Skip to main content

Advertisement

Log in

COPD is associated with production of autoantibodies to a broad spectrum of self-antigens, correlative with disease phenotype

  • Immunology in Colorado
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

The role of autoimmune pathology in development and progression of chronic obstructive pulmonary disease (COPD) is becoming increasingly appreciated. In this study, we identified serum autoantibody reactivities associated with chronic bronchitis or emphysema, as well as systemic autoimmunity and associated lung disease. Using autoantigen array analysis, we demonstrated that COPD patients produce autoantibodies reactive to a broad spectrum of self-antigens. Further, the level and reactivities of these antibodies, or autoantibody profile, correlated with disease phenotype. Patients with emphysema produced autoantibodies of higher titer and reactive to an increased number of array antigens. Strikingly, the autoantibody reactivities observed in emphysema were increased over those detected in rheumatoid arthritis patients, and included similar reactivities to those associated with lupus. These findings raise the possibility that autoantibody profiles may be used to determine COPD risk, as well as provide a diagnostic and prognostic tool. They shed light on the heterogeneity of autoantibody reactivities associated with COPD phenotype and could be of use in the personalization of medical treatment, including determining and monitoring therapeutic interventions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Kochanek KD, Xu J, Murphy SL, Miniño AM, Kung H-C. Deaths: preliminary data for 2009. National Vital Statistics Reports: US Department of Health and Human Services. Centers for Disease Control and Prevention. National Center for Health Statistics. 2011:51. http://www.cdc.gov/nchs/data/nvsr/nvsr59/nvsr59_04.pdf. Accessed 14 Jun 2012.

  2. The top 10 causes of death. WHO Media Centre: Fact Sheet N˚310. World Health Organization. 2011. http://www.who.int/mediacentre/factsheets/fs310/en/. Accessed 14 Jun 2012.

  3. Fletcher C, Peto R. The natural history of chronic airflow obstruction. Br Med J. 1977;1:1645–8.

    Article  PubMed  CAS  Google Scholar 

  4. Løkke A, Lange P, Scharling H, Fabricius P, Vestbo J. Developing COPD: a 25 year follow up study of the general population. Thorax. 2006;61:935–9.

    Article  PubMed  Google Scholar 

  5. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS, Committee GS. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med. 2001;163:1256–76.

    PubMed  CAS  Google Scholar 

  6. Gamble E, Grootendorst DC, Hattotuwa K, O’Shaughnessy T, Ram FS, Qiu Y, Zhu J, Vignola AM, Kroegel C, Morell F, Pavord ID, Rabe KF, Jeffery PK, Barnes NC. Airway mucosal inflammation in COPD is similar in smokers and ex-smokers: a pooled analysis. Eur Respir J. 2007;30:467–71.

    Article  PubMed  CAS  Google Scholar 

  7. Motz GT, Eppert BL, Sun G, Wesselkamper SC, Linke MJ, Deka R, Borchers MT. Persistence of lung CD8 T cell oligoclonal expansions upon smoking cessation in a mouse model of cigarette smoke-induced emphysema. J Immunol. 2008;181:8036–43.

    PubMed  CAS  Google Scholar 

  8. Birring SS, Brightling CE, Bradding P, Entwisle JJ, Vara DD, Grigg J, Wardlaw AJ, Pavord ID. Clinical, radiologic, and induced sputum features of chronic obstructive pulmonary disease in nonsmokers: a descriptive study. Am J Respir Crit Care Med. 2002;166:1078–83.

    Article  PubMed  Google Scholar 

  9. Hagstad S, Ekerljung L, Lindberg A, Backman H, Rönmark E, Lundbäck B. COPD among non-smokers—Report from the Obstructive Lung Disease in Northern Sweden (OLIN) studies. Respir Med. 2012;106(7):980–8.

    Google Scholar 

  10. Feghali-Bostwick CA, Gadgil AS, Otterbein LE, Pilewski JM, Stoner MW, Csizmadia E, Zhang Y, Sciurba FC, Duncan SR. Autoantibodies in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008;177:156–63.

    Article  PubMed  Google Scholar 

  11. Karayama M, Inui N, Suda T, Nakamura Y, Nakamura H, Chida K. Antiendothelial cell antibodies in patients with COPD. Chest. 2010;138:1303–8.

    Article  PubMed  Google Scholar 

  12. Kirkham PA, Caramori G, Casolari P, Papi AA, Edwards M, Shamji B, Triantaphyllopoulos K, Hussain F, Pinart M, Khan Y, Heinemann L, Stevens L, Yeadon M, Barnes PJ, Chung KF, Adcock IM. Oxidative stress-induced antibodies to carbonyl-modified protein correlate with severity of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2011;184:796–802.

    Article  PubMed  CAS  Google Scholar 

  13. Kuo YB, Chang CA, Wu YK, Hsieh MJ, Tsai CH, Chen KT, Chen CY, Chan EC. Identification and clinical association of anti-cytokeratin 18 autoantibody in COPD. Immunol Lett. 2010;128:131–6.

    Article  PubMed  CAS  Google Scholar 

  14. Lee SH, Goswami S, Grudo A, Song LZ, Bandi V, Goodnight-White S, Green L, Hacken-Bitar J, Huh J, Bakaeen F, Coxson HO, Cogswell S, Storness-Bliss C, Corry DB, Kheradmand F. Antielastin autoimmunity in tobacco smoking-induced emphysema. Nat Med. 2007;13:567–9.

    Article  PubMed  CAS  Google Scholar 

  15. Leidinger P, Keller A, Heisel S, Ludwig N, Rheinheimer S, Klein V, Andres C, Hamacher J, Huwer H, Stephan B, Stehle I, Lenhof HP, Meese E. Novel autoantigens immunogenic in COPD patients. Respir Res. 2009;10:20.

    Article  PubMed  Google Scholar 

  16. Núñez B, Sauleda J, Antó JM, Julià MR, Orozco M, Monsó E, Noguera A, Gómez FP, Garcia-Aymerich J, Agustí A, Investigators P-C. Anti-tissue antibodies are related to lung function in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2011;183:1025–31.

    Article  PubMed  Google Scholar 

  17. Bruder D, Westendorf AM, Geffers R, Gruber AD, Gereke M, Enelow RI, Buer J. CD4 T Lymphocyte-mediated lung disease: steady state between pathological and tolerogenic immune reactions. Am J Respir Crit Care Med. 2004;170:1145–52.

    Article  PubMed  Google Scholar 

  18. Gereke M, Gröbe L, Prettin S, Kasper M, Deppenmeier S, Gruber AD, Enelow RI, Buer J, Bruder D. Phenotypic alterations in type II alveolar epithelial cells in CD4 + T cell mediated lung inflammation. Respir Res. 2007;8:47.

    Article  PubMed  Google Scholar 

  19. Gereke M, Jung S, Buer J, Bruder D. Alveolar type II epithelial cells present antigen to CD4(+) T cells and induce Foxp3(+) regulatory T cells. Am J Respir Crit Care Med. 2009;179:344–55.

    Article  PubMed  Google Scholar 

  20. Tosiek MJ, Gruber AD, Bader SR, Mauel S, Hoymann HG, Prettin S, Tschernig T, Buer J, Gereke M, Bruder D. CD4 + CD25 + Foxp3 + regulatory T cells are dispensable for controlling CD8 + T cell-mediated lung inflammation. J Immunol. 2011;186:6106–18.

    Article  PubMed  CAS  Google Scholar 

  21. Taraseviciene-Stewart L, Scerbavicius R, Choe KH, Moore M, Sullivan A, Nicolls MR, Fontenot AP, Tuder RM, Voelkel NF. An animal model of autoimmune emphysema. Am J Respir Crit Care Med. 2005;171:734–42.

    Article  PubMed  Google Scholar 

  22. Motz GT, Eppert BL, Wesselkamper SC, Flury JL, Borchers MT. Chronic cigarette smoke exposure generates pathogenic T cells capable of driving COPD-like disease in Rag2-/- mice. Am J Respir Crit Care Med. 2010;181:1223–33.

    Article  PubMed  CAS  Google Scholar 

  23. Alimohammadi M, Dubois N, Sköldberg F, Hallgren A, Tardivel I, Hedstrand H, Haavik J, Husebye ES, Gustafsson J, Rorsman F, Meloni A, Janson C, Vialettes B, Kajosaari M, Egner W, Sargur R, Pontén F, Amoura Z, Grimfeld A, De Luca F, Betterle C, Perheentupa J, Kämpe O, Carel JC. Pulmonary autoimmunity as a feature of autoimmune polyendocrine syndrome type 1 and identification of KCNRG as a bronchial autoantigen. Proc Natl Acad Sci USA. 2009;106:4396–401.

    Article  PubMed  CAS  Google Scholar 

  24. Shum AK, DeVoss J, Tan CL, Hou Y, Johannes K, O’Gorman CS, Jones KD, Sochett EB, Fong L, Anderson MS. Identification of an autoantigen demonstrates a link between interstitial lung disease and a defect in central tolerance. Sci Transl Med. 2009; 1:9ra20.

    Google Scholar 

  25. Brusselle GG, Joos GF, Bracke KR. New insights into the immunology of chronic obstructive pulmonary disease. Lancet. 2011;378:1015–26.

    Article  PubMed  CAS  Google Scholar 

  26. Cosio MG, Saetta M, Agusti A. Immunologic aspects of chronic obstructive pulmonary disease. N Engl J Med. 2009;360:2445–54.

    Article  PubMed  CAS  Google Scholar 

  27. Brandsma CA, Kerstjens HA, Geerlings M, Kerkhof M, Hylkema MN, Postma DS, Timens W. The search for autoantibodies against elastin, collagen and decorin in COPD. Eur Respir J. 2011;37:1289–92.

    Article  PubMed  CAS  Google Scholar 

  28. Greene CM, Low TB, O’Neill SJ, McElvaney NG. Anti-proline-glycine-proline or antielastin autoantibodies are not evident in chronic inflammatory lung disease. Am J Respir Crit Care Med. 2010;181:31–5.

    Article  PubMed  Google Scholar 

  29. Toyoshima M, Chida K, Suda T, Sato M. Is autoimmunity really related to the pathogenesis of COPD? Am J Respir Crit Care Med. 2011; 184:1212–3; author reply 3.

  30. Sant SM, Doran M, Fenelon HM, Breatnach ES. Pleuropulmonary abnormalities in patients with systemic lupus erythematosus: assessment with high resolution computed tomography, chest radiography and pulmonary function tests. Clin Exp Rheumatol. 1997;15:507–13.

    PubMed  CAS  Google Scholar 

  31. Gochuico BR, Avila NA, Chow CK, Novero LJ, Wu HP, Ren P, MacDonald SD, Travis WD, Stylianou MP, Rosas IO. Progressive preclinical interstitial lung disease in rheumatoid arthritis. Arch Intern Med. 2008;168:159–66.

    Article  PubMed  CAS  Google Scholar 

  32. Steen VD, Medsger TA. Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum. 2000;43:2437–44.

    Article  PubMed  CAS  Google Scholar 

  33. Cottin V, Nunes H, Brillet PY, Delaval P, Devouassoux G, Tillie-Leblond I, Israel-Biet D, Court-Fortune I, Valeyre D, Cordier JF. Combined pulmonary fibrosis and emphysema: a distinct underrecognised entity. Eur Respir J. 2005;26:586–93.

    Article  PubMed  CAS  Google Scholar 

  34. Samara KD, Margaritopoulos G, Wells AU, Siafakas NM, Antoniou KM. Smoking and pulmonary fibrosis: novel insights. Pulm Med. 2011;2011:461439.

    PubMed  Google Scholar 

  35. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease.: Global Initiative for Chronic Obstructive Lung Disease, Inc. 2011:80.

  36. Society AT, Society ER. American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med. 2002; 165:277–304.

    Google Scholar 

  37. Li QZ, Karp DR, Quan J, Branch VK, Zhou J, Lian Y, Chong BF, Wakeland EK, Olsen NJ. Risk factors for ANA positivity in healthy persons. Arthritis Res Ther. 2011;13:R38.

    Article  PubMed  Google Scholar 

  38. Li QZ, Zhen QL, Xie C, Wu T, Mackay M, Aranow C, Putterman C, Mohan C. Identification of autoantibody clusters that best predict lupus disease activity using glomerular proteome arrays. J Clin Invest. 2005;115:3428–39.

    Article  PubMed  Google Scholar 

  39. Li QZ, Zhou J, Lian Y, Zhang B, Branch VK, Carr-Johnson F, Karp DR, Mohan C, Wakeland EK, Olsen NJ. Interferon signature gene expression is correlated with autoantibody profiles in patients with incomplete lupus syndromes. Clin Exp Immunol. 2010;159:281–91.

    Article  PubMed  CAS  Google Scholar 

  40. Li QZ, Zhou J, Wandstrat AE, Carr-Johnson F, Branch V, Karp DR, Mohan C, Wakeland EK, Olsen NJ. Protein array autoantibody profiles for insights into systemic lupus erythematosus and incomplete lupus syndromes. Clin Exp Immunol. 2007;147:60–70.

    PubMed  CAS  Google Scholar 

  41. Marrack P, Kappler J, Kotzin BL. Autoimmune disease: why and where it occurs. Nat Med. 2001;7:899–905.

    Article  PubMed  CAS  Google Scholar 

  42. Vij R, Noth I, Strek ME. Autoimmune-featured interstitial lung disease: a distinct entity. Chest. 2011;140:1292–9.

    Article  PubMed  Google Scholar 

  43. Källberg H, Ding B, Padyukov L, Bengtsson C, Rönnelid J, Klareskog L, Alfredsson L, Group ES. Smoking is a major preventable risk factor for rheumatoid arthritis: estimations of risks after various exposures to cigarette smoke. Ann Rheum Dis. 2011;70:508–11.

    Article  PubMed  Google Scholar 

  44. Costenbader KH, Karlson EW. Cigarette smoking and systemic lupus erythematosus: a smoking gun? Autoimmunity. 2005;38:541–7.

    Article  PubMed  CAS  Google Scholar 

  45. Popler J, Alimohammadi M, Kämpe O, Dalin F, Dishop MK, Barker JM, Moriarty-Kelsey M, Soep JB, Deterding RR. Autoimmune polyendocrine syndrome type 1: utility of KCNRG autoantibodies as a marker of active pulmonary disease and successful treatment with rituximab. Pediatr Pulmonol. 2012;47:84–7.

    Article  PubMed  Google Scholar 

  46. Drolet JP, Frangie H, Guay J, Hajoui O, Hamid Q, Mazer BD. B lymphocytes in inflammatory airway diseases. Clin Exp Allergy. 2010;40:841–9.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors would like to thank Dr. Steve Groshong for his contribution to histological analyses, and the patients of National Jewish Health for their blood donations. This work was funded by the NJC COPD Institutional Program and the generous donation by Joel Farkas to National Jewish Health.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to John C. Cambier.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Packard, T.A., Li, Q.Z., Cosgrove, G.P. et al. COPD is associated with production of autoantibodies to a broad spectrum of self-antigens, correlative with disease phenotype. Immunol Res 55, 48–57 (2013). https://doi.org/10.1007/s12026-012-8347-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-012-8347-x

Keywords

Navigation