Invited Perspective: Air Pollutants, Genetics, and the Mucosal Paradigm for Rheumatoid Arthritis Risk.

Vol. 131, No. 3 Invited PerspectiveOpen AccessInvited Perspective: Air Pollutants, Genetics, and the Mucosal Paradigm for Rheumatoid Arthritis Riskis accompanied byAssociation of Combined Exposure to Ambient Air Pollutants, Genetic Risk, and Incident Rheumatoid Arthritis: A Prospective Cohort Study in the UK Biobank Gregory C. McDermott and Jeffrey A. Sparks Gregory C. McDermott Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, Massachusetts, USA Harvard Medical School, Boston, Massachusetts, USA Search for more papers by this author and Jeffrey A. Sparks Address correspondence to Jeffrey A. Sparks, Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, 60 Fenwood Rd., #6016U, Boston, MA 02115 USA. Telephone: (617) 525-1040. Email: E-mail Address: [email protected] https://orcid.org/0000-0002-5556-4618 Division of Rheumatology, Inflammation, and Immunity, Brigham and Women’s Hospital, Boston, Massachusetts, USA Harvard Medical School, Boston, Massachusetts, USA Search for more papers by this author Published:13 March 2023CID: 031303https://doi.org/10.1289/EHP12167AboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InReddit Rheumatoid arthritis (RA) is a chronic, debilitating inflammatory condition that is triggered by a combination of environmental and genetic factors.1–3 Several decades of RA research have contributed to the development of the “mucosal paradigm” of RA disease pathogenesis, which posits that local inflammation of the mucosa in airways and other mucosal sites leads to the loss of immune tolerance and the production of autoantibodies.4,5 This process often occurs years before patients develop the joint-related symptoms that are the clinical hallmarks of RA.Support for the mucosal origins hypothesis derives from several sources. Respiratory exposures, such as cigarette smoking and silica dust, have been associated with RA risk, demonstrating that airway damage and inflammation likely serve as key drivers of RA autoantibody formation and disease pathogenesis.6–8 Cigarette smoking in particular has been shown to strongly interact with known genetic risk factors for RA, including the major histocompatibility complex, class II, DR beta 1 (HLA-DRB1) “shared epitope,” suggesting that people with specific genetic variants may be more likely to generate autoantibodies that place them on the path toward RA development.9–11 Recent evidence showing an association between childhood passive smoking and future development of adult-onset seropositive RA further emphasizes the potential for a long latency period for environmental exposures and the development of clinical RA symptoms.12 However, because many people who develop RA do not smoke cigarettes or have significant exposure to secondhand smoke, there has been intense interest in identifying other inhalants that may also affect RA risk.In this issue of Environmental Health Perspectives, Zhang et al. report on their comprehensive study investigating ambient air pollution, genetic factors, and RA risk.13 They found that higher levels of specific pollutants and a higher overall air pollution score were each associated with increased RA risk. They noted a strong dose effect for the air pollution score on RA risk among subjects with low and intermediate RA genetic risk.These findings contribute to the growing literature investigating the impact of inhalants other than cigarette smoke on RA risk. An investigation in the Nurses’ Health Study of 90,297 women found that living within 50 m of a road conferred increased risk of RA compared with living 200 meters200m or farther away.14 A study of 640,041 people in the British Columbia Border Air Quality Study found a similar association between traffic proximity and RA risk.15 However, the data linking specific pollutants to RA risk have been conflicting. In both the Nurses’ Health Study and the British Columbia study, specific pollutants, including particulate matter with aerodynamic diameters of less than or equal to 2.5 micrometers≤2.5μm or greater than or equal to 10 micrometers≥10μm, nitrogen dioxide, and sulfur dioxide, were not associated with RA risk.15,16 Similarly, there was no significant association between pollutants and RA risk after adjustment for smoking and education in a large case–control study of 1,497 incident RA cases and 2,536 age- and sex-matched controls in the Swedish Epidemiological Investigations of Rheumatoid Arthritis study.17 In contrast, large population-based studies of 322,301 people in Taiwan18 and 230,034 people in South Korea19 did find associations between specific pollutants and RA. However, none of these previous studies incorporated genetic factors to investigate possible gene–pollutant interactions as in the study by Zhang et al.13Although Zhang et al. included several single-nucleotide polymorphisms of the human HLA genes in the RA genetic risk score,13 they did not specifically determine shared epitope status or other classical HLA alleles. Because these HLA proteins play a central role in the presentation of neoantigens to T cells,20 it is possible that the lack of strong gene–pollutant interaction could be due to omission of this important RA genetic risk factor. Important future directions include the incorporation of HLA into RA genetic risk scores, as well as investigating occupational inhalants and seropositive RA, while integrating RA genetic risk.In conclusion, it is increasingly clear that air pollutants and genetic factors each likely contribute to RA risk. The important findings reported by Zhang et al.13 offer more rationale to encourage policies to improve air quality to lower risk of RA and other autoimmune conditions that have been associated with respiratory exposures. These findings also provide additional evidence of the mucosal paradigm of RA risk related to pulmonary mucosal injury from air pollutants, which will continue to be a key area of mechanistic RA research.References1. Sparks JA. 2019. Rheumatoid arthritis. Ann Intern Med 170(1):ITC1–ITC16, PMID: 30596879, 10.7326/AITC201901010. Crossref, Medline, Google Scholar2. Kowalski EN, Qian G, Vanni KMM, Sparks JA. 2022. A roadmap for investigating preclinical autoimmunity using patient-oriented and epidemiologic study designs: example of rheumatoid arthritis. Front Immunol 13:890996, PMID: 35693829, 10.3389/fimmu.2022.890996. Crossref, Medline, Google Scholar3. Sparks JA, Costenbader KH. 2014. Genetics, environment, and gene–environment interactions in the development of systemic rheumatic diseases. Rheum Dis Clin North Am 40(4):637–657, PMID: 25437282, 10.1016/j.rdc.2014.07.005. Crossref, Medline, Google Scholar4. Holers VM, Demoruelle MK, Kuhn KA, Buckner JH, Robinson WH, Okamoto Y, et al.2018. Rheumatoid arthritis and the mucosal origins hypothesis: protection turns to destruction. Nat Rev Rheumatol 14(9):542–557, PMID: 30111803, 10.1038/s41584-018-0070-0. Crossref, Medline, Google Scholar5. Klareskog L, Stolt P, Lundberg K, Källberg H, Bengtsson C, Grunewald J, et al.2006. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)–restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum 54(1):38–46, PMID: 16385494, 10.1002/art.21575. Crossref, Medline, Google Scholar6. Hutchinson D, Shepstone L, Moots R, Lear JT, Lynch MP. 2001. Heavy cigarette smoking is strongly associated with rheumatoid arthritis (RA), particularly in patients without a family history of RA. Ann Rheum Dis 60(3):223–227, PMID: 11171682, 10.1136/ard.60.3.223. Crossref, Medline, Google Scholar7. Stolt P, Källberg H, Lundberg I, Sjögren B, Klareskog L, Alfredsson L, et al.2005. Silica exposure is associated with increased risk of developing rheumatoid arthritis: results from the Swedish EIRA study. Ann Rheum Dis 64(4):582–586, PMID: 15319232, 10.1136/ard.2004.022053. Crossref, Medline, Google Scholar8. Prisco LC, Martin LW, Sparks JA. 2020. Inhalants other than personal cigarette smoking and risk for developing rheumatoid arthritis. Curr Opin Rheumatol 32(3):279–288, PMID: 32141952, 10.1097/BOR.0000000000000705. Crossref, Medline, Google Scholar9. Kim K, Jiang X, Cui J, Lu B, Costenbader KH, Sparks JA, et al.2015. Interactions between amino acid–defined major histocompatibility complex class II variants and smoking in seropositive rheumatoid arthritis. Arthritis Rheumatol 67(10):2611–2623, PMID: 26098791, 10.1002/art.39228. Crossref, Medline, Google Scholar10. Padyukov L, Silva C, Stolt P, Alfredsson L, Klareskog L. 2004. A gene–environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis. Arthritis Rheum 50(10):3085–3092, PMID: 15476204, 10.1002/art.20553. Crossref, Medline, Google Scholar11. Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K, et al.2014. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506(7488):376–381, PMID: 24390342, 10.1038/nature12873. Crossref, Medline, Google Scholar12. Yoshida K, Wang J, Malspeis S, Marchand N, Lu B, Prisco LC, et al.2021. Passive smoking throughout the life course and the risk of incident rheumatoid arthritis in adulthood among women. Arthritis Rheumatol 73(12):2219–2228, PMID: 34406709, 10.1002/art.41939. Crossref, Medline, Google Scholar13. Zhang J, Fang XY, Wu J, Fan YG, Leng RX, Liu B, et al.2023. Association of combined exposure to ambient air pollutants, genetic risk and incident rheumatoid arthritis: a prospective cohort study in UK biobank. Environ Health Perspect 131(3):037008, 10.1289/EHP10710. Google Scholar14. Hart JE, Laden F, Puett RC, Costenbader KH, Karlson EW. 2009. Exposure to traffic pollution and increased risk of rheumatoid arthritis. Environ Health Perspect 117(7):1065–1069, PMID: 19654914, 10.1289/ehp.0800503. Link, Google Scholar15. De Roos AJ, Koehoorn M, Tamburic L, Davies HW, Brauer M. 2014. Proximity to traffic, ambient air pollution, and community noise in relation to incident rheumatoid arthritis. Environ Health Perspect 122(10):1075–1080, PMID: 24905961, 10.1289/ehp.1307413. Link, Google Scholar16. Hart JE, Källberg H, Laden F, Costenbader KH, Yanosky JD, Klareskog L, et al.2013. Ambient air pollution exposures and risk of rheumatoid arthritis. Arthritis Care Res (Hoboken) 65(7):1190–1196, PMID: 23401426, 10.1002/acr.21975. Crossref, Medline, Google Scholar17. Hart JE, Källberg H, Laden F, Bellander T, Costenbader KH, Holmqvist M, et al.2013. Ambient air pollution exposures and risk of rheumatoid arthritis: results from the Swedish EIRA case–control study. Ann Rheum Dis 72(6):888–894, PMID: 22833374, 10.1136/annrheumdis-2012-201587. Crossref, Medline, Google Scholar18. Jung CR, Hsieh HY, Hwang BF. 2017. Air pollution as a potential determinant of rheumatoid arthritis: a population-based cohort study in Taiwan. Epidemiology 28(suppl 1):S54–S59, PMID: 29028676, 10.1097/EDE.0000000000000732. Crossref, Medline, Google Scholar19. Park JS, Choi S, Kim K, Chang J, Kim SM, Kim SR, et al.2021. Association of particulate matter with autoimmune rheumatic diseases among adults in South Korea. Rheumatology (Oxford) 60(11):5117–5126, PMID: 33560298, 10.1093/rheumatology/keab127. Crossref, Medline, Google Scholar20. van Drongelen V, Holoshitz J. 2017. Human leukocyte antigen–disease associations in rheumatoid arthritis. Rheum Dis Clin North Am 43(3):363–376, PMID: 28711139, 10.1016/j.rdc.2017.04.003. Crossref, Medline, Google ScholarG.C.M. is supported by the Value and Evidence in Rheumatology using bioinformaTics and advanced analYtics (VERITY) Pilot and Feasibility Award and grant T32 AR007530, both through the National Institute of Arthritis and Musculoskeletal and Skin Diseases. J.A.S. is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grants R01 AR077607, P30 AR070253, and P30 AR072577), the R. Bruce and Joan M. Mickey Research Scholar Fund, and the Llura Gund Award for Rheumatoid Arthritis Research and Care. J.A.S. has also received research support from Bristol Myers Squibb and performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer unrelated to this work. The funders had no role in the decision to publish or preparation of this manuscript, and no specific funding was received from any funding bodies in the public, commercial or not-for-profit sectors to carry out the work described in this manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard University, its affiliated academic health care centers, or the National Institutes of Health.FiguresReferencesRelatedDetailsRelated articlesAssociation of Combined Exposure to Ambient Air Pollutants, Genetic Risk, and Incident Rheumatoid Arthritis: A Prospective Cohort Study in the UK Biobank13 March 2023Environmental Health Perspectives Vol. 131, No. 3 March 2023Metrics About Article Metrics Publication History Manuscript received16 September 2022Manuscript revised8 November 2022Manuscript accepted6 February 2023Originally published13 March 2023 Financial disclosuresPDF download License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. 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