Complement is the center of inflammatory reaction
Complement is an important and conservative system for natural immune, and provides pathways for rapid and effective elimination of invasive micro-organisms [14, 15]. It is a "bridge" between natural immune and acquired immune. Besides direct immune mechanism, complement can also release many types of small molecular fragments which have broad biological effects, such as chemotaxis of neutrophils and lymphocytes, phagocytosis, and participation in regulating immune response of cells and body fluid. In addition, Complement system is also an important medium for inflammation and immune reaction, and poses great potential threat to the body. If complement system is over activated, many complement components will be consumed, and reduce the anti-infection ability of the body; many active substances derived from the activation will induce severe inflammatory reaction or tissue injury, resulting in pathological process . For example, complement activation can produce inflammatory media including C2a, C3a, C4a and C5a. C2a has kinin-like function, and can expand small vessels and improve permeability; C3a, C4a and C5a have anaphylatoxin function, and can degranulate mast cells and basophils, release vasoactive mediators and induce inflammatory reaction; C3a, C5a and C5b67 have chemotaxis function, and can attract inflammatory cells to concentrate and migrate toward the inflammatory region activated by the complement, and thus increase inflammatory reaction.
CR2 is the central molecule for the immune response regulation by complement system. Split products of C3 molecules includes C3dg, iC3b, C3d and C3b, which are deposited on the activating cell surface and are the specific ligands for CR2 molecules. So CR2 is a good choice as a tarteting vector for delivery of complement inhibitors such as Crry and CD59 to sites of inflammation induced by complement activation. Many studies have indicated that CR2 targeting complement inhibitors can significantly mitigate inflammatory reaction in local sites [17, 18]. CD59 and Crry are important complement regulatory protein and the ideal complement inhibitor. CD59 can interfere the combination of C7, C8 with C5b-6 complex and inhibite the formation of membrane attack complex, MAC. Crry can block the complement activation by inhibite the activity of C3/C5 convertase.
Influenza viral lung injury and complement activation
Many studies have proved that excessive inflammatory injury in lung tissues induced by influenza virus infection is closely related to complement activation. Complement activation can affect influenza virus-specific immune response in the lung [19, 20]. After being infected by influenza virus, C3-deficient mice see significant decrease of T-cell reaction, and complement activation plays an important role in T-cell activation or recruitment [21, 22]. Martin has found that C3a and C5a can induce neutrophil migration in the lung infected by influenza virus . All the above studies show that complement activation following influenza virus infection can significantly influence pulmonary infiltration and lung injury degree. Hohenthal U and Nuutila J found that complement receptors have strong expression in influenza viral pneumonia [24, 25]. Kase T found that human MBL can directly or indirectly remove influenza virus particles and inhibit viral transmission through complement activation and opsonization . Through coupling with influenza antigen HA, C3d can increase the level of anti-influenza virus HA antibody, reduce the activation threshold of B-cell and improve the intensity of immune response [27, 28]. M. Paula Longhi et al. found that CD59a-deficient mice (Cd59a(-/-)) inflected with influenza virus have more serious pneumonia than wild-type, with more significant pulmonary hemorrhage and leukocytic infiltrate, neutrophil and lymphocyte aggregation, lung cell fibrosis and CD4+ T-cell activation; after injection of complement inhibitors, Cd59a(-/-) mice have improved lung inflammatory reaction and significant neutrophil infiltration decrease .
The above studies indicate that through inhibiting complement activation, excessive inflammatory reaction in lung tissues induced by influenza can be inhibited, and as a result, lung tissue injury can be mitigated and the mortality can be reduced. As complement is both a physiological defense and a pathological damage medium, it functions as a double-edged sword. Systematic complement inhibition may result in potential side effects including infection. Therefore, we design targeting complement inhibitors for complement activation sites with CR2 as targeting vector, complement inhibitors like CD59 and Crry are targeted to inflammatory sites to specially inhibit the complement activation in the local injury, thus local inflammatory reaction is inhibited, without side effects caused by systematic inhibition.