The complement system plays a crucial role in protecting against invading microorganisms, and acts through three activation pathways: the classic, alternative, and lectin pathways. The lectin pathway of complement activation is the most recently discovered of the three complement pathways. Mannose-binding lectin (MBL) and ficolins represent the first components of the lectin branch of the complement system. The anti-microbial activity of MBL has been widely studied, and it recognizes many different microorganisms, including fungi, bacteria, viruses, and protozoa (Dommett R M, et al., 2006; Jack D L, et al., 1998). Both MBL and the recently identified ficolins act as pattern recognition receptors (PRRs). These are soluble oligomeric defense proteins with lectin-like activity, and are able to recognize pathogen-associated molecular patterns (PAMPs), which are carbohydrate molecules on the surface of pathogens and of apoptotic, necrotic, and malignant cells. PRRs are either secreted or membrane-bound. Secreted PRRs are also called opsonins, and include MBL, ficolins, C-reactive protein (CRP), and serum amyloid protein (SAP) (Medzhitov R, 2007; Medzhitov R, et al., 2002). PRRs recognize charged ligandsand facilitate elimination of their ligands by phagocytes, and also mediate removal of apoptotic cells. PRRs serve several important roles in the innate immune response, including opsonization, phagocytosis, induction of apoptosis, and activation of cascades of complement, coagulation, and inflammation (Medzhitov R, et al., 2002).
The ficolins were originally identified as transforming growth factor (TGF)-1-binding proteins on porcine uterine membranes (Ichijo H, et al., 1993). Several members of the ficolin family have been identified to date, including human L-ficolin-2/P35 (FCN2 or ficolin 2) (Matsushita M, et al., 1996), M-ficolin (FCN1 or ficolin 1) (Endo Y, et al., 1996; Lu J, et al., 1996), and H-ficolin/Hakata antigen (FCN3 or ficolin 3) (Akaiwa M, et al., 1999), the mouse ficolins A and B (Fujimori Y, et al., 1998) (Table 1), the pig ficolins α and β, and the tachylectins 5A/5B (TL 5A/5B) from the horseshoe crab Tachypleus tridentatus (Gokudan S, et al., 1999). All ficolins function as recognition molecules, and trigger either the lectin pathway of complement or other effector mechanisms, following binding to several ligands.
Species Ficolin Tissues of origin Tissues of presentation Sugar specificity Gene localization Complement activation Human L-ficolin(ficolin-2) Liver Serum GlcNAc/ManNAc>>GalNAc/CysNAc/GlyNAc, acetylcholine, elastin, corticosteroids, 1, 3-b-D-glucan, LTA 9q34 Yes H-ficolin(ficolin-3) Liver, type Ⅱ alveolar cells Serum, bronchus, alveolus, bile GlcNAc, GalNAc, fucose, glucose, PSA 1p36.11 Yes M-ficolin (ficolin-1) Monocytes Monocyte surface, serum GlcNAc-BSA, GalNAc-BSA, SiaLacNAc-BSA 9q34 Yes Mouse Ficolin-A Liver and spleen Serum GlcNAc, GalNAc 2A3 Yes Ficolin-B BM and spleen Peritoneal macrophages GlcNAc, GalNAc, SiaLacNAc, fetuin 2A3 No
Table 1. Expression, sugar specificity, and target pathogens of ficolins in human and mouse
Human L-ficolin is mainly synthesized in the liver and secreted into blood circulation. H-ficolin is expressed in the lung and liver, and can also be found in serum. Another human ficolin, M-ficolin, is a secretory protein from neutrophils and monocytes in peripheral blood and from type Ⅱ alveolar epithelial cells in lung. Ficolins and MBL are associated with MBL-associated serine proteases (MASPs) and with small MBL-associated protein (sMAP), a truncated protein of MASP-2, and both ficolins and MBL activate the lectin pathway of complement (Matsushita M, et al., 2001; Zhang X L, et al., 2008). Ficolins act as pattern recognition molecules that specifically bind to many clinically important microorganisms. They also function as opsonins when binding to certain types of oligosaccharides on the surfaces of pathogens via their lectin activity (Liu Y, et al., 2005; Matsushita M, et al., 2001; Matsushita M, et al., 1996).
An increasing body of data suggests that ficolin is an important aspect in host innate defenses against viral and bacterial diseases (Table 2), while defective or abnormal expression will cause the pathogenic activities of these organisms. Ficolins may trigger activation of the immune or by stimulating the secretion of IFN-γ, IL-17, IL-6, TNF-α and NO production by macrophages, thus limiting the infection. These results will provide insight into ficolins as novel innate immune therapeutic options to treat many infectious diseases.
Roles of ficolins during viral and bacterial infection References Viral infection Ficolins and HCV L-ficolin binds to viral N-glycans, and triggers complement lectin pathway activation; L-ficolin serum concentrations were positively correlated with ALT and HCV RNA levels after therapy in vivo (Hu Y L, et al., 2013; Liu J, et al., 2009) Ficolins and HBV Higher serum L-ficolin levels were observed in patients with acute HBV compared with patients with HCC or healthy donors (Hoang T V, et al., 2011) Ficolins and IAV and other viruses L-and H-ficolins bind to HA and NA glycoproteins and different subtypes of influenza A virus, and inhibit virus infection both in vitro and in vivo (Chang W C, et al., 2011; Michelow I C, et al., 2010; Pan Q, et al., 2012; Verma A, et al., 2012) Bacterial infection Ficolins and MTB L-ficolin binds to the surface glycolipid portion of H37Rv, and blocks H37Rv infection (Luo F, et al., 2013) Ficolins and Gram-negative bacteria L-, M-, and H-ficolins bind to Gram-negative bacteria, such as the rough type of Salmonella typhimurium TV119, and Pseudomonas aeruginosa via the FBG domain, and serve as opsonins, increasing phagocytosis (Akaiwa M, et al., 1999; Frederiksen P D, et al., 2005; Kilpatrick D C, et al., 2009; Liu Y, et al., 2005; Matsushita M, et al., 2001; Taira S, et al., 2000) Ficolins and Gram-positive bacteria Both L-ficolin and M-ficolin bind to Gram-positive bacteria, such as streptococci (GBS) and Staphylococcus aureus, and lead to activation of the lectin pathway. H-ficolin binds to the Gram-positive bacterium Aerococcus viridans (Aoyagi Y, et al., 2005; Kjaer T R, et al., 2011; Lynch N J, et al., 2004; Tsujimura M, et al., 2001) FBG, fibrinogen-like; HA, hemagglutinin; HBV, hepatitis B virus; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; GBS, group B streptococci; IAV, influenza A virus; MTB, Mycobacterium tuberculosis; NA, neuraminidase.
Table 2. Ficolins and infectious diseases