The intricate system of serum complement proteins provides resistance to infection. A pivotal step in the complement pathway is the assembly of a C3 convertase, which digests the C3 complement component to form microbial-binding C3 fragments recognized by leukocytes. The spleen and C3 provide resistance against blood-borne S.pneumoniae infection. To better understand the mechanisms involved, we studied SIGN-R1, a lectin that captures microbial polysaccharides in spleen. Surprisingly, conditional SIGN-R1 knockout mice developed deficits in C3 catabolism when given S.pneumoniae or its capsular polysaccharide intravenously. There were marked reductions in proteolysis of serum C3, deposition of C3 on organisms within SIGN-R1+ spleen macrophages, and formation of C3 ligands. We found that SIGN-R1 directly bound the complement C1 subcomponent, C1q, and assembled a C3 convertase, but without the traditional requirement for either antibody or factor B. The transmembrane lectin SIGN-R1 therefore contributes to innate resistance by an unusual C3 activation pathway.
The complement system is an integral component of innate immunity. Since the third pathway of complement activation, the mannan-binding lectin (MBL) pathway, was recently discovered, it has been thought that everything of interest had been already discovered in the field of complement system. However, we found the 4th ⇔閻?n Unusual Complement Pathway⇔影 which is mediated by a transmembrane C-type lectin, SIGN-R1.These findings is the first example showing that a transmembrane C-type lectin can mediate C3 catabolism on its cellular surface. Furthermore, it is a critical finding that macrophages need complement system to efficiently protect the host against pathogens in innate immunity.
1. Funtiction role of other lectins and lectin-like receptors in complementary and innate immune system.
Given cells of the immune system are equipped with many lectins and lectin-like receptors (LLRs, carbohydrate-binding proteins) functions of which still remain unknown in large part, these studies will give a deep insight on unraveling functions of other lectins that could be intimately related with complement system. Next, we should determine that the fixation of C3 inside the endocytic vesicle allows the SIGN-R1 ligand to elute and be regurgitated, e.g., to go to the FDC or to go to the T cell in the case of SIGN-R1/polysaccharide or DC-SIGN/HIV. These studies would identify that a transmembrane C-type lectin link between innate and adaptive immunity by mediating the localization of complement fragments into B cells or FDCs in vivo. Because the localization of antigens at B cells or FDCs should be considered important in an ongoing immune responses against pathogens, especially such as HIV or Prion, the further studies should be followed to examine the exact mechanism of the roles of transmembrane C-type lectins on the translocation of antigens into B cells or FDCs. First of all, It will be most prior to all others to determin weather other transmembrane C-type lectins can mimic the SIGN-R1-mediated complement activation pathway, and these works could lead to unravel the potential therapeutic targets against diverse pathogens.
2. Application of C-type lectins and complement system in immunotherapeutics.
There is now substantial evidence that the complement system contribute to the efficient elimination of monoclonal antibody-opsonized tumor cells. Also, exosomes, which are released by various healthy and cancerous cells, may be a good source of cancer antigens in immunotherapy. With our preliminary data showing that complement C3 fixation mediated by SIGN-R1 is critical for endocyotosis and regurgitation of polysaccharides, this complex formation could be the pivotal step to generate exosomes from various cells. Therefore, it would be valuable to investigate whether C-type lectins could be applied to several immunotherapeutics in the near future.