Fig. 10: Proposed mechanism for microbial-driven preterm birth.

The complement system is an integral component of the immune response and bridges the adaptive and innate response to pathogens. MBL activates the lectin pathway, whereas IgM and IgG1-3 complexes activate the classical pathway (a). Both pathways converge on the central component C3, which is activated via C3 convertase. Upon activation C3 is cleaved to generate C3b and C3a.C3b binds to C3 convertase to form C5 convertase, which leads to release of C5b and C5a.C3a and the more potent C5a lead to increased vascular permeability and chemoattract phagocytes, and C3b opsonises pathogens and aids phagocytosis via C3b receptors. The alternative pathway also activates a positive feed forward amplification loop via C3b deposition on the surface of pathogens. We propose that in women who deliver preterm, CST III (L. iners) and CST IV (diverse species) activate the complement cascade, which leads to a local pro-inflammatory immune milieu. It is likely that the presence of activated neutrophils leads to an increase in the local concentration of IL-8, IL-6, and IL-1β, prostaglandins (PGs) and matrix metalloproteinases (MMPs). If a dysregulated response occurs, this may lead to cervical shortening and preterm labour (b). In women who deliver at term (c), there is a predominance of CST I (L. crispatus). However, if CST III (L. iners) or CST IV (diverse species) is seen, we propose that a more regulated immune response prevents cervical shortening and the triggering of early parturition. Figure created with BioRender.com.