Jin-Yeon Park

The C-type lectin CD209b is expressed on microglia and it mediates the uptake of capsular polysaccharides of Streptococcus pneumoniae

Although Streptococcus pneumoniae is the major cause of meningitis, how it causes disease is poorly understood. The C-type lectin SIGN-R1 mediates the recently described SIGN-R1 complement activation pathway, which operates against capsular polysaccharides (CPSs) of S. pneumoniae in splenic marginal macrophages. Here, we demonstrate that SIGN-R1, as well as the rat SIGN-R1 homologue CD209b are expressed in most regions of mouse or rat brain, respectively. Moreover, both C-type lectins are obviously expressed on microglia, but not on neurons or astrocytes. We also found that rat CD209b mediates the uptake of dextran or CPS14 within the rat splenic marginal zone, similar to SIGN-R1. On microglia, rat CD209b also mediates the uptake of CPS14 of S. pneumoniae. Our findings strongly suggest that both rat CD209b and SIGN-R1 on microglia mediate the SIGN-R1 complement activation pathway against S. pneumoniae, and thereby plays an important role in the pathogenesis of pneumococcal meningitis.

Intravenous immunoglobulin-mediated immunosuppression and the development of an IVIG substitute

Immunoglobulins are glycoproteins produced by the cells of the immune system. Their primary function is to protect the body from pathogenic infection. Moreover, a concentrated polyclonal mixture of immunoglobulin G (IgG), the so-called intravenous IgG (IVIG), has been used to treat various chronic and systemic disorders of the immune system. Studies on the effects of IVIG in autoimmune disease models have revealed that IgG Fc fragments confer protection against various autoimmune diseases. The identification of this IgG Fc immunomodulatory component is important for the development of IVIG substitutes. The focus of this review is to introduce one of the Fc regulatory entities and to provide a summary of the current knowledge of the putative general mechanisms underlying IVIG activity in vivo on the basis of these Fc fragments. We also address the recent insights into several approaches for the development of IVIG substitutes.

Functionality of insect‐cell‐derived colorectal cancer vaccine candidate protein EpCAM‐Fc in human dendritic cells

The baculovirus–insect cell expression system is widely used to produce recombinant proteins for various biomedical applications. Our previous study demonstrated that EpCAM, a colorectal cancer vaccine candidate protein, can be expressed in the baculovirus–insect cell expression system. However, its functionality (the ability to elicit an immune response), which is important for its possible use as a colorectal cancer vaccine for immunotherapy, still needed to be confirmed. In this study, we examined the ability of recombinant EpCAM to induce maturation of immature dendritic cells (DCs) derived from CD34+ cells isolated from human umbilical cord blood. We demonstrated that EpCAM induces the expression of four DC maturation markers: CD80, CD83, CD86 and MHC II. These results suggest that EpCAM produced in the baculovirus–insect cell expression system is functional in terms of its ability to trigger maturation of human DCs.

SIGN-R1, a C-type lectin, binds to Bip/GRP78 and this interaction mediates the regurgitation of T-cell-independent type 2 antigen dextran through the endoplasmic reticulum

Capsular polysaccharides of Streptococcus pneumoniae are representative T-cell-independent type 2 (TI-2) antigens, frequently causing serious infections in children, the elderly, and immunocompromised patients. However, the detailed mechanism of this immune escape by CPSs is poorly understood. To pursue this question, polysaccharide dextran, ligand of SIGN-R1 as well as an appropriate model of the immunogenicity of many TI-2 polysaccharide antigens was used. SIGN-R1 bound to binding immunoglobulin protein (BiP), a well-characterized endoplasmic reticulum (ER) chaperone, primarily in non-ER compartments. Interestingly, SIGN-R1(+) macrophages in the MZ showed high expression of BiP, implying an important role of SIGN-R1 binding to BiP in vivo. To our surprise, dextran is rapidly transported into the ER and subsequently regurgitated out of cells in vitro or in vivo. BiP down-regulation in SIGN-R1 transfectant reduced the regurgitation of dextran, causing the accumulation of dextran in the ER. Therefore, these results demonstrated the first example to describe the intracellular trafficking and the regurgitation of TI-2 antigen dextran, suggesting the novel pathway of TI-2 antigen presentation to immune cells.

SIGN-R1 and complement factors are involved in the systemic clearance of radiation-induced apoptotic cells in whole-body irradiated mice

Although SIGN-R1-mediated complement activation pathway has been shown to enhance the systemic clearance of apoptotic cells, the role of SIGN-R1 in the clearance of radiation-induced apoptotic cells has not been characterized and was investigated in this study. Our data indicated that whole-body γ-irradiation of mice increased caspase-3(+) apoptotic lymphocyte numbers in secondary lymphoid organs. Following γ-irradiation, SIGN-R1 and complements (C4 and C3) were simultaneously increased only in the mice spleen tissue among the assessed tissues. In particular, C3 was exclusively activated in the spleen. The delayed clearance of apoptotic cells was markedly prevalent in the spleen and liver of SIGN-R1 KO mice, followed by a significant increase of CD11b(+) cells. These results indicate that SIGN-R1 and complement factors play an important role in the systemic clearance of radiation-induced apoptotic innate immune cells to maintain tissue homeostasis after γ-irradiation.

Systemic Clearance of Radiation-Induced Apoptotic Cells by SIGN-R1 andComplement Factors and their Involvement in Autoimmune Diseases

Although ionizing radiation has been used for treating a variety of human cancers, radiotherapy inadvertently results in the damage of normal tissues, functionally altering the immune system and being able to cause various organ specific autoimmune diseases. Macrophages and complements play pivotal roles in the clearance of the apoptotic cells, facilitating their opsonindependent phagocytosis and systemic clearance of apoptotic cells. SIGN-R1, a membrane bound C-type lectin expressed on the splenic marginal macrophages, mediates a classical but Ig-independent complement activation pathway by interacting with C1q, and SIGN-R1 and complement factors might play the integral role in the clearance of radiation-induced apoptotic cells. Also, DC-SIGN, the human homolog of SIGN-R1 on dendritic cells and macrophage subpopulations, directly binds to C1q, probably providing an initiation site for the classical complement pathway in the presence of a pathogenic surface. Autoimmune diseases are becoming a serious public health problems and there is increasing evidence that C-type lectins and complement system are involved in the pathogenesis of the autoimmune diseases. Therefore, further works are required to identify the existence of diverse membranebound C-type lectins that could mediate complement activation against apoptotic cells in vivo and its involvement in the pathogenesis of the autoimmune diseases.

Enhanced immune response of T-cell independent or dependent antigens in SIGN-R1 knock-out mice.

Dextran was used to explore a novel method of enhancing an immune response against T-cell independent type 2 (TI-2) polysaccharide antigens, because of its suitability as a model for the immunogenecity of many TI-2 polysaccharide antigens and its high affinity to SIGN-R1. Here we showed that the primary immune response of IgM, IgG3, and IgG2b was enhanced by dextran in SIGN-R1 knock-out (KO) mice, further evoking the induction of a secondary immune response to IgG2b in parallel. On the other hand, an immune response of IgG1 and IgG2b against T-cell dependent (TD) antigen was strongly enhanced by the administration of ovalbumin (OVA) in SIGN-R1 KO mice. These results indicate that SIGN-R1 is critical in the regulation of immune responses. Therefore, our study suggests that inhibition of TI-2 polysaccharide antigen uptake in SIGN-R1(+) macrophages contributes to the development of novel vaccination strategies against TI-2 polysaccharide antigens.