Chronic obstructive pulmonary disease (COPD) and asthma are two common progressive lung diseases, asthma affects more than 300 million people worldwide and its prevalence is increasing,1 and COPD is the third leading cause of death worldwide.2,3 Asthma and COPD are complex inflammatory diseases of the airways, which possibly related to impaired host defenses lead to increased susceptibility to pathogens, pollutants and allergens.4 Decreased lung function is the main clinical feature of asthma and COPD. Immune system may be a key driver in the pathogenesis of COPD, and the immune response is significantly associated with acute exacerbations of COPD.5 Evidence from observational studies suggests that more immune cells are present in the lung tissue of COPD and asthma sufferers compared to healthy individuals, along with a significant immune response.6 Mendelian randomization (MR) studies found that a variety of immune cells and inflammatory factors are risk factors for the development of COPD and asthma.7,8 However, changes in immune cells are the process by which an immune response occurs in the body, and immune cells recognise foreign substances such as antigens and activate, proliferate and differentiate to form effector cells and produce effector molecules to remove the foreign substances. In this process, foreign substances such as antigens are the initiators of the body's immune response, while pathogenic microorganisms are the most common cause of the body's immune response. Antibody-mediated immune responses persist in all stages of asthma and COPD from initial to end-stage,9 but whether there is a clear causal relationship between the development of COPD and asthma remains unclear. It is suggested that antibody-mediated immune responses may be causally related to the development of COPD and asthma. Guillaume et al. measured serological measurements of 20 different microorganisms in 9724 participant serum samples, selected the ones with a seroprevalence of >15% for genome-wide association studies (GWAS).10 Whether these detected antibody-mediated immune responses are causally associated with the development of COPD, asthma, and reduced lung function remains unclear. MR is a potential method of causal inference aimed at estimating the effect of exposure factors on outcomes and being able to control for potential confounders, thus avoiding reverse causation bias.11

The objective of this study was to investigate the causal relationship between antibody-mediated immune responses and COPD, asthma and lung function by bidirectional two-sample MR analysis.

To our knowledge, this is the first study to analyses the causal relationship between antibody-mediated immune responses and COPD patients, asthmatics, and lung function. The results show that a total of 20 antibody-mediated immune responses that could have a significant causal effect on COPD, asthma, FEV1, and FVC. There was a total of seven antibody-mediated immune responses that could have a significant effect on COPD, asthma, FEV1, FVC at the same time, namely anti-Merkel cell polyomavirus IgG seropositivity, anti-polyomavirus 2 IgG seropositivity, anti-varicella zoster virus IgG seropositivity, Epstein-Barr virus EBNA-1 antibody levels, Epstein-Barr virus VCA p18 antibody levels, polyomavirus 2 JC VP1 antibody levels, and varicella zoster virus glycoproteins E and I antibody levels. More importantly, we find little difference between the results of the different analyses in terms of the risk causal impact of anti-polyomavirus 2 IgG seropositivity, and varicella zoster virus glycoproteins E and I antibody levels on COPD, asthma, FEV1, and FVC.

Infectious diseases are a major contributor to the global burden of disease and can have some impact on systemic diseases, such as fatigue, dyspnoea, pain, anxiety, depression and cognitive dysfunction following infection with COVID-19.25 And as this class of viruses is usually preventable, clarifying the causal relationship between viruses and COPD, asthma, and lung function will contribute to better clinical management and treatment of patients with COPD and asthma. The results of this study showed that polyomavirus and varicella zoster virus-induced immune responses were risk factors for COPD, asthma, FEV1, and FVC, and the results were consistent across the five MR analysis methods.

Polyomaviruses are small DNA viruses that are widely distributed in nature. Polyomaviruses usually infect immunocompromised individuals and can be transmitted through the respiratory system. Their infections are common and they do not show symptoms after infection.26 It has been shown that the CD8+ T cell response is specific for polyomavirus and is associated with clinical improvement in patients with polyomavirus infection.27 CD8+ T cells were found to be increased in mild to moderate COPD lungs and may contribute to inflammation before severe disease.28 Recent findings have identified the presence of polyomavirus infections in COPD patients.29 It is suggested that polyomavirus may have elicited the CD8+ T cell response that led to exacerbation in COPD patients. Polyomavirus has been thought to be closely associated with CD4+ T with B cells,30 and there is an interactive relationship between CD4+ T and CD8+ T,31 as well as CD4+ T driving B cell differentiation. And B cells may be potential transmitters of polyomavirus or involved in the control of polyomavirus.32 CD4+ T can be found to be crucial in the cellular immune response to polyomavirus, and Cao et al. found that CD4+ T is a protective factor against COPD.8 Some findings suggest that polyomavirus infection or persistence may not lead to the development of COPD.33,34 This is inconsistent with the results of the present study, and we believe that the possible reason for this is that all their studies were observational, and there may be errors in the findings.

The varicella zoster virus is left in the body after experiencing chickenpox and reactivates years later in a form called shingles. It can often occur in people whose immune systems are not working properly, such as in respiratory diseases like asthma and COPD.35 For varicella zoster virus, several guidelines have recommended vaccination against varicella zoster virus, and herpes zoster vaccination rates may be low in patients aged 50 years ≥COPD, which may indicate a lack of awareness of herpes zoster virus risk factors among clinicians and patients.36 The results of the present study identified varicella zoster virus as a risk factor for COPD, asthma, and reduced lung function, and therefore varicella zoster virus vaccination may be appropriate for all immunocompromised populations. Importantly, the increased economic burden and morbidity of herpes zoster, its prevention should be done with the use of vaccines, but specific vaccinations are not discussed in this study.

Unlike the present study, risk factors for immune responses to varicella zoster virus-induced immune responses were observed only in asthma. A meta-analysis reports that patients with asthma and COPD have a 24% and 41% increased risk of developing herpes zoster, respectively, compared with healthy controls.37 Asthma and COPD increase the risk of herpes zoster and related complications at any age and may be further elevated in patients receiving inhaled corticosteroids. A Spanish observational, retrospective, non-interventional study found that the most prevalent respiratory diseases (asthma, COPD, and lung cancer) were associated with a higher risk of herpes zoster and postherpetic neuralgia in a standard clinical practice setting.38 The mechanism may be a Th1/Th2 immune imbalance. Similarly, many studies have described an association between asthma and herpes zoster,39 which is consistent with our study. It has been shown that COPD is also a risk factor for herpes zoster virus infection and that the incidence of acute exacerbations of COPD is higher before and after herpes zoster virus attacks.40 However, the results of this study did not find COPD as a risk factor for herpes zoster virus infection.

This study still has some limitations. Firstly, the data for this study were all derived from European populations and further validation with more data from other ethnic populations is still needed to improve the extrapolation of the findings. Second, this study did not find statistical differences in the sensitivity analyses of multiple causal relationships, which may have led to false-positive results in this study. Third, lung diseases usually include both airway and alveolar lesions, and the lack of alveolar-related GWAS data led this study to focus primarily on lung diseases with airway alterations.

This study provides a comprehensive assessment of the causal relationship between antibody-mediated immune responses phenotypes and COPD, asthma, and lung function, and that the relationship is not confounded by other factors. Seven antibody-mediated immune responses phenotypes that may simultaneously have a causal effect on COPD, asthma, FEV1, and FVC, and anti-polyomavirus 2 IgG seropositivity, and varicella zoster virus glycoproteins E and I antibody levels had a clear role. The results of this study can help to screen people at risk of COPD, asthma, and for early prevention and preemptive diagnosis of pre-COPD, asthma condition.

Drs. LDH and LFR had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: LDH and LFR. Acquisition, analysis, or interpretation of data: XGX, LYL. Drafting of the manuscript: XGX. Statistical analysis: XGX. Obtained funding: LDH and LFR. Supervision: FHY. All authors have read and agreed to the published version of the manuscript.

This study was funded by the Innovation Team and Talents Cultivation Program of the National Administration of Traditional Chinese Medicine (Grant No. ZYYCXTD-D-202003); Natural Science Foundation of China (No: 82374602). The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

The authors declare that they have no competing interests.