A Computational and Experimental Study of the Regulatory Mechanisms of the Complement System

The complement system is key to innate immunity and its activation is necessary for the clearance of bacteria and apoptotic cells. However, insufficient or excessive complement activation will lead to immune-related diseases. It is so far unknown how the complement activity is up- or down- regulated and what the associated pathophysiological mechanisms are. To quantitatively understand the modulatory mechanisms of the complement system, we built a computational model involving the enhancement and suppression mechanisms that regulate complement activity. Our model consists of a large system of Ordinary Differential Equations (ODEs) accompanied by a dynamic Bayesian network as a probabilistic approximation of the ODE dynamics. Applying Bayesian inference techniques, this approximation was used to perform parameter estimation and sensitivity analysis. Our combined computational and experimental study showed that the antimicrobial response is sensitive to changes in pH and calcium levels, which determines the strength of the crosstalk between CRP and L-ficolin. Our study also revealed differential regulatory effects of C4BP. While C4BP delays but does not decrease the classical complement activation, it attenuates but does not significantly delay the lectin pathway activation. We also found that the major inhibitory role of C4BP is to facilitate the decay of C3 convertase. In summary, the present work elucidates the regulatory mechanisms of the complement system and demonstrates how the bio-pathway machinery maintains the balance between activation and inhibition. The insights we have gained could contribute to the development of therapies targeting the complement system.Author Summary: The complement system, which is the frontline immune defense, constitutes proteins that flow freely in the blood. It quickly detects invading microbes and alerts the host by sending signals into immune responsive cells to eliminate the hostile substances. Inadequate or excessive complement activities harm the host and may lead to immune-related diseases. Thus, it is crucial to understand how the host boosts the complement activity to protect itself and simultaneously establishes tight surveillance to attain homeostasis. Towards this goal, we developed a detailed computational model of the human complement system. To overcome the challenges resulting from the large model size, we applied probabilistic approximation and inference techniques to train the model on experimental data and explored the key network features of the model. Our model-based study highlights the importance of infection-mediated microenvironmental perturbations, which alter the pH and calcium levels. It also reveals that the inhibitor, C4BP induces differential inhibition on the classical and lectin complement pathways and acts mainly by facilitating the decay of the C3 convertase. These predictions were validated empirically. Thus, our results help to elucidate the regulatory mechanisms of the complement system and potentially contribute to the development of complement-based immunomodulation therapies.