti-glomerular basement membrane disease. Kidney international. 2003;64(4):1535-1550. 3. McAdoo SP, Pusey CD. Anti-glomerular Basement Membrane Disease. In: Mackay IR, Rose NR, Diamond B, Davidson A, eds. Encyclopedia of Medical Immunology: Autoimmune Diseases. New York, NY: Springer New York; 2014:50-56. 4. Zhou XJ, Lv JC, Bu DF, et al. Copy number variation of FCGR3A rather than FCGR3B and FCGR2B is associated with susceptibility to anti-GBM disease. International immunology. 2010;22(1):45-51. 5. Zhou XJ, Lv JC, Yu L, et al. FCGR2B gene polymorphism rather than FCGR2A, FCGR3A and FCGR3B is associated with anti-GBM disease in Chinese. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association European Renal Association. 2010;25(1):97-101. 6. Persson U, Hertz JM, Carlsson M, et al. Patients with Goodpasture's disease have two normal COL4A3 alleles encoding the NC1 domain of the type IV collagen alpha 3 chain. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2004;19(8):2030-2035. 7. Fisher M, Pusey CD, Vaughan RW, Rees AJ. Susceptibility to anti-glomerular basement membrane disease is strongly associated with HLA-DRB1 genes. Kidney international. 1997;51(1):222-229. 8. Williams PS, Davenport A, McDicken I, Ashby D, Goldsmith HJ, Bone JM. Increased incidence of anti-glomerular basement membrane antibody (anti-GBM) nephritis in the Mersey Region, September 1984-October 1985. Q J Med. 1988;68(257):727-733. 9. Savage CO, Pusey CD, Bowman C, Rees AJ, Lockwood CM. Antiglomerular basement membrane antibody mediated disease in the British Isles 1980-4. British medical journal. 1986;292(6516):301-304. 10. Canney. Spatial and temporal clustering of anti-glomerular basement membrane disease. CJASN. 2016. 11. Gonzalez-Galarza FF, Christmas S, Middleton D, Jones AR. Allele frequency net: a database and online repository for immune gene frequencies in worldwide populations. Nucleic Acids Res. 2011;39(Database issue):D913-919. 12. Levy JB, Hammad T, Coulthart A, Dougan T, Pusey CD. Clinical features and outcome of patients with both ANCA and anti-GBM antibodies. Kidney international. 2004;66(4):15351540. 13. Ohlsson S, Herlitz H, Lundberg S, et al. Circulating anti-glomerular basement membrane antibodies with predominance of subclass IgG4 and false-negative immunoassay test results in anti-glomerular basement membrane disease. American journal of kidney diseases : the official journal of the National Kidney Foundation. 2014;63(2):289-293. 14. Nasr SH, Collins AB, Alexander MP, et al. The clinicopathologic characteristics and outcome of atypical anti-glomerular basement membrane nephritis. Kidney international. 2016;89(4):897-908. 15. Donaghy M, Rees AJ. Cigarette smoking and lung haemorrhage in glomerulonephritis caused by autoantibodies to glomerular basement membrane. Lancet. 1983;2(8364):1390-1393. 16. Bombassei GJ, Kaplan AA. The association between hydrocarbon exposure and antiglomerular basement membrane antibody-mediated disease (Goodpasture's syndrome). American journal of industrial medicine. 1992;21(2):141-153. 17. D'Apice AJ, Kincaid-Smith P, Becker GH, Loughhead MG, Freeman JW, Sands JM. Goodpasture's syndrome in identical twins. Annals of internal medicine. 1978;88(1):61-62. 18. Pedchenko V, Bondar O, Fogo AB, et al. Molecular architecture of the Goodpasture autoantigen in anti-GBM nephritis. The New England journal of medicine. 2010;363(4):343354. 19. Goodpasture E. The significance of certain pulmonary lesions in relation to the etiology of influenza. Am J Med Sci. 1919;158:863-870. 20. Perez GO, Bjornsson S, Ross AH, Aamato J, Rothfield N. A mini-epidemic of Goodpasture's syndrome clinical and immunological studies. Nephron. 1974;13(2):161-173. 21. Wilson CB, Smith RC. Goodpasture's syndrome associated with influenza A2 virus infection. Annals of internal medicine. 1972;76(1):91-94. 22. Wilson CB, Dixon FJ. Anti-glomerular basement membrane antibody-induced glomerulonephritis. Kidney international. 1973;3(2):74-89. 23. Cui Z, Zhao MH, Segelmark M, Hellmark T. Natural autoantibodies to myeloperoxidase, proteinase 3, and the glomerular basement membrane are present in normal individuals. Kidney international. 2010;78(6):590-597. 24. Zou J, Hannier S, Cairns LS, et al. Healthy individuals have Goodpasture autoantigenreactive T cells. Journal of the American Society of Nephrology : JASN. 2008;19(2):396-404. 25. Salama AD, Chaudhry AN, Ryan JJ, et al. In Goodpasture's disease, CD4(+) T cells escape thymic deletion and are reactive with the autoantigen alpha3(IV)NC1. Journal of the American Society of Nephrology : JASN. 2001;12(9):1908-1915. 26. Kain R, Exner M, Brandes R, et al. Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis. Nature medicine. 2008;14(10):1088-1096. 27. Pendergraft WF, 3rd, Preston GA, Shah RR, et al. Autoimmunity is triggered by cPR-3(105201), a protein complementary to human autoantigen proteinase-3. Nature medicine. 2004;10(1):72-79. 28. Reynolds J, Preston GA, Pressler BM, et al. Autoimmunity to the alpha 3 chain of type IV collagen in glomerulonephritis is triggered by 'autoantigen complementarity'. Journal of autoimmunity. 2015;59:8-18.