Chronic Obstructive Pulmonary Disease (COPD) is a heterogeneous disorder primarily characterized by airway pathologies (bronchitis, bronchiolitis) and/or alveolar abnormalities (emphysema), leading to chronic respiratory symptoms (dyspnea, cough, sputum production) and progressively worsening airflow limitation (1). Globally, COPD accounts for more than half of all chronic respiratory disease cases (2), gradually becoming the third leading cause of death worldwide (3). With the increasing prevalence of an aging population, both the incidence and mortality rates of COPD are on the rise annually (4), imposing a significant economic burden on society (5).

Immune cells possess multifaceted functions in maintaining homeostasis and facilitating repair after injury (6). The lungs may serve as a battleground for the interaction between various microbes and the host’s innate and adaptive immune defenses (7). Consequently, the immune system could be a pivotal driving force in the pathogenesis of COPD, with immune responses being significantly associated with acute exacerbations of COPD (8). However, the detailed physiological mechanisms remain insufficiently explored (9). Most existing evidence, primarily from observational studies, indicates that compared to healthy controls, individuals with COPD have an increased presence of immune cells in lung tissue (10, 11) and an upregulated immune cell response (12). Cells such as CD68+ myeloid antigen-presenting cells, CD4+ T cells, and CD8 T cells are found to proliferate in the lungs of patients with COPD, potentially leading to persistent inflammation (13, 14). Certain immune cells exhibit a negative correlation with the frequency of COPD exacerbations (15), such as CD4 T cells and resting natural killer cells (16). Consequently, the causal relationship and underlying mechanisms between immune cells and COPD remain unclear. Metabolites, as intermediates of metabolic reactions, can influence disease progression (17) and serve as targets for therapeutic intervention (18). They have the potential to improve the diagnosis and treatment of COPD (19) and may play a synergistic role in its pathogenesis (20), possibly mediating important immunoregulatory functions (21). Compared to healthy controls, COPD patients exhibit reduced levels of the metabolites 1-methylnicotinamide creatinine, and lactate (17). Glutamylphenylalanine may serve as a biomarker for acute exacerbations of COPD (22), while sphingolipids are associated with pulmonary function (23). Therefore, we hypothesize a causal relationship between immune cells, metabolites, and COPD. Elucidating these associations and understanding the true causal relationships among immune cells, metabolites, and COPD could aid in the early identification, prevention, and management of COPD.

Mendelian Randomization (MR) represents a potential method for causal inference, designed to estimate the causal effects of exposure factors on outcomes, with the capability to control for potential confounding factors and circumvent reverse causation biases (24). Utilizing the methodology of MR, we are poised to conduct a bidirectional MR study concerning immune cells and COPD, concurrently undertaking two mediating analyses to dissect the causal relationships among immune cells, metabolites, and COPD.

In our MR study, the findings indicated a causal relationship between 41 immune cell phenotypes and COPD. However, a reverse MR analysis revealed that 35 immune cell phenotypes bore no causal relationship with COPD, while 6 did exhibit a causal connection. Further employing TSMR and MVMR for mediation analysis, we identified that 8 cell phenotypes could be causally linked to COPD through 8 plasma metabolites (including one unidentified), among which the mediation proportion of 1-methylnicotinamide levels was the highest at 26.4%.

Our research has corroborated the existence of a causal relationship between 41 immune cell phenotypes and COPD, aligning with previous studies that posit chronic inflammation leading to compromised immunity and immunosuppression as pivotal in the pathogenesis of COPD (40), a condition persistently present in the disease (41). It has been observed that, compared to healthy individuals, patients with COPD exhibit an increase in B cells and their products in the blood and lungs (42), alongside an upsurge in the expression of genes related to inflammation, B cell activation, and proliferation. This activation of B cells is associated with an autoimmune-mediated mechanism of COPD pathogenesis (43, 44). However, the association between B cells and COPD does not imply causality (45). Our study, however, confirms a causal relationship between specific B cell phenotypes and COPD, with an increase in memory B-cells being linked to impaired lung function and small airway dysfunction (46), consistent with our findings that CD24 on memory B cells increases the risk of COPD. Furthermore, the subgroups of peripheral blood TBNK lymphocytes in COPD patients show a certain correlation with COPD (47) and its severity (48), aligning with our MR results and suggesting a causal relationship. Regulatory T (Treg) cells play a crucial role in the immune system by suppressing excessive immune responses and maintaining immune balance. The relationship between Treg cells and lung function (49), the imbalance of Treg cells during COPD progression (50), and the potential of modulating Treg cells to improve COPD (51) and lung inflammation underscore their significance (52). Myeloid cells, capable of phagocytosing pathogens, initiating inflammatory responses, and presenting antigens to other immune cells, contribute to tissue repair and remodeling. Our analysis identified six immune cell phenotypes with a causal relationship to COPD in both directions, namely CD14+ CD16+ monocyte AC, CD4+ CD8dim %lymphocyte, CD4+ CD8dim %leukocyte, CD3- lymphocyte AC, CD3 on EM CD8br, and CD45 on Im MDS, all associated with a reduced risk of COPD. The CD14+ CD16+ monocyte AC, a monocyte subgroup expressing CD14 and CD16, plays a role in modulating inflammatory responses and promoting tissue repair, with monocytes being etiologically related to COPD (53) and influencing its pathogenesis and diagnosis (54, 55), serving as key drivers of lung inflammation and tissue remodeling (56). The CD4+ CD8dim %lymphocyte, a unique lymphocyte, plays a role in regulating immune responses and maintaining immune balance, with CD4-regulated T cells controlling autoimmunity and thus managing lung inflammation in COPD (57, 58), while CD4 and CD8 are related to bronchiolar wall remodeling in COPD (59) and the reduction of terminal bronchioles (60).

Metabolites play a crucial role in the early identification of individuals at high risk and in the prevention of diseases (61). Clinically, they enable us to differentiate the disease characteristics of COPD (62), identify diagnostic biomarkers (63, 64), and evaluate the efficacy indicators of COPD treatments (65). Our study has discovered a causal relationship between CD24 on memory B cells and COPD, mediated by two intermediaries: 1-methylnicotinamide and 1-palmitoyl-GPG (16:0). There is a positive correlation between CD24 on memory B cells and COPD, where an increase in CD24 on memory B cells elevates the risk of COPD. Furthermore, CD24 on memory B cells is positively correlated with 1-methylnicotinamide, which, in turn, is positively associated with COPD. 1-methylnicotinamide, a primary metabolite found in all living organisms and involved in growth, development, or reproduction, possesses various immunomodulatory properties. It is linked to inflammatory responses in lung epithelial cells (66)and the activation of the NLRP3 inflammasome (67), a significant mediator in COPD inflammation (68). Through NLRP3, lung inflammation can be regulated (69, 70), indicating a certain correlation between 1-methylnicotinamide and COPD. Our research confirms a causal relationship between 1-methylnicotinamide and COPD, with CD24 on memory B cells influencing COPD risk through the mediation of 1-methylnicotinamide. Conversely, CD24 on memory B cells is negatively correlated with 1-palmitoyl-GPG (16:0), which is positively associated with COPD. Research on 1-palmitoyl-GPG (16:0) is limited, but it is generally considered part of lipid metabolism, related to vitamin D deficiency (71) and pulmonary hypertension (72). Vitamin D may be a risk factor for COPD (73), though specific studies on COPD are lacking. Lipid metabolism plays a key role in the adaptive immune response to chronic inflammation (74) and is associated with lung inflammation in mice (75), with COPD patients exhibiting higher lipid expression (76). Our MR analysis concludes a causal relationship between CD24 on memory B cells and COPD through 1-palmitoyl-GPG (16:0).

Taurochenodeoxycholate could potentially serve as an intermediary in the causal relationship between CD27 on unsw mem and COPD, demonstrating a negative correlation with both CD27 on unsw mem and COPD. Taurochenodeoxycholate, a bile acid functionally related to chenodeoxycholic acid, is involved in inflammatory responses (77), immune cell regulation (78), endoplasmic reticulum stress inhibition (79), and is associated with pulmonary fibrosis (80). However, research specifically targeting its role in COPD is scarce. MR analysis suggests that CD27 on unsw mem may have a causal relationship with COPD through the mediation of taurochenodeoxycholate. Alpha-tocopherol, the most active form of Vitamin E, has been observed in studies to reduce the risk of COPD in women (81), exhibiting anti-inflammatory and antioxidant properties that improve bronchial epithelial thickening, alveolar destruction, and lung function (82). Consistent with our MR analysis, alpha-tocopherol is negatively correlated with the risk of COPD, mediating a causal relationship between COPD and the percentage of HLA DR+ T cells among T cells. Alpha-hydroxyisovalerate, initially identified in studies related to human aging and early development (83), is associated with the severity of bronchiolitis (84) and, consistent with our MR analysis, positively correlated with the risk of COPD. It mediates a causal relationship between COPD and the phenotype of CD28+ CD45RA- CD8 bright %T cells. Cinnamoylglycine, with limited research related to COPD, has been found through MR analysis to be positively correlated with COPD. CD25 on transitional cells has a causal relationship with COPD mediated by cinnamoylglycine. N-oleoylserine, a secondary metabolite functionally related to oleic acid and with scant research in the context of lung inflammation (85), has been found through MR analysis to be negatively correlated with COPD, suggesting a protective factor.

This study represents a comprehensive assessment of the causal relationships between immune cell phenotypes, plasma metabolites, and COPD. We have identified 8 immune cell phenotypes that exhibit a causal relationship with COPD, mediated by 8 metabolites. These findings illuminate the significance of the underlying mechanisms between immune cells, metabolites, and COPD. They contribute to the screening of individuals at high risk for COPD and offer insights into early prevention and the preemptive diagnosis of Pre-COPD conditions.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

Ethical approval was not required for the study involving humans in accordance with the local legislation and institutional requirements. Written informed consent to participate in this study was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and the institutional requirements.

ZC: Writing – review & editing, Writing – original draft, Conceptualization. TW: Writing – original draft, Data curation. YF: Writing – original draft, Data curation. FS: Writing – original draft, Supervision, Data curation. HD: Writing – original draft, Data curation. LZ: Writing – original draft, Data curation. LS: Writing – review & editing, Writing – original draft, Conceptualization.