Introduction
Asthma is a widespread and heterogeneous disorder characterized by persistent airway inflammation [
1]. Recent studies have indicated that the prevalence of asthma has been on the rise for many years and currently affects 45.7 million adults in China [
2]. The importance of innate immune pathways in controlling adaptive immune responses has brought to light the role of innate immune pathways in the pathogenesis of asthma [
3], with the complement system acting as a bridge between the two [
4]. In recent years, the involvement of complement activation in allergic airway inflammation has been widely acknowledged [
5]. Additionally, high levels of plasma complement C3 have been linked to an increased risk of asthma hospitalizations and exacerbations in asthmatic patients, suggesting a causal role of the complement system in the development of asthma [
6].
Ficolins are components of the innate immune system, which activate one of the three pathways of complement activation, known as the lectin pathway [
7]. Three human ficolins have been identified: ficolin-1 (M-ficolin), ficolin-2 (L-ficolin), and ficolin-3 (H-ficolin) [
8], as well as two murine variants, ficolin A and B [
9]. According to phylogenetic analysis, ficolin B is the homologue of human ficolin-1, and ficolin A is closely related to human ficolin-2 [
10]. The gene encoding the mouse ficolin-3 is a pseudogene [
11]. Structurally, ficolin genes consist of a basic homotrimer, where each chain comprises an N-terminal region, followed by a collagen-like domain and a C-terminal fibrinogen-like domain [
12]. The collagen-like domain interacts with the MBL-associated serine proteases (MASPs), and the ficolin-MASP complex binds to carbohydrates present on the surface of microorganisms to initiate complement activation through the lectin pathway [
13]. Ficolin-1 is mainly produced in peripheral leukocytes, the spleen, and the lung [
14], while ficolin-2 is expressed solely by hepatocytes in the liver and secreted into the bloodstream, and ficolin-3 is synthesized by hepatocytes in the liver and the lung, and can also be found in the serum [
15].
As soluble pattern recognition receptors, ficolins have been observed to bind to various clinically relevant microorganisms, such as fungi, bacteria, and viruses, suggesting that they may play a role in defending the host against infection. However, the same components of the humoral innate immune response can be pathogenic in autoimmune and chronic inflammatory disorders [
16]. The accumulated evidence, including mouse models and clinical studies, suggests that genetic variation or insufficient expression of ficolins is associated with increased susceptibility to various infections, such as
Aspergillus fumigatus [
17],
Mycobacterium avium [
18],
Mycobacteria tuberculosis [
19], and
Streptococcus pneumoniae [
20]. Moreover, a growing body of research has indicated that ficolins play a significant role in the onset and progression of several autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis, systemic sclerosis, type 1 diabetes, and inflammatory bowel disease, as reviewed by Wang et al. [
21]. However, no investigations have been conducted to examine the involvement of ficolins in asthma.
Taken together, it is tempting to speculate that ficolins may be involved in the pathogenesis of asthma, and associated with the clinical features. In this research, we investigated the expression of ficolins in asthmatic patients and found that only ficolin-1 plasma levels were substantially raised in asthmatic patients compared to healthy individuals. Additionally, the correlation of ficolin-1 expressions with pulmonary function and clinical syndromes in asthma patients was also analyzed.
Discussion
Our data was the initial evidence of ficolin-1 expression in asthma patients, with asthmatic patients displaying significantly higher plasma ficolin-1 levels than healthy controls. Furthermore, plasma ficolin-1 levels in asthmatic patients were significantly reduced after ICS treatment. Additionally, there were significant associations between plasma ficolin-1 levels and clinical indices, including lung function and ACQ score, with those with high plasma ficolin-1 levels having poor lung function.
It has been well established that uncontrolled activation of the complement system in the airways is a contributing factor to asthma pathogenesis [
5,
26,
27]. Ficolins are pattern recognition molecules with collagen-like and fibrinogen-like domains and can activate the complement system through the lectin pathway [
28]. However, no data on this topic has been available on asthma patients. Another trigger of the lectin pathway, mannose binding lectin (MBL), has been studied about allergic inflammation, though the results have been somewhat contradictory. Allergen extracts have been found to bind purified MBL and activate the complement cascade in vitro [
29]. In contrast, MBL deficiency has been found to reduce airway hyperresponsiveness, inflammation, and type 2 cytokine levels in a model of chronic fungal asthma [
30], suggesting that the MBL-induced lectin pathway is involved in allergic disorders. Uguz et al. reported that serum MBL levels were significantly higher in children with asthma and correlated with peripheral blood eosinophils in these patients [
31]. Furthermore, MBL levels have been found to differ in asthmatic children of varying severity [
32]. Nagy et al. concluded that MBL2 gene polymorphisms are significant in the susceptibility to asthma in children infected with C.
pneumoniae [
33]. However, MBL2 gene polymorphisms have been reported not to be associated with the atopy status and asthma phenotype in adults [
34,
35].
It is possible to hypothesize that ficolins, which activate the complement lectin pathway, may be involved in the development of asthma. A prospective study found that serum ficolin-2 concentrations were significantly lower in patients with allergic airway disease and respiratory infections. However, the gap between those with allergic disorders and healthy controls appeared less pronounced [
36]. The authors proposed that decreased ficolin-2 levels could make individuals more vulnerable to respiratory infections, which could result in allergic diseases [
36]. Studies examining the direct involvement of ficolins in allergic inflammation are limited. To address this, we conducted a study to evaluate the expression of all three ficolins in asthma. Ficolin-2 and ficolin-3 are mainly synthesized in the liver, while ficolin-1 is the only human ficolin produced in the bone marrow and expressed primarily to granulocytes, monocytes, and type II alveolar epithelial cells [
14]. Additionally, ficolin-1 concentrations in plasma are lower than those of ficolin-2 or ficolin-3 [
21]. Our findings revealed that only ficolin-1 concentrations significantly differed between asthmatic patients and healthy controls.
In addition to recognizing pathogens, studies have revealed that ficolin-1 binds to natural killer (NK)‐cells and activates T-cell subsets through its FBG domain, creating a connection between innate and adaptive immunity [
37]. Numerous studies have examined the involvement of ficolin-1 in the start and evolution of autoimmune and chronic inflammatory diseases. Hein et al. observed that the serum ficolin-1 in SLE patients was significantly reduced and linked to the severity of the condition in those with SLE [
38]. Ammitzboll et al. and Kasperkiewicz et al. demonstrated that serum ficolin-1 levels were associated with increased disease activity in patients with rheumatoid arthritis [
39] and juvenile idiopathic arthritis [
40], respectively. Furthermore, both ficolin B deficiency and the administration of anti-ficolin-1 mAb were found to decrease the severity of collagen Ab–induced arthritis, with a reduction in the infiltration of synovial macrophages and neutrophils [
41]. Elevated transcriptional levels of ficolin-1 in peripheral leukocytes and a heightened presence of ficolin-1-positive monocytes in glomeruli in individuals with microscopic polyangiitis have been documented [
42].
Our data indicated a negative correlation between elevated ficolin-1 expression and pulmonary function, with asthma patients exhibiting worse lung function when their plasma ficolin-1 levels were high. This was further supported by a positive correlation between ficolin-1 concentrations and ACQ scores. These findings suggest that ficolin-1 may be a potential biomarker for clinical monitoring in asthma. Furthermore, our data showed that plasma ficolin-1 levels decreased after four weeks of ICS treatment. Taken together, these results suggest that elevated ficolin-1 may play a role in asthma development.
However, this study still has some limitations. First, though we found that asthma patients have higher levels of ficolin-1 in their plasma, we did not investigate the expression of ficolins in bronchoalveolar lavage fluid or induced sputum. Second, our study had a relatively small sample size, and may be subject to potential selection bias; however, our conclusion was considered acceptable, as there was no significant disparity between subjects with asthma and heathy controls regarding demographic factors. Thirdly, our study utilized ACQ questionnaire to score asthma symptoms, relied on self-reported data, and therefore may be subject to recall bias. Fourth, our study was a 4-week observational study, which was not sufficient to determine asthma severity, and therefore the association between asthma severity and ficolin-1 expression was not evaluated. Fifth, we only examined the expression of ficolin-1 in this study; further investigations will be conducted to explore the mechanism through in vitro studies and by utilizing a ficolin-1 knockout mouse model.
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