Asthma, as a complex inflammatory disease, is influenced by an intricate interplay among genetic predispositions, environmental exposures, and immune responses[28, 29]. Our study underscores the critical role of immune cells in orchestrating the inflammatory milieu that characterizes asthma. The findings from our MR analysis highlight how specific immune cell phenotypes contribute distinctively to asthma pathogenesis.
HLA-DR on plasmacytoid dendritic cells (pDCs) plays a pivotal role in the pathogenesis of asthma through its involvement in immune regulation and response to inflammation[30]. Plasmacytoid DCs are primarily known for their ability to produce large amounts of type I interferons in response to viral infections, which are critical in the innate immune defense[31, 32]. The expression of HLA-DR, a major histocompatibility complex class II molecule, on these cells facilitates their role in antigen presentation[33]. In asthma, HLA-DR on pDCs allows them to present allergen-derived peptides to T cells, particularly initiating the differentiation of naive T cells into Th2 cells during the sensitization phase of allergic asthma[34]. This Th2 cell differentiation leads to the production of cytokines like IL-4, IL-5, and IL-13, which further drive the inflammatory processes characteristic of asthma, such as eosinophilic inflammation and hypersecretion of mucus in the airways[35]. By modulating the activity of pDCs or their interaction with T cells, it may be possible to influence the course of asthma, highlighting the importance of these cells in both the initiation and exacerbation of the disease[10].CD62L − CD86 + myeloid dendritic cells (DCs) play a crucial role in asthma by modulating immune responses, particularly in inflammation and T cell activation. The absence of CD62L suggests these DCs are activated or mature, primarily located in peripheral tissues or inflammation sites[36], while the presence of CD86 indicates readiness to activate T cells by presenting antigens and providing co-stimulatory signals[37]. In asthma, these cells facilitate the activation of naive T cells into Th2 cells, which produce cytokines like IL-4, IL-5, and IL-13, driving key asthma features such as eosinophil recruitment, mucus production, and airway hyperresponsiveness[38]. CD33, a sialic acid-binding immunoglobulin-like lectin, marks a subset of myeloid cells known as CD33dim HLA-DR + CD11b−[39], which play a complex role in asthma's immune landscape. These cells, with moderate CD33 expression and high levels of HLA-DR but no CD11b, potentially modulate immune responses to reduce inflammation, influencing asthma severity and symptom progression[40, 41]. Additionally, CD33 expression on monocytic myeloid-derived suppressor cells (Mo MDSCs) significantly impacts asthma by suppressing immune responses, particularly through inhibiting T cell proliferation and cytokine production, which can perpetuate inflammation and affect disease resolutionCD3 on CD4 + regulatory T cells (Tregs) plays a crucial role in modulating the immune response associated with asthma, primarily through their immunoregulatory functions[42]. On CD4 + Tregs, CD3 is involved in the activation of these cells, which are essential for maintaining immune tolerance and preventing autoimmunity[43]. In the context of asthma, CD4 + Tregs help to control and suppress excessive immune responses to allergens, which are a common trigger for asthma attacks[44]. They achieve this by inhibiting the proliferation of effector T cells and reducing the production of pro-inflammatory cytokines[45]. This suppressive activity helps to prevent the overactive inflammatory responses that lead to airway hyperresponsiveness and remodeling, characteristic features of asthma. Enhancing the function or number of Tregs might provide a therapeutic strategy to reduce inflammation and improve asthma outcomes, highlighting the importance of these cells in maintaining immune homeostasis and controlling asthma exacerbations[46]. Our study also explores the causal relationship between asthma and immune phenotypes. Following adjustment for multiple testing using the FDR method, we did not observe significant associations between asthma and immune traits at a significance level of 0.05. This finding suggests that the pathogenesis of asthma may be a multifactorial process influenced not only by the immune system but also by other regulatory factors.
The use of MR analysis in our study provides a robust framework for understanding the causal impact of immune cell phenotypes on asthma susceptibility. By leveraging genetic variants as instrumental variables, MR helps in mitigating confounding factors typical of observational studies. This approach is particularly valuable in dissecting the complex genetic architecture underlying immune responses in asthma. The identification of causal relationships between specific immune cell phenotypes, such as the expression of HLA-DR on plasmacytoid dendritic cells and asthma risk, potentially opens new avenues for targeted therapeutic interventions. These immune cells could serve as biomarkers for predicting asthma severity or as direct targets for biologic therapies aimed at modulating their function.While our findings provide significant insights into the immunological underpinnings of asthma, several challenges remain. The complexity of asthma phenotypes and the heterogeneity in patient responses to treatments indicate that multiple genetic and environmental factors are at play. Future research should focus on integrating comprehensive genomic data with detailed environmental exposure data to better characterize the gene-environment interactions that drive asthma pathogenesis.Furthermore, the clinical translation of these findings requires validation in diverse populations. Given the genetic diversity and varying environmental exposures across populations, the generalizability of our results needs to be rigorously tested in multi-centric, international cohorts.In conclusion, our MR analysis has elucidated several key immune cell phenotypes that hold causal associations with asthma. These findings enhance our understanding of the immunological mechanisms of asthma and underscore the potential of immune-focused therapies. By continuing to leverage advanced genetic analytical techniques like MR, the path toward precision medicine in asthma looks promising, with the potential to tailor interventions based on individual immune profiles to improve patient outcomes.