Increased total plasma TGF-β1 levels and deregulated IgA - IgM axis in chronic obstructive pulmonary disease

  • Rajna Minic Institute of Virology, Vaccines and sera, Torlak
  • Olivera Đukić Department of Bromatology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, Belgrade, Serbia
  • dr Dejana Kosanović Group of Immunology, Institute for Medical Research, University of Belgrade, Belgrade, Serbia.
  • de Dejan Žujović Municipal Institute for Lung Diseases and Tuberculosis
  • Prof. dr sci. med. Aleksandra Ilić Faculty of Medicine, University of Belgrade
  • dr Marko Panić Institute of Virology, Vaccines and Sera, “Torlak”
  • Prof. dr Brižita Đorđević Department of Bromatology, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, Belgrade, Serbia
DOI: https://doi.org/10.5937/jomb0-57461
Keywords: Chronic obstructive pulmonary disease; TGF-β1; IgA; IgM; Pseudomonas aeruginosa

Abstract


Background: Chronic obstructive pulmonary disease (COPD) is displayed as the obstruction of the small airways and includes “flare-ups”, sudden and significant worsening of symptoms, sometimes caused by infections.

Methods: COPD (n=38) and acute bronchitis (AB, n=35) patients were grouped based on age and examined at two time points: during flare-ups/infections and at day 30. We measured various biomarkers, including total plasma TGF-β1 levels, total IgA, total IgM, and Pseudomonas aeruginosa specific IgA levels.

Results: Increased TGF-β1 levels were detected in COPD patients, with no significant change observed at day 30. A significant lowering of total plasma IgA level was observed in COPD patients on day 30. No significant difference in specific P. aeruginosa IgA levels were observed between the two patient groups, or over time. Interestingly, a correlation between total IgM and IgA levels was absent in COPD patients. While positive correlation between age and IgA level existed in acute bronchitis patients, this correlation was negative in COPD patients. A significant correlation was observed between total IgA and P. aeruginosa specific IgA in acute bronchitis patients. On the other hand, COPD patients showed no correlation at t=0 but a correlation was seen between total IgA and P. aeruginosa specific IgA1 at t=30, implying that flare-up resolution is accompanied with consolidation, a corresponding reinforcement or stabilization, of P. aeruginosa specific IgA levels in COPD patients.

Conclusion: Here we report on deregulated IgA - IgM axis in COPD, and call for thorough, larger scale studies of the humoral immune system in this pathology.

 

References

1. Orozco RJ, Rodriguez D, Hunter K, Roy S. The 2021 Global Initiative for Chronic Obstructive Pulmonary Disease (GOLD) guidelines and the outpatient management: Examining physician adherence and its effects on patient outcome. J Family Med Prim Care. 2024;13:736-742. https://doi.org/10.4103/jfmpc.jfmpc_1397_23

2. Fletcher C, Peto R. The natural history of chronic airflow obstruction. Br Med J. 1977; 1:1645-8. https://doi.org/10.1136/bmj.1.6077.1645.

3. Hnizdo E, Sullivan PA, Bang KM, Wagner G. Airflow obstruction attributable to work in industry and occupation among U.S. race/ethnic groups: a study of NHANES III data. Am J Ind Med. 2004;46:126-35. https://doi.org/10.1002/ajim.20042

4. Eisner MD, Anthonisen N, Coultas D, Kuenzli N, Perez-Padilla R, Postma D, Romieu I, Silverman EK, Balmes JR; Committee on Nonsmoking COPD, Environmental and Occupational Health Assembly. An official American Thoracic Society public policy statement: Novel risk factors and the global burden of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2010;182:693-718. https://doi.org/10.1164/rccm.200811-1757ST.

5. Durham AL, Adcock IM. The relationship between COPD and lung cancer. Lung Cancer. 2015 ;90:121-7. https://doi.org/10.1016/j.lungcan.2015.08.017

6. Morgan AD, Zakeri R, Quint JK. Defining the relationship between COPD and CVD: what are the implications for clinical practice? Ther Adv Respir Dis. 2018;12:1753465817750524. https://doi.org/10.1177/1753465817750524.

7. GBD 2019 Chronic Respiratory Diseases Collaborators. Global burden of chronic respiratory diseases and risk factors, 1990-2019: an update from the Global Burden of Disease Study 2019. EClinicalMedicine. 2023;59:101936. https://doi.org/10.1016/j.eclinm.2023.101936

8. Mirza S, Clay RD, Koslow MA, Scanlon PD. COPD Guidelines: A Review of the 2018 GOLD Report. Mayo Clin Proc. 2018;93:1488-1502. https://doi.org/10.1016/j.mayocp.2018.05.026.

9. Evans, M. D., Pryor, W. A. Cigarette smoking, emphysema, and damage to α1-proteinase inhibitor. American Journal of Physiology - Lung Cellular and Molecular Physiology 1994;266: L593-L611. https://doi.org/10.1152/ajplung.1994.266.6.l593

10. Lomas DA, Silverman EK. The genetics of chronic obstructive pulmonary disease. Respir Res. 2001;2:20-6. https://doi.org/10.1186/rr34.

11. Sharp RR, de Serres F, Newman L, Sandhaus RA, Walsh JW, Hood E, Harry GJ. Environmental, occupational, and genetic risk factors for alpha-1 antitrypsin deficiency. Environ Health Perspect. 2003;111:1749-52. https://doi.org/10.1289/ehp.6325.

12. Meseeha M, Sankari A, Attia M. Alpha-1 Antitrypsin Deficiency. [Updated 2024 Aug 17]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK442030/

13. Königshoff M, Kneidinger N, Eickelberg O. TGF-beta signaling in COPD: deciphering genetic and cellular susceptibilities for future therapeutic regimen. Swiss Med Wkly. 2009;139:554-63. https://doi.org/10.4414/smw.2009.12528

14. Wu L, Chau J, Young RP, Pokorny V, Mills GD, Hopkins R, McLean L, Black PN. Transforming growth factor-beta1 genotype and susceptibility to chronic obstructive pulmonary disease. Thorax. 2004;59:126-9. https://doi.org/10.1136/thorax.2003.005769

15. Celedón JC, Lange C, Raby BA, Litonjua AA, Palmer LJ, DeMeo DL, et al. The transforming growth factor-beta1 (TGFB1) gene is associated with chronic obstructive pulmonary disease (COPD). Hum Mol Genet. 2004;13:1649-56. https://doi.org/10.1093/hmg/ddh171.

16. Putcha N, Paul GG, Azar A, Wise RA, O'Neal WK, Dransfield MT, et al. Lower serum IgA is associated with COPD exacerbation risk in SPIROMICS. PLoS One. 2018;13:e0194924. https://doi.org/10.1371/journal.pone.0194924

17. Pilette C, Godding V, Kiss R, Delos M, Verbeken E, Decaestecker C, et al. Reduced epithelial expression of secretory component in small airways correlates with airflow obstruction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;163:185-94. https://doi.org/10.1164/ajrccm.163.1.9912137

18. Polosukhin VV, Cates JM, Lawson WE, Zaynagetdinov R, Milstone AP, Massion PP, et al. Bronchial secretory immunoglobulin a deficiency correlates with airway inflammation and progression of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2011;184:317-27. https://doi.org/10.1164/rccm.201010-1629OC

19. Gohy ST, Detry BR, Lecocq M, Bouzin C, Weynand BA, Amatngalim GD, et al. Polymeric immunoglobulin receptor down-regulation in chronic obstructive pulmonary disease. Persistence in the cultured epithelium and role of transforming growth factor-β. Am J Respir Crit Care Med. 2014;190:509-21. https://doi.org/10.1164/rccm.201311-1971OC

20. Ladjemi MZ, Lecocq M, Weynand B, Bowen H, Gould HJ, Van Snick J, et al. Increased IgA production by B-cells in COPD via lung epithelial interleukin-6 and TACI pathways. Eur Respir J. 2015;45:980-93. https://doi.org/10.1183/09031936.00063914

21. Sánchez Montalvo A, Gohy S, Rombaux P, Pilette C, Hox V. The Role of IgA in Chronic Upper Airway Disease: Friend or Foe? Front Allergy. 2022;3:852546. https://doi.org/10.3389/falgy.2022.852546

22. Millares L, Martí S, Ardanuy C, Liñares J, Santos S, Dorca J, et al. Specific IgA against Pseudomonas aeruginosa in severe COPD. Int J Chron Obstruct Pulmon Dis. 2017;12:2807-2811. https://doi.org/10.2147/COPD.S141701

23. Martínez-Solano L, Macia MD, Fajardo A, Oliver A, Martinez JL. Chronic Pseudomonas aeruginosa infection in chronic obstructive pulmonary disease. Clin Infect Dis. 2008;47:1526-1533. https://doi.org/10.1086/593186

24. Maurice NM, Bedi B, Sadikot RT. Pseudomonas aeruginosa Biofilms: Host Response and Clinical Implications in Lung Infections. Am J Respir Cell Mol Biol. 2018;58:428-439. https://doi.org/10.1165/rcmb.2017-0321TR

25. Rodrigo-Troyano A, Melo V, Marcos PJ, Laserna E, Peiro M, Suarez-Cuartin G, et al. Pseudomonas aeruginosa in Chronic Obstructive Pulmonary Disease Patients with Frequent Hospitalized Exacerbations: A Prospective Multicentre Study. Respiration. 2018;96:417-424. https://doi.org/10.1159/000490190.

26. Eklöf J, Sørensen R, Ingebrigtsen TS, Sivapalan P, Achir I, Boel JB, et al. Pseudomonas aeruginosa and risk of death and exacerbations in patients with chronic obstructive pulmonary disease: an observational cohort study of 22 053 patients. Clin Microbiol Infect. 2020;26:227-234. https://doi.org/10.1016/j.cmi.2019.06.011.


27. Minić R, Papić Z, Đorđević B, Michaličkova D, Ilić V, Mathiesen G, et al. Profiling of microorganism-binding serum antibody specificities in professional athletes. PLoS One. 2018 Sep 25;13(9):e0203665. https://doi.org/10.1371/journal.pone.0203665

28. Knežević S, Kosanović D, Dragačević L, Živković I, Ilić V, Hajduković L, et al. Age and gender associated changes in immunoglobulin subclass levels specific to S. pneumoniae, serotype 1. Comp Immunol Microbiol Infect Dis. 2022;87:101834. https://doi.org/10.1016/j.cimid.2022.101834.

29. van Eeden SF, Hogg JC. Immune-Modulation in Chronic Obstructive Pulmonary Disease: Current Concepts and Future Strategies. Respiration. 2020;99:550-565. https://doi.org/10.1159/000502261

30. Mahmood MQ, Reid D, Ward C, et al. Transforming growth factor (TGF) β1 and Smad signalling pathways: A likely key to EMT-associated COPD pathogenesis. Respirology. 2017;22:133-140. https://doi.org/10.1111/resp.12882

31. Moon J, Yoon JY, Yang JH, Kwon HH, Min S, Suh DH. Atrophic acne scar: a process from altered metabolism of elastic fibres and collagen fibres based on transforming growth factor-β1 signalling. Br J Dermatol. 2019 Dec;181(6):1226-1237. https://doi.org/10.1111/bjd.17851.

32. Takizawa H, Tanaka M, Takami K, Ohtoshi T, Ito K, Satoh M, et al. Increased expression of transforming growth factor-beta1 in small airway epithelium from tobacco smokers and patients with chronic obstructive pulmonary disease (COPD). American journal of respiratory and critical care medicine. 2001;163(6):1476–83. https://doi.org/10.1164/ajrccm.163.6.9908135

33. Togo S, Holz O, Liu X, Sugiura H, Kamio K, Wang X, et al. Lung fibroblast repair functions in patients with chronic obstructive pulmonary disease are altered by multiple mechanisms. American journal of respiratory and critical care medicine. 2008;178(3):248–60. https://doi.org/10.1164/rccm.200706-929OC

34. Brandtzaeg, P. (2003). Immunology of tonsils and adenoids: everything the ENT surgeon needs to know. International Congress Series, 1254. https://doi.org/10.1016/s0531-5131(03)00964-6

35. Zhou, L., & Sonnenberg, G. F. (2018). Essential immunologic orchestrators of intestinal homeostasis. Science Immunology, 3(20). https://doi.org/10.1126/sciimmunol.aao1605

36. Pilette C, Godding V, Kiss R, Delos M, Verbeken E, Decaestecker C, De Paepe K, Vaerman JP, Decramer M, Sibille Y. Reduced epithelial expression of secretory component in small airways correlates with airflow obstruction in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001 Jan;163(1):185-94. https://doi.org/10.1164/ajrccm.163.1.9912137.

37. Gomez-Olivas JD, Oscullo G, Martinez-Garcia MA. Isolation of Pseudomonas aeruginosa in Stable Chronic Obstructive Pulmonary Disease Patients-Should We Treat It?. J Clin Med. 2023;12(15):5054. https://doi.org/10.3390/jcm12155054

38. Kwok WC, Tam TCC, Chau CH, Lam FM, Ho JCM. Clinical Implications of Pseudomonas Aeruginosa Colonization in Chronic Obstructive Pulmonary Disease Patients. Chronic Obstr Pulm Dis. Published online February 5, 2025. https://doi.org/10.15326/jcopdf.2024.0582

39. Rello J, Krenn CG, Locker G, et al. A randomized placebo-controlled phase II study of a Pseudomonas vaccine in ventilated ICU patients. Crit Care. 2017;21(1):22. Published 2017 Feb 4. https://doi.org/10.1186/s13054-017-1601-9

40. Adlbrecht C, Wurm R, Depuydt P, et al. Efficacy, immunogenicity, and safety of IC43 recombinant Pseudomonas aeruginosa vaccine in mechanically ventilated intensive care patients-a randomized clinical trial. Crit Care. 2020;24(1):74. Published 2020 Mar 4. https://doi.org/10.1186/s13054-020-2792-z

41. Bhat, T. A., Panzica, L., Kalathil, S. G., & Thanavala, Y. (2015). Immune Dysfunction in Patients with Chronic Obstructive Pulmonary Disease. Annals of the American Thoracic Society, 12 Suppl 2(Suppl 2), S169–S175. https://doi.org/10.1513/AnnalsATS.201503-126AW
Published
2025/11/25
Issue
Ahead of print
Section
Original paper

Copyright (c) 2025 Rajna Minic, Olivera Đukić, Dejana Kosanović, Dejan Žujović, Aleksandra Ilić, Marko Panić, Brižita Đorđević

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