![]() first showed that, in contrast with wild type mice, mice deficient for C3 did not lose mechanosensation in the cornea when infected with HSV-1. ![]() Now, in eLife, Derek Royer and colleagues at Duke University Medical School and the University of Oklahoma Health Sciences Center report on the effects of complement activation on the nerves in the cornea ( Royer et al., 2019). The activation of the complement system occurs within seconds of a pathogen being recognized, and while its main purpose is to control pathogen spread, additional activities have been discovered. Labeling of a pathogen by C3 is a unique event that tags the target for clearance ( Gadjeva et al., 1998). Once cleaved, C3 undergoes a conformational change, exposing an active site that allows it to covalently bind to target surfaces. Every activation of the complement system eventually leads to the proteolytic cleavage of a protein called C3. The complement system is usually activated by antibodies bound to the surfaces of pathogens such as viruses, bacteria or fungi, and it self-assembles through a well-coordinated cascade of proteolytic events. Infectious and non-infectious responses to inflammation often activate the complement system – an evolutionarily conserved system with over 30 soluble and membrane-associated proteins that enhance the ability of the immune system to clear infection. Understanding which molecules initiate the process could lead to new therapies for targeted pain management. However, the molecular mechanisms that govern neuropathy are still unknown. For example, mice with a herpes simplex virus type 1 (HSV-1) infection in the eye stop perceiving mechanical stimuli due to nerve loss. Infections and other inflammatory conditions, such as graft versus host disease (where the host immune system attacks transplanted tissue), are often associated with neuropathies. The majority of neurons in the cornea are nociceptors: they respond to noxious stimuli, such as touch, temperature, and toxins, by signaling pain. The cornea is likely the most densely innervated part of the human body with approximately 7,000 sensory neurons per square millimeter, making it 300 to 600 times more sensitive to stimuli than the skin ( Siran et al., 2018 Cruzat et al., 2017 González-González et al., 2017).
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