Clustering of Anti-GBM Disease: Clues to an Environmental Trigger?
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Editorial Clustering of Anti-GBM Disease: Clues to an Environmental Trigger? Stephen P. McAdoo*† and Charles D. Pusey*† Clin J Am Soc Nephrol 11: 1324–1326, 2016. doi: 10.2215/CJN.05580516 The classic paradigm of autoimmune disease patho- importance of other factors, including environmental fi *Renal and Vascular genesis describes the role of an environmental insult exposures, in the development of this speci c condi- Inflammation Section, to a genetically predisposed individual, which results tion. Previous reports of clustering or outbreaks of Department of in miscommunication between the innate and adaptive anti-GBM disease (8) and seasonal variations in disease Medicine, Imperial immune systems, breakdown of tolerance, and the rec- incidence (9) support a role for environmental factors, College London, London, United ognition of self-antigens as the target of a damaging such as infection, in triggering disease onset, although Kingdom; and immunologic response. This paradigm is perhaps best they are limited to anecdotal observation. The report †Vasculitis Clinic, exemplified by the interaction of HLA genotype and by Canney et al. (10) in this issue of the Clinical Journal of Hammersmith smoking in the developmentofautoantibodiesto the American Society of Nephrology is the first to assess Hospital, Imperial citrullinated peptides and the onset of rheumatoid ar- geographic or temporal clustering using formal statis- College Healthcare National Health thritis (1). It is assumed that similar pathogenic mech- tical methods in a national cohort of patients. Service Trust, London, anisms are involved in other autoimmune diseases, In this well designed study, Canney et al. (10) sys- United Kingdom although few are so well delineated as in this example. tematically identified all patients with anti-GBM dis- In antiglomerular basement membrane (anti-GBM) ease in Ireland over an 11-year period by screening Correspondence: disease, the components of the aberrant adaptive immune results from referral immunology laboratories and Dr. Stephen P. response that are involved in disease pathogenesis are using a national renal histopathology database. This McAdoo, Renal and fi fi Vascular Inflammation clearly described, such as pathogenic autoantibodies allowed them to de ne, for the rst time, a national Section, Department directed to a well defined autoantigen supported by a incidence rate for this rare condition. This rate is higher of Medicine, Imperial population of autoreactive T cells (2,3). The putative than previous estimates in other European popula- College London, environmental triggers, however, and how they inter- tions, as discussed by Canney et al. (10), most likely Hammersmith fl Hospital Campus, Du act with the known genetic determinants of disease sus- re ecting the methodologic inadequacies of previous Cane Road, London ceptibility to initiate this aberrant response are not fully studies, which were prone to ascertainment bias and W112 0NN. Email: understood. unable to accurately define at-risk populations. It s.mcadoo@imperial. These genetic determinants of anti-GBM disease are might also reflect the moderate over-representation ac.uk increasingly well described. Although there has not of the DR2 haplotype and DRB1 risk alleles in the Irish been an undirected genetic survey, such as a genome– population (11) or perhaps a genuine increase in the wide association study, perhaps reflecting the overall frequency of anti-GBM disease in recent years com- rarity of anti-GBM disease, targeted genetic analysis pared with historical cohorts. has been informative. Polymorphisms in certain non– The study, in addition, has used variable window HLA genes, such as those encoding Fcg-receptors, are scan statistics and Bayesian spatial modeling methods associated with disease susceptibility (4,5), consistent to identify temporal and geographic clustering of pa- with the contribution of pathogenic autoantibodies in tients, respectively. These formal statistical methods mediating organ damage, whereas polymorphisms in confirm the prior anecdotal experience of many other COL4A3, the gene encoding the target autoantigen, authors. Notably, some differences in disease pheno- have been excluded from playing a significant role type were observed in the two clusters. It is striking, for (6). Better characterized are the HLA associations of example, that the temporal cluster had a very high anti-GBM disease, with 80% of patients inheriting an prevalence of positivity for ANCA (found in .70% of HLA-DR2 haplotype. Genotyping studies have identi- patients), particularly in view of the strict diagnostic fied a hierarchy of associations with particular DRB1 criteria used by Canney et al. (10) that excluded pa- alleles: DRB1*1501, DRB1*03,andDRB1*04 are posi- tients who had overt clinical features of vasculitis. tively associated with disease, whereas DRB1*01 and Double positivity for ANCA and anti-GBM antibodies DRB1*07 seem to confer a dominant negative protec- is a well recognized phenomenon, with previous stud- tive effect (7). These susceptibility alleles, however, are ies estimating that approximately 30% of patients with associated with other autoimmune diseases (such as anti-GBM disease have a concurrent ANCA (12), con- multiple sclerosis and Sjogren syndrome), and they sistent with overall prevalence reported in the entire are common in most populations, whereas anti-GBM Irish cohort. The fact that the temporal cluster had an disease remains exceptionally rare, highlighting the over-representation of ANCA suggests that a different 1324 Copyright © 2016 by the American Society of Nephrology www.cjasn.org Vol 11 August, 2016 Clin J Am Soc Nephrol 11: 1324–1326, August, 2016 Editorial: Clustering of Anti-GBM Disease, McAdoo et al. 1325 disease mechanism may be acting in these patients or as in a more common form of crescentic GN that associated suggested by Canney et al. (10), that the disease may present with ANCA may be informative. A variant ANCA type di- variably in different subpopulations. This is perhaps in rected against LAMP2, a human protein that bears a high keeping with other recent reports that have identified atyp- degree of homology to FimH (a protein expressed in fimbri- ical presentations of anti-GBM disease, such as those asso- ated Gram–negative bacilli), has been identified in human ciated with IgG4 anti–GBM antibodies (13) or what might be patients with ANCA-associated vasculitis and is purported termed idiopathic linear Ig deposition (14), and it illustrates to arise via a process of molecular mimicry after bacterial the challenges in reliably characterizing the full phenotypic infection (26). It has also been shown that certain Staphylo- spectrum of a very rare disorder. coccus aureus peptides bear high homology to complemen- Of greater significance, the identification of these disease tary PR3, and it is, thus, suggested that anti-PR3 antibodies clusters also supports a role for an environmental trigger may arise via a process of idiotype-anti–idiotype interac- in anti-GBM disease. Many such environmental triggers tions after Staphylococcal infection (27). Although there are have been suggested previously. Perhaps best known is the no specific mechanisms suggested for the infectious induc- association of cigarette smoking with the development of tion of anti-GBM antibodies, it is notable that comparable lung hemorrhage (15). Inhalation of hydrocarbons has also idiotype-anti–idiotype interactions have recently been de- been associated with anti-GBM disease (16), and an interest- scribed in the induction of experimental anti–GBM disease ing report of identical twins who both developed anti-GBM in a rodent model (28). disease after hydrocarbon exposure supports a link between Canney et al. (10) do not comment on the potential infec- genetics and environmental factors (17). It is hypothesized tive, occupational, or other environmental exposures that that localized airway inflammation induced by smoking or may have initiated disease in their cohort, and exploring inhaled hydrocarbons may disrupt the architecture of the these features in more detail may be informative in the fu- alveolar basement membrane, revealing usually sequestered ture. In addition, analysis of concurrent patterns of infec- epitopes in type 4 collagen, thus permitting access to patho- tious disease, such as influenza, in the general population genic autoantibodies. Whether these factors have a role in the during the study period might be considered. It may also be initiation of the autoimmune response per se, however, is not of interest to determine the pattern of disease in the adjacent so clear. A similar process of conformational transition of the six counties of Northern Ireland, particularly in view of the autoantigen within the kidney has been suggested to account shared border with the spatial cohort of patients described for the association of anti-GBM disease with other glomeru- by Canney et al. (10) in Donegal, because this may identify lar lesions (such as ANCA-associated GN and membranous additional patients in the same region, providing additional nephropathy) and lithotripsy for renal stones, which may opportunity to identify shared exposures in a larger cohort disrupt the quaternary structure of GBM (18). of patients. These associations with smoking and other specific dis- This study is notable for being the first to accurately eases, however, are not likely to account for the clustering determine the frequency of anti-GBM disease in any country, of diseases that