Biomedical subjects

Byung S Kim

Publications and source records attributed to Byung S Kim.

At least 19 recordsLinked to original sources

PubMed2006

The immunodominant CD8+ T cell epitope region of Theiler's virus in resistant C57BL/6 mice is critical for anti-viral immune responses, viral persistence, and binding to the host cells.

Theiler's virus infection induces an immune-mediated demyelinating disease, providing a relevant animal model of human multiple sclerosis. VP2(121-130)-specific CD8+ T cells in resistant H-2b mice account for the majority of CNS-infiltrating CD8+ T cells. To further study the role of the CD8(+) T cells, we generated a panel of mutant viruses substituted with L, G, or T at the anchor residue (M130) of the VP2(121-130) epitope. M130L virus (M130L-V) with a substitution of M with L displayed similar properties as wild-type virus (WT-V). However, M130G-V and M130T-V could not establish a persistent infection in the CNS. The level of both virus-specific CD8+ and CD4+ T cell responses is significantly reduced in mice infected with these variant viruses. While all mutant and wild-type viruses replicate comparably in BHK cells, replication of M130G-V and M130T-V in macrophages was significantly lower compared to those infected with WT-V and M130L-V. Interestingly, these mutant viruses deficient in replication in primary mouse cells showed drastically reduced binding ability to the cells. These results suggest that the anchor residue of the predominant CD8+ T cell epitope of TMEV in resistant mice is critical for the virus to infect target cells and this deficiency may result in poor viral persistence leading to correspondingly low T cell responses in the periphery and CNS. Thus, selection of the cellular binding region of the virus as the predominant epitope for CD8+ T cells in resistant mice may provide a distinct advantage in controlling viral persistence by preventing escape mutations.

Animals↗

PubMed2006

Initial capsid-specific CD4(+) T cell responses protect against Theiler's murine encephalomyelitisvirus-induced demyelinating disease.

Central nervous system (CNS) infection by Theiler's murine encephalomyelitis virus (TMEV) causes an immune-mediated demyelinating disease similar to human multiple sclerosis in susceptible mice. To understand the pathogenic mechanisms, we analyzed the level, specificity, and function of CD4(+) Th cells in susceptible SJL/J and resistant C57BL/6 mice. Compared to resistant mice, susceptible mice have three- to fourfold higher levels of overall CNS-infiltrating CD4(+) T cells during acute infection. CD4(+) T cells in the CNS of both strains display various activation markers and produce high levels of IFN-gamma upon stimulation with anti-CD3 antibody. However, susceptible mice display significantly fewer (tenfold) IFN-gamma-producing Th1 cells specific for viral capsid epitopes as compared to resistant mice. Furthermore, preimmunization with capsid-epitope peptides significantly increased capsid-specific CD4(+) T cells in the CNS during the early stages of viral infection and delayed the development of demyelinating disease in SJL/J mice. This suggests a protective role of capsid-reactive Th cells during early viral infection. Therefore, a low level of the protective Th1 response to viral capsid proteins, in conjunction with Th1 responses to unknown epitopes may delay viral clearance in susceptible mice leading to pathogenesis of demyelination during acute infection, as compared to resistant mice.

Acute Disease↗

PubMed2006

Induction of chemokine and cytokine genes in astrocytes following infection with Theiler's murine encephalomyelitis virus is mediated by the Toll-like receptor 3.

Theiler's murine encephalomyelitis virus (TMEV) infection in the central nervous system (CNS) induces a demyelinating disease similar to human multiple sclerosis. TMEV infection results in activation of various chemokine and cytokine genes that are important in the initiation of an inflammatory response. We have previously shown that the production of these chemokines and cytokines in astrocytes is induced via the NF-kappaB pathway following TMEV and Coxsackie virus infection. In this study, we investigated whether the NF-kappaB-dependent inflammatory responses after TMEV infection is triggered through TLR3 and/or TLR7. The activation of NF-kappaB or IRF/ISRE, as well as the production of both MCP-1/CCL2 and IL-8/CXCL8, was observed in only TLR3-transfected HEK 293 cells, but not in TLR7-tranfected cells. The potential involvement of TLR3 in mouse embryonic fibroblasts and primary astrocytes was further investigated following transfection with wildtype or dominant negative form of TLRs and MyD88, as well as astrocytes from TLR3- and MyD88-deficient mice. Similarly, the activation of transcription factors and chemokine genes is induced in these mouse cells through primarily TLR3 signaling pathway, but not TLR7 or other MyD88-mediated pathways following TMEV infection. However, the TLR3-mediated cellular activation does not appear to affect the level of viral replication in astrocytes. These results strongly suggest that TLR3-signaling by TMEV alone is sufficient to induce the initial inflammatory cytokine responses that could be very important for the outcome of virus-induced encephalitis and/or demyelinating diseases, such as multiple sclerosis.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Motion artifact reduction in photoplethysmography using independent component analysis.

Removing the motion artifacts from measured photoplethysmography (PPG) signals is one of the important issues to be tackled for the accurate measurement of arterial oxygen saturation during movement. In this paper, the motion artifacts were reduced by exploiting the quasi-periodicity of the PPG signal and the independence between the PPG and the motion artifact signals. The combination of independent component analysis and block interleaving with low-pass filtering can reduce the motion artifacts under the condition of general dual-wavelength measurement. Experiments with synthetic and real data were performed to demonstrate the efficacy of the proposed algorithm.

Algorithms↗

PubMed2006

Wavelet-based low-delay ECG compression algorithm for continuous ECG transmission.

The delay performance of compression algorithms is particularly important when time-critical data transmission is required. In this paper, we propose a wavelet-based electrocardiogram (ECG) compression algorithm with a low delay property for instantaneous, continuous ECG transmission suitable for telecardiology applications over a wireless network. The proposed algorithm reduces the frame size as much as possible to achieve a low delay, while maintaining reconstructed signal quality. To attain both low delay and high quality, it employs waveform partitioning, adaptive frame size adjustment, wavelet compression, flexible bit allocation, and header compression. The performances of the proposed algorithm in terms of reconstructed signal quality, processing delay, and error resilience were evaluated using the Massachusetts Institute of Technology University and Beth Israel Hospital (MIT-BIH) and Creighton University Ventricular Tachyarrhythmia (CU) databases and a code division multiple access-based simulation model with mobile channel noise.

Algorithms↗

PubMed2006

Induction of autoimmunity by immunization with hapten-modified hen egg lysozyme in hen egg lysozyme-transgenic mice.

To understand the mechanism of autoimmunity induction, hen egg lysozyme (HEL)-transgenic (Tg) C57BL/6 (B6) mice were immunized with HEL or phosphorylcholine-conjugated HEL (PC-HEL). Repeated immunization of HEL-Tg mice with native HEL failed to induce the antibody response against HEL. However, immunization with PC-HEL generated a significant anti-HEL antibody response. Immunization of the Tg mice with dominant (HEL(74-88)) or cryptic (HEL(47-61)) T-cell epitope peptide stimulated the corresponding T-cell response and similarly yielded the anti-HEL antibody response. Predominance of immunoglobulin G1 (IgG1) anti-HEL antibody response in the HEL-Tg mice and preferential IL-4 production by HEL-specific T cells suggested the dependency of the antibody response to the presence of T helper 2. HEL-Tg mice received HEL-primed B6 T cells, but not HEL-primed Tg T cells, were able to generate anti-HEL antibody response following PC-HEL immunization. The pattern and the level of epitope peptides generated by splenic antigen-presenting cells indicated that PC-HEL results in much more efficient processing as compared to HEL. These results strongly suggest that the enhancement of antigen processing by hapten (PC) conjugation to the antigen facilitates more efficient stimulation of T cells reactive to self antigen, HEL in HEL-Tg mice resulting in the production of anti-self HEL antibody.

Adoptive Transfer↗

PubMed2005

Effects of the major histocompatibility complex loci and T-cell receptor beta-chain repertoire on Theiler's virus-induced demyelinating disease.

We have investigated the potential effects of H-2 and T-cell receptor (TCR) V beta family genes on induction of T-cell immunity and susceptibility to virally induced demyelinating disease by using BALB.S (H-2K(s)A(s)D(s)) and BALB.S 3 R (H-2K(s)A(s)D(d)/L(d)) mice. These parameters were compared with those of highly susceptible SJL/J (H-2K(s)A(s)D(s)) mice that contain only one-half of TCR V beta family genes compared with the above-mentioned strains. Our results demonstrate that BALB.S but not BALB.S 3 R mice are susceptible similar to SJL/J mice. Although the level of CD4(+) T-cell infiltration to the CNS was elevated in susceptible mice, virus-specific immune responses restricted with H-2(s) were similar in these mice. No preferential use of V beta families associated with differences in the major histocompatibility complex (MHC) components was apparent. However, the pattern and sequence of CDR 3 distribution shows T-cell clonal accumulation in the CNS associated with the H-2 components. Further anti-CD8 antibody treatment of resistant BALB.S 3 R mice abrogated resistance to demyelinating disease, indicating that CD8(+) T cells restricted with H-2D(d)/L(d) are most likely to exert resistance in BALB.S 3 R mice. These studies indicated that TCR V beta and MHC class II genes are the secondary to a particular MHC class I gene expression in susceptibility to virally induced demyelinating disease.

Animals↗

PubMed2005

Antibody response is required for protection from Theiler's virus-induced encephalitis in C57BL/6 mice in the absence of CD8+ T cells.

Intracerebral infection of susceptible mice with Theiler's murine encephalomyelitis virus (TMEV) induces immune-mediated demyelinating disease and this system serves as a relevant infectious model for human multiple sclerosis. It was previously shown that beta2M-deficient C57BL/6 mice lacking functional CD8+ T cells display increased viral persistence and enhanced susceptibility to TMEV-induced demyelination, and yet the majority of mice are free of clinical signs. To understand the mechanisms involved in this general resistance of C57BL/6 mice in the absence of CTL responses, mice (muMT) deficient in the B-cell compartment lacking membrane IgM molecules were treated with anti-CD8 antibody and then infected with TMEV. Although little difference in the proliferative responses of peripheral T cells to UV-inactivated TMEV and the resistance to demyelinating disease was observed between virus-infected muMT and control B6 mice, the levels of CD4(+) T cells were higher in the CNS of muMT mice. However, after treatment with anti-CD8 antibody, 100% of the mice displayed clinical gray matter disease and prolonged viral persistence in muMT mice, while only 10% of B6 mice showed clinical symptoms and very low viral persistence. Transfusion of sera from TMEV-infected B6 mice into anti-CD8 antibody-treated muMT mice partially restored resistance to virus-induced encephalitis. These results indicate that the early anti-viral antibody response is also important in the protection from TMEV-induced encephalitis particularly in the absence of CD8+ T cells.

Animals↗

PubMed2005

Gender bias in Theiler's virus-induced demyelinating disease correlates with the level of antiviral immune responses.

Multiple sclerosis is an immune-mediated disease of the CNS and shows a sex-biased distribution in which 60-75% of all cases are female. A mouse model of multiple sclerosis, Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease, also displays a gender bias. However, in the C57L/J strain of mice, males are susceptible to disease whereas females are completely resistant. In this study we determined the gender differences in the TMEV-specific immune response, which may be responsible for the gender bias in clinical disease. Our data clearly demonstrate that female C57L/J mice induce significantly higher levels of TMEV-specific neutralizing Ab as well as a stronger peripheral T cell response throughout the course of viral infection. In contrast, male mice have a higher level of TMEV-specific CD4(+) and CD8(+) T cell infiltration into the CNS as well as viral persistence. These results suggest that a higher level of the initial antiviral immune response in female mice may be able to effectively clear virus from the periphery and CNS and therefore prevent further disease manifestations. Male mice in contrast do not mount as effective an immune response, thereby allowing for eventual viral persistence in the CNS and continuous T cell expansion leading to clinical symptoms.

Animals↗

PubMed2005

Tim-3+ T-bet+ tumor-specific Th1 cells colocalize with and inhibit development and growth of murine neoplasms.

Although T cells infiltrate many types of murine and human neoplasms, in many instances tumor-specific cytotoxicity is not observed. Strategies to stimulate CTL-mediated antitumor immunity have included in vitro stimulation and/or genetic engineering of T cells, followed by adoptive transfer into tumor-bearing hosts. In this model of B cell lymphoma in SJL/J mice, we used Tim-3(+) T-bet(+) Th1 cells to facilitate the development of tumor-specific CTL. Tumor-specific Th1 cell lines were polarized with IL-12 during in vitro stimulation and long term maintenance. As few as 5 million Tim-3(+) T-bet(+) Th1 cells enabled recipients to resist growth of malignant transplantable cells. In addition, similar numbers of Th1 cells injected into 2- to 3-mo-old mice inhibited development of the spontaneous primary lymphomas, which normally arise in 90% of aging mice. CFSE(+) Th1 cells colocalized with injected tumor cells in vivo and formed conjugates with the tumor cells within follicles, whereas in nontumor-challenged recipients the CFSE(+) Th1 cells localized only within the T cell zones of the spleen. These results provide evidence that adoptive immunotherapy with Tim-3(+) T-bet(+) tumor-specific Th1 cells can be used to induce host cytotoxic responses that inhibit the development and growth of neoplastic cells.

Adoptive Transfer↗

PubMed2005

Identification of capsid epitopes of Theiler's virus recognized by CNS-infiltrating CD4+ T cells from virus-infected C57BL/6 mice.

Intracerebral infection of Theiler's murine encephalomyelitis virus (TMEV) induces immune-mediated demyelinating disease in some mouse strains but not in others. We report here for the first time two new predominant capsid epitopes (VP4(21-40) and VP2(201-220)) recognized by CD4+ T cells from virus-infected resistant C57BL/6 mice based on IFNgamma ELISPOT assay utilizing a 20-mer peptide library covering the entire capsid proteins. Further experiments by IFNgamma ELISPOT and flow cytometry for intracellular IFNgamma production using truncated peptides indicated that the epitope regions recognized by CNS-infiltrating CD4+ T cells are VP4(25-38) and VP2(206-220), respectively. No apparent reduction in the T cell response to these viral epitopes is seen in the CNS of IL-12- and ICAM-1-deficient C57BL/6 mice compared to those in control C57BL/6 mice, suggesting that T cell response to TMEV in the CNS is largely insensitive to the absence of these proinflammatory cytokine and adhesion molecules. Therefore, these newly defined CD4+ T cell epitopes are likely to provide an important tool to investigate the role of CD4+ T cell responses in H-2b-bearing congenic strains.

Animals↗

PubMed2005

4-1BB (CD137) is required for rapid clearance of Listeria monocytogenes infection.

4-1BB (CD137), a member of the tumor necrosis factor receptor superfamily, is a T-cell-costimulatory receptor that is expressed on activated T cells, dendritic cells, and NK cells. Little has been reported about its role in early host defense against bacterial infection. In this study, we report that 4-1BB-deficient (4-1BB(-/-)) mice are much more susceptible to Listeria monocytogenes (intracellular bacteria) infections than wild-type mice. Upon L. monocytogenes infection, 4-1BB(-/-) mice showed a lower survival rate, a higher bacterial burden in organs, and larger hepatic microabscesses than 4-1BB(+/+) mice. 4-1BB(-/-) mice also had impairment in clearance of bacteria from the bloodstream. Neutrophils from 4-1BB(+/+) mice constitutively expressed 4-1BB, which could be activated to induce intracellular Ca(2+) influx by ligation with anti-4-1BB antibody. On the other hand, neutrophils from 4-1BB(-/-) mice were defective in reactive oxygen species generation, phagocytic activities, and intracellular Ca(2+) mobilization. In addition, mice pretreated with anti-4-1BB monoclonal antibody were much more resistant to L. monocytogenes infection than control antibody-treated mice. Our results support the notion that 4-1BB may play a major role in host defense against intracellular pathogens through neutrophil activation.

Animals↗

PubMed2005

Innate immune response induced by Theiler's murine encephalomyelitis virus infection.

Although the causative agents of human multiple sclerosis (MS) are not known, it is suspected that a viral infection may be associated with the initiation of the disease. Several viral disease models in mice have been studied to understand the pathogenesis of demeylination. In particular, Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) has been extensively studied as a relevant model. Various cytokines and chemokines are produced upon viral infection by different cell types, including antigen-presenting cells (APCs) such as macrophages; dendritic cells (DCs); and glial cells, such as astrocytes, microglia, and oligodendrocytes. The upregulation of the corresponding molecules are also found in MS and are likely to play an important role in the protection and/or pathogenesis of chronic inflammatory demyelinating disease. In this review, the type of cells and molecules, gene-activation mechanisms as well as their potential roles in protection and pathogenesis will be discussed.

Animals↗

PubMed2004

Quantitative, not qualitative, differences in CD8(+) T cell responses to Theiler's murine encephalomyelitis virus between resistant C57BL/6 and susceptible SJL/J mice.

Theiler's murine encephalomyelitis virus (TMEV) infection of the CNS induces an immune-mediated demyelinating disease in susceptible mouse strains and serves as a relevant infection model for human multiple sclerosis. However, it is not yet clear what immunological parameters determine the susceptibility of SJL/J mice compared to resistant mice. We have here compared the TMEV-specific CD8(+) T cell responses in highly susceptible SJL/J mice with those of highly resistant C57BL/6 mice. Our results clearly indicate that the levels of initial responses of infiltrating CD8(+) T cells to viral capsid proteins are higher in resistant C57BL/6 mice compared to susceptible SJL/J mice. However, the level of virus-specific CD8(+) T cells was much more rapidly reduced in resistant C57BL/6, resulting in a higher CD8(+) T cell level in SJL/J mice later in viral infection. The activation states, cytokine production, as well as the cytolytic function of the CD8(+) T cells were similar to each other in these mice. These results suggest that an initial induction of a vigorous CD8(+) T cell response to TMEV is critically important for the resistance to virally induced demyelinating disease.

Animals↗

PubMed2004

Induction of chemokines in human astrocytes by picornavirus infection requires activation of both AP-1 and NF-kappa B.

Infection with different picornaviruses can cause meningitis/encephalitis in humans and experimental animals. To investigate the mechanisms of such inflammatory diseases, potential chemokine gene activation in human astrocytes was investigated following infection with Theiler's murine encephalomyelitis virus (TMEV), coxsackievirus B3 (CVB3), or coxsackievirus B4 (CVB4). We report that all these viruses are potent inducers for the expression of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) genes in primary human astrocytes, as well as in an established astrocyte cell line (U-373MG). Further studies indicated that both activator protein-1 (AP-1) and NF-kappaB transcription factors are required in the activation of chemokine genes in human astrocytes infected with various picornaviruses. Interestingly, the pattern of activated chemokine genes in human astrocytes is quite restricted compared to that in mouse astrocytes infected with the same viruses, suggesting species differences in gene activation. This may result in potential differences in the pathogenic outcome in each species.

Animals↗

PubMed2004

The scope and activation mechanisms of chemokine gene expression in primary astrocytes following infection with Theiler's virus.

Intracerebral infection with Theiler's virus induces a demyelinating disease that resembles human MS. In order to delineate the early events in virus-induced inflammatory disease, we have analyzed chemokine gene activation following Theiler's murine encephalomyelitis virus (TMEV) infection. Infection of primary astrocyte cultures results in activation of various chemokine genes (GRO-1, MCP-1, MCP-5, MIP-1alpha, MIP-1beta, MIP-2, RANTES, IP-10 and MCP-3) that are important in the initiation of an inflammatory response. As early as 1-3 h after TMEV infection, chemokine gene expression is strongly activated. In addition, proinflammatory cytokines do not interfere with TMEV-induced chemokine gene expression and some cytokines may function synergistically for virus-induced upregulation of chemokine gene expression. Chemokine gene activation by TMEV appears to be largely independent of the IFNalphabeta pathway and partly dependent on dsRNA-dependent protein kinase (PKR) and MAP kinase pathways. However, TMEV-induced chemokine gene expression is completely dependent on the NFkappaB pathway. These results strongly suggest that the expression of select chemokine genes upon TMEV infection is activated via the NFkappaB pathway, similar to that of proinflammatory cytokine genes, and these cellular gene products appear to synergistically promote inflammatory responses in the CNS.

Animals↗

PubMed2004

Functional maturation of proteolipid protein(139-151)-specific Th1 cells in the central nervous system in experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is a widely adopted animal model system for studying human multiple sclerosis that affects the central nervous system (CNS). To understand the underlying pathogenic mechanisms of the autoimmune T cell response, localization, enumeration and characterization of autoreactive T cells are essential. We assessed encephalitogenic proteolipid protein epitope (PLP(139-151))-specific T cells in the periphery and CNS of SJL/J mice using MHC class II I-As multimers during both pre-clinical and clinical phases of PLP-induced EAE in conjunction with T cell function. Our results strongly suggest that PLP(139-151)-specific CD4+ T cells first expand primarily in the CNS-draining cervical lymph nodes and then migrate to the CNS. In the CNS, these PLP-specific CD4+ T cells accumulate, become activated and differentiate into effector cells that produce IFN-gamma in response to the self-peptide.

Animals↗

PubMed2004

Role of the major histocompatibility complex class II transmembrane region in antigen presentation and intracellular trafficking.

While a sorting signal in the cytoplasmic tail of the major histocompatibility complex (MHC) class II molecules is known to influence their endocytic transport, potential effects of the transmembrane (TM) domain of the MHC class II molecules on endocytic transport remain unclear. We have examined the role of the TM domain by comparing antigen-presenting functions of the wildtype (WT) I-Ab and mutant (MT) I-Ab molecule substituted in the beta-chain TM with alpha chain TM. A20 cells transfected with WT I-Ab were able to present antigen (hen egg lysozyme) better to some hybridomas, while those transfected with MT I-Ab consistently outperformed WT for other hybridomas recognizing different epitopes. This difference in antigen processing and presentation is not caused by the differences in H-2M (DM) requirement or association with Ii. The time required for processing of specific epitopes appears to be different, suggesting sequential involvement of various endocytic compartments in the antigen processing. Although both WT and MT molecules were found in the early endocytic (transferrin receptor-rich) compartments, MT molecules accumulated in these compartments in higher quantities for longer time periods. Similarly, the MT molecule is retained for a longer time period than WT in late endocytic (LAMP-1 associated) compartments. Together, our data indicate an important role of the TM domain of the MHC class II molecules in the intracellular trafficking and, consequently, antigen processing and presentation.

Animals↗