Complement-Mediated Mechanisms in Allergic Asthma

Allergic asthma is driven by a complex interplay between innate and adaptive immunity in which the complement system plays a central role. Activation of complement via the classical, lectin or alternative pathways generates effector molecules such as C3b (an opsonin), C3a and C5a (anaphylatoxins) and the terminal membrane attack complex. In the asthmatic airway, C3a and C5a enhance vascular permeability, recruit eosinophils and neutrophils, and promote Th2- and Th17-polarised responses, thereby aggravating bronchoconstriction and airway hyperresponsiveness. Complement also modulates dendritic cell function and the balance between effector and regulatory T cells, influencing sensitisation to aeroallergens and susceptibility to viral exacerbations. Local complement regulatory proteins, including Factor H and I, appear altered in patients with asthma, suggesting that dysregulated complement activation contributes to airway inflammation, remodelling and mucus overproduction. Insights into these mechanisms have revealed complement components as potential biomarkers of disease activity and targets for novel therapeutic interventions aimed at restoring immune balance in the asthmatic lung.

Research from Nature Portfolio

Recent experimental work has demonstrated that respiratory viral infection can amplify complement-mediated airway pathology in allergic asthma. In a murine model of ovalbumin-driven asthma complicated by respiratory syncytial virus, levels of C5a and expression of C5a receptor 1 rose sharply in the lung, correlating with increased airway hyperresponsiveness, tissue inflammation and skewing of CD4+ T-cell subsets towards Th1, Th2 and Th17 at the expense of regulatory T cells. Pharmacological blockade of the C5a–C5aR1 axis attenuated lung injury, reduced cytokine release and restored T-cell homeostasis, highlighting the receptor as a viable target to mitigate virus-induced asthma exacerbations.

Research from all publishers

A systematic review of clinical and experimental studies has recently synthesised evidence on complement components in asthma patients. Although methodologies and patient populations varied, a recurring finding was the elevation of complement regulatory proteins such as Factor H and I in bronchial samples and peripheral blood, suggesting that compensatory upregulation of inhibitors may reflect chronic complement activation in allergic airways. The authors propose that complement regulators could serve as biomarkers of disease severity and control.

Analyses of exhaled particle samples from adults with asthma have further characterised local complement activity. Using a high-throughput proteomics platform, investigators identified nine complement and coagulation proteins differentially abundant in the small airway lining fluid of asthmatic subjects compared to healthy controls. Notably, C3 levels were highest in individuals with poorly controlled disease, and several proteins correlated with measures of small airway dysfunction, underscoring the potential of complement profiling to stratify patients for complement-directed therapies.

In a house-dust-mite murine model, therapeutic blockade of C5 during the effector phase selectively reduced recruitment and differentiation of Th2 cells, dampened interleukin-4 release and lowered allergen-specific IgE, without affecting group 2 innate lymphoid cell responses. C5 inhibition also attenuated airway hyperresponsiveness despite unchanged histopathology, indicating that modulating complement can decouple functional airway constriction from tissue remodelling.

Complement-Mediated Mechanisms in Allergic Asthma publication trend

The graph below shows the total number of articles in complement-mediated mechanisms in allergic asthma across all publications each year (not limited to Nature Index journals).

Technical terms

Complement system: A network of plasma and cell-surface proteins that, once activated, facilitate opsonisation, inflammation and cell lysis.

Anaphylatoxin: Small peptide fragments (C3a, C5a) generated during complement activation that increase vascular permeability and recruit immune cells.

Opsonin: A molecule (e.g., C3b) that tags pathogens or debris for enhanced phagocytosis by immune cells.

Airway hyperresponsiveness (AHR): Exaggerated bronchoconstrictive response to stimuli, characteristic of asthma.

C5a receptor 1 (C5aR1): The G-protein-coupled receptor on immune and structural cells that mediates the effects of C5a.

Dendritic cell (DC): Antigen-presenting cell that bridges innate and adaptive immunity by activating naïve T cells.

References

1. Respiratory Syncytial Virus Exacerbates OVA-mediated asthma in mice through C5a-C5aR regulating CD4+T cells Immune Responses. Scientific Reports (2017).
2. Role of Complement Components in Asthma: A Systematic Review. Journal of Clinical Medicine (2024).
3. Activation of the Complement and Coagulation Systems in the Small Airways in Asthma. Respiration (2023).
4. Complement factor C5 inhibition reduces type 2 responses without affecting group 2 innate lymphoid cells in a house dust mite induced murine asthma model. Respiratory Research (2019).