By Dr. Maria Benito
Chronic obstructive pulmonary disease (COPD) is a pathological disorder characterized by deregulated chronic inflammation of the airways and persistent airflow obstruction, which lead to emphysematous destruction of lung tissue and deterioration of the pulmonary function. The characteristic of COPD include infiltration of neutrophils, macrophages, B and T lymphocytes, and dendritic cells. It also comprises mucociliary dysfunction, apoptosis, and structural changes in the airways causing emphysema, and extrapulmonary systemic effects, with a calculated prevalence of 10% in over forty years old adults.
Clinical features of COPD include chronic bronchitis and loss of alveolar tissue, with conventional therapies working only as palliative treatments. Respiratory infections, increase of cardiovascular risk, lung cancer, pulmonary hypertension, and depression are some of the most common complications caused by this disorder.
COPD shares many clinical and pathophysiological features with autoimmune diseases, with a strong evidence for an active adaptive T cell response. Autoimmunity plays a role in COPD and can explain the perpetuation of the unregulated inflammatory process. COPD patients may be divided according to their lung immunological and inflammatory status –innate and adaptive immunity–, presence of autoantigens –adaptive immunity with Th1 and B cells involvement–, and epigenetic modifications –inflammation and structural changes.
The idea of a strong autoimmune component in COPD is sustained by the evidence of a strong prevalence of IgG autoantibodies in COPD patients, and the findings that autoantibodies against pulmonary epithelium are widespread in COPD and participate in the disease development, while the endothelium of the lung vasculature is also exposed to autoimmune attacks. However, the nature of antigens reacting with autoantibodies is still mostly unknown, with a large number of possible candidates. Some of these candidates for epitopes and autoimmune activity include antihuman cytokeratin 18 protein antibodies, antineutrophil antibodies directed against lactoferrin, or antielastin antibodies –which have been proposed to drive COPD progression–, but data on this last one are inconsistent. A recent study also suggests that in COPD, rheumatoid factor antibodies and auto-antibodies to heat shock protein (HSP) 70 are elevated, and may play a role in the disease.
It remains however to be elucidated what mechanisms contribute to the immunogenicity of each antigen in COPD patients. One hypothesis is that the humoral immune response against disease associated antigens results from overexpression. Although there is some evidence for an association of overexpression and immunogenicity of antigens, there is still no conclusive experimental proof of its causative role. Posttranslational modifications –including altered protein folding and processing– may also cause a humoral immune response against antigens associated with the disease.
Cigarette smoking is considered a major instigator of parenchymal inflammation, and possibly responsible for multiple mechanisms to express novel epitopes or antigenic determinants, which as a result of self-attack, induce damage in the lung tissue and lead to structural alterations and further generation of neoantigens. Thus, cigarette smoke and wood smoke-induced-COPD is also associated with citrullination of proteins. Oxidative stress inducers also stimulate structural protein carbonylation that serves as autoepitopes in patients with COPD.
It has also been demonstrated the relationship between antibody titers and lung function. Non-specific autoantibodies are present in the circulation and may play a role in disease development. In a complex disease as COPD, systemic autoantigens are also involved. In addition, the triggering hypothesis suggests that specific microbes, particularly viruses, may also trigger autoimmunity. All these results make scientist question if autoimmune process in COPD is the cause or just a consequence of the process, or may even be a mere coincidence.
The cellular infiltration of the lungs is made up of cells of both the innate and the adaptive immune response including macrophages, neutrophils, dendritic cells, and T and B lymphocytes. Although the considerable number of macrophages –cells that are implicated in promoting alveolar airspace enlargement through the release of matrix metalloproteinases (MMPs)– and neutrophils –which play a role in tissue destruction through elastases and reactive oxygen species– that are present in the airways helped supporting the hypothesis that both cell types are critical mediators in COPD, the role of infiltrating lymphocytes and dendritic cells in promoting inflammation in the lungs of COPD patients was mostly ignored or left aside, and it has been more taking into account lately.
The normal immune response comprises the innate and the adaptive responses. The innate response –long been considered as dominating the pathogenesis of COPD– involves phagocytic cells –including neutrophils and macrophages–, cells that release inflammatory mediators –such as mast cells and eosinophils–, and natural killer cells. Macrophages secrete IL-8, which promotes neutrophil infiltration and amplifies tissue destruction, while promoting T cell infiltration through the expression of T helper and T cytotoxic cells (Th1/Tc1) chemokines such as CXCL9, CXCL10 and CXCL11. Macrophages and infiltrating T cells may then act in a coordinated way to promote tissue destruction in COPD patients. However, in this disorder, there are many elements of both types of immune response acting in an abnormal way.
Historically, there has been much focus on the role of the innate immune system in COPD. However, there is increasing evidence of an adaptive immune component to the disease; T cells, and in particular CD8 T cells, increased in number in the lungs of COPD patients and may contribute towards an autoimmune process in COPD leading to persistent and progressive airway inflammation.
The onset of COPD is associated with an increase in the number of infiltrated CD8 cells, possibly contributing to the pathogenesis of COPD through their cytotoxic effect and by releasing pro-inflammatory cytokines –such as interleukin 2 (IL-2), interferon gamma (IFNγ) and tumour necrosis factor alpha (TNFα), and chemokines such as C-X-C chemokine motif 10 (CXCL10) and chemokine (C-C) motif ligand 5 (CCL5), which recruit other inflammatory cells– that leads to tissue destruction and consequently increases the exposure of self-antigens.
Evidence of the accumulation of both helper (CD4+) and cytotoxic T lymphocytes (CD8+) in the lung parenchyma supports the role of the acquired immunity –which requires the proliferation of B and T cells after antigen presentation by specialised cells such as macrophages and dendritic cells– in COPD. In addition, CD8+ T cells induce apoptosis of target cells through Fas ligand (FasL) or perforin/granzyme mechanism, and studies have demonstrated a correlation between T cell infiltration and apoptosis in the emphysematous lung. Alternatively, CD4+ T cells –which can differentiate into several subsets with specific cytokine expression profiles– are associated with the humoral immune response and co-localize with B cells forming lymphoid follicles containing germinal centers that increase with the disease severity, and consequently, play a role in the adaptive immune response in COPD, too.
Th1 cells –the predominant type in COPD– express IFN-g, Th2 cells –present in lung infiltrated in patients with COPD too– produce IL-4 and IL-5, while Th17 cells –characterized by the expression of IL-17, which promotes neutrophil chemotaxis and stimulates mucin production from respiratory epithelium– also play a role in the pathogenesis of COPD.
The T cell receptor (TCR) recognises antigens in order to produce an immune response. Thus, autoimmune diseases are associated with downregulation by myeloid suppressor cells of T cell receptor signalling pathway components such as zeta chain (ζ or CD247) –that plays a key role in both transduction of TCR signalling and also in anchoring the TCR to the cell membrane–, leading to T cell dysfunction, which may have important physiological consequences for the regulatory mechanism of the adaptive immune system.
The down regulation of some of the TCR signalling molecules –whose signalling is abnormal in COPD pulmonary CD8 cells– occurs in autoimmune diseases with the subsequent T cell dysfunction. Altered TCR signalling may be involved in the increased susceptibility to COPD exacerbations in a particular subset of COPD patients that suffer recurrent airway infection.
The TCR reacts to specific antigens, while CD8 cells can be activated through non-antigen specific mechanisms such as cytokine stimulation or TLR signalling. TLR expression increases on pulmonary infiltrated CD8 cells in COPD, escalating the release of cytokine when co-stimulated with a toll-like receptor family (TLR) 1/2 ligand, accounting for some of the increasing in effector functions seen in COPD. The down regulation of CD247, in contrast, suggests an inability to respond specifically to pathogens, and may account for the predisposition to recurrent airway infections in some of the COPD patients.
It has been assumed that an increase in the pro-inflammatory and cytotoxic activity of CD8 cells is the principal mechanism by which these cells contribute to the pathophysiology of COPD. There is increasing evidence, however, that non-antigen specific stimulation is responsible for the activation of these cells. Furthermore, other studies have shown that key T cell receptor signalling molecules are down regulated in pulmonary CD8 cells leading to the hypothesis that dysfunction of the antigen specific response of CD8 cells in COPD predispose to recurrent infections.
In addition to the protease imbalance model of disease pathogenesis, evidence-based research has shown that the interaction of a number of cell types contributes to specific disease related mechanisms. It is also widely accepted that the adaptive immune response is an important characteristic of emphysematous tissue damage in COPD patients, and the hypothesis of an autoimmune component in COPD nurture the possibility of discovering novel therapeutic treatments.REFERENCES
- Bagdonas E, Raudoniute J, Bruzauskaite I, Aldonyte R. “Novel aspects of pathogenesis and regeneration mechanisms in COPD”.Int J Chron Obstruct Pulmon Dis. 2015 Jun 2; 10:995-1013. doi: 2147/COPD. S82518
- Cosio MG, Saetta M, Agusti A Immunologic aspects of chronic obstructive pulmonary disease. N Engl J 2009; 360(23): 2445-54. doi: 10.1056/NEJMra0804752
- Daffa NI, Tighe PJ, Corne JM, Fairclough LC, Todd I. Natural and disease-specific autoantibodies in chronic obstructive pulmonary disease. Clin Exp Immunol. 2014 doi: 1111/cei.12565
- Freeman CM, Han MK, Martinez FJ, Murray S, Liu LX, Chensue SW, Polak TJ, Sonstein J, Todt JC, Ames TM, Arenberg DA, Meldrum CA, Getty C, McCloskey L, Curtis JL. Cytotoxic potential of lung CD8(+) T cells increases with chronic obstructive pulmonary disease severity and with in vitro stimulation by IL-18 or IL-15. J Immunol. 2010; 184(11): 6504-13. doi: 4049/jimmunol. 1000006
- Getts DR, Chastain EML, Terry RL, Miller SD. Virus infection, antiviral immunity, and autoimmunity. Immunol Rev.2013; 255(1):197-209. doi: 1111/imr.12091
- Grundy S, Plumb J, Lea S, Kaur M, Ray D, Singh D. Down Regulation of T cell Receptor Expression in COPD Pulmonary CD8 Cells. PLoS One. 2013; 8(8): e71629. doi: 1371/journal.p one.0071629
- Hurst JR, Vestbo J, Anzueto A, Locantore N, Mullerova H. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363(12): 1128-38. doi: 1056/ NEJMoa0909883
- 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. doi: 1164/rccm.201010-1605OC
- Leidinger P, Keller A, Heisel S, Ludwig N, Rheinheimer S, Klein V, Andres C, Hamacher J, Huwer H, Stephan B, Ingo Stehle, Lenhof HP, Meese E. Novel autoantigens immunogenic in COPD patients. Respir Res. 2009; 10(1): 20.doi: 1186/1465-9921-10-20
- Packard TA, Li QZ, Cosgrove GP, Bowler RP, Cambier JC. COPD is associated with production of autoantibodies to a broad spectrum of self-antigens, correlative with disease phenotype. Immunol Res.2013; 55(1-3):48-57. doi: 1007/s12026-012-8347-x
- Rinaldi M, Lehouck A, Heulens N, Lavend’homme R, Carlier V, Saint-Remy JM, Decramer M, Gayan-Ramirez G, Janssens W. Antielastin B cell and T cell immunity in patients with chronic obstructive pulmonary disease. 2012; 67(8):694-700. doi: 10.1136/thoraxjnl-2011-200 690
- Sigari N, Moghimi N, Shahraki FS, Mohammadi S, Roshani D. Anti-cyclic citrullinated peptide (CCP) antibody in patients with wood-smoke-induced chronic obstructive pulmonary disease (COPD) without rheumatoid arthritis. Rheumatol Int. 2015; 35(1):85-91. doi: 1007/s00296-014-3083-2
- Stefanska AM, Walsh PT. Chronic Obstructive Pulmonary Disease: Evidence for an Autoimmune Cell Mol Immunol. 2009; 6(2):81-86. doi: 10.1038/cmi.2009.11
- Walter U, Santamaria P. CD8+ T cells in autoimmunity. Curr Opin Immunol. 2005; 17(6): 624-31. doi: 1016/j.coi.2005.09.014