Current therapies for autoimmune diseases are not cures but merely palliatives, aimed at reducing symptoms. For the most part, these treatments provide nonspecific suppression of the immune system and thus do not distinguish between a pathogenic autoimmune response and a protective immune response. Recently emerging evidence not only has indicated the involvement of members of the TNF receptor/ligand superfamilies but also has revealed exciting innovative strategies for the treatment of autoimmune diseases and other chronic inflammatory diseases without depressing the immune response in general. In this review, we will discuss the regulatory mechanisms of TNF receptor/ligand family members, such as HVEM/ LIGHT, 4-1BB/4-1BBL, and GITR/GITRL that regulate T and B cell functions and participate in the process of inflammatory diseases. We will also discuss how intervening in the costimulatory pathways mediated by these molecules might have some potential as a therapeutic approach to immune disorders.
Animals ; Apoptosis ; Autoimmune Diseases/immunology/metabolism/pathology ; B-Lymphocytes/immunology/physiology ; Dendritic Cells/physiology ; Human ; Inflammation/*immunology ; Lymphocyte Activation/immunology ; Models, Biological ; Receptors, Tumor Necrosis Factor/*physiology ; T-Lymphocytes/immunology/physiology ; Tumor Necrosis Factor/immunology/*physiology

By searching an EST database, we identified two TNF receptor superfamily members (named mTNFRH1 and mTNFRH2). Amino acid sequences are highly conserved between the two receptors (78% identity). The chromosomal loci of mTnfrh1 and mTnfrh2 genes are found in distal chromosome 7 in the mouse. mTNFRH1 and mTNFRH2 do not contain the cytoplasmic domain, indicating that they might function as decoy receptors. Furthermore, an alternatively spliced form of mTNFRH1 was found which contains neither the transmembrane domain nor the cytoplasmic domain, thus presumably existing as a soluble form. Northern blot analysis showed that mTnfrh1 mRNA was negligibly expressed in tissues, while mTnfrh2 mRNA was strongly expressed in spleen, lung, liver, kidney, and testis. When the extracellular domains of mTNFRH1 and mTNFRH2 were expressed in bacteria, their molecular weight of extracellular region was approximately 15 kDa. Both of the soluble forms were effective in inhibiting T-cell proliferation stimulated by anti-CD3 monoclonal antibody. Our data suggest that mTNFRH1 and mTNFRH2 may be implicated in exerting a modulatory role in the immune response.
Alternative Splicing/genetics ; Amino Acid Sequence ; Animals ; Base Sequence ; Cell Division/*physiology ; Databases, Nucleic Acid ; Gene Expression/genetics ; Mice ; Molecular Sequence Data ; Receptors, Tumor Necrosis Factor/*biosynthesis ; Recombinant Proteins/*biosynthesis ; T-Lymphocytes/*cytology

Rhizomelic chondrodysplasia punctata(RCDP) is a rare autosomal recessive disorder clinically characterized by symmetrical shortening of the proximal limbs, contractures of joints, a typical dysmorphic face, cataracts, and itchyosis. Patients with RCDP can be subdivided into three subgroups based on biochemical analysis and complementation studies. RCDP type I results from mutations in the PEX7 gene encoding the peroxisomal targeting signal type II(PST2) receptors and presents with both a defect in plasmalogen biosynthesis and phytanic acid oxidation. RCDP type II is deficient in the activity of dihydroxyacetonephosphate acyltransferase(DHAP-AT). RCDP type III is deficient in alkyl-dihydroxyacetonephosphate synthase(alkyl-DHAP). We report a case of RCDP type I which was confirmed with biochemical study, fibroblast culture, and gene study.
Cataract ; Chondrodysplasia Punctata, Rhizomelic* ; Complement System Proteins ; Contracture ; Extremities ; Fibroblasts ; Humans ; Joints ; Phytanic Acid

Rheumatoid arthritis (RA) is a multifactorial autoimmune disease whose etiopathogenesis is not well understood. Although soluble (s) forms of 4-1BB (s4-1BB) and 4-1BB legand (s4-1BBL) have been detected in the sera of RA patients, their significance is not known. We compared the serum levels of s4-1BB and s4-1BBL in RA patients with those in systemic lupus erythematosus (SLE) and Behcet's disease (BD) patients. Serum levels of s4-1BB and s4-1BBL were significantly higher in RA patients compared with healthy controls, SLE or BD patients, and the abundance was correlated with disease severity in patients with RA. The serum levels of s4-1BB in RA patients were inversely corroborated with 4-1BB expression levels on activated T lymphocytes. In addition, there was a correlation between serum levels of s4-1BB and s4-1BBL. The augmented secretion of s4-1BB and s4-1BBL levels into the serum may reflect the clinical symptoms of RA and levels of s4-1BB and s4-1BBL in sera at the time of diagnosis may be indicative of the severity and outcome of RA.
Adult ; Aged ; Antigens, CD/metabolism ; Arthritis, Rheumatoid/*blood/drug therapy/immunology/*pathology ; Behcet Syndrome/blood/immunology ; Comparative Study ; Female ; Humans ; Immunosuppressive Agents/metabolism/therapeutic use ; Leukocytes, Mononuclear/metabolism ; Lupus Erythematosus, Systemic/blood/immunology ; Male ; Middle Aged ; Random Allocation ; Receptors, Nerve Growth Factor/*blood ; Receptors, Tumor Necrosis Factor/*blood ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S. ; Severity of Illness Index ; Statistics ; Tumor Necrosis Factor-alpha/*metabolism

PURPOSE: To evaluate the result of tibial shaft fractures in children treated with pin and plaster method. MATERIALS AND METHODS: From March 1998 to February 2003, Tibial shaft fractures in thirty six pediatric patients which were treated with pin and plaster method were clinically and radiologicaly evaluated retrospectively. RESULTS: Mean bony union duration was 9.8 weeks. All fractures healed within acceptable angulations. There was neither delayed union nor nonunion. There were complications related to the pins, including superficial and deep infection, skin sloughing. There were 7 cases of tibial overgrowth but they had no functional disability. CONCLUSION: Pin and plaster method can substitute other operative methods in tibial fractures in children which is difficult to reduce or maintain reduction by conservative treatment.
Child* ; Humans ; Retrospective Studies ; Skin ; Tibial Fractures*

PURPOSE: Enterovirus (EV) infection in children can manifest various diseases from asymptomatic infection to nonspecific febrile illness, hand-foot-mouth disease, and aseptic meningitis. This study was aimed to investigate epidemiology and clinical significance of various genotypes of EV infections in pediatric inpatient. METHODS: We collected the stool samples from the admitted pediatric patients in Inha University Hospital from March 2014 to March 2015. EV detection and genotype identification were performed by real-time RT-PCR and semi-nested RT-PCR. Phylogenetic trees were constructed by neighbor joining method. RESULTS: A total of 400 samples were collected during study period and 112 patients (28%) were diagnosed with EV infections. The mean age of EV positive patients was 2.66 years (0.1-14) and sex ratio was 1.73:1. Genetic sequences of EVs were identified; coxsackievirus B5 (17, 15.2%), coxsackievirus A16 (13, 11.6%), enterovirus 71 (10, 8.9%), and coxsackievirus A2 (9, 8.0%). Nonspecific febrile illness (96, 86%) was the most common clinical manifestation and the duration of fever was 0-11 days (mean 3.1 days). Rash (44, 39%) and meningitis (43, 38%) were followed. Patients who were attending daycare center or had siblings accounted for 82.1%. Phylogenetic relationship tree revealed 6 distinct genogroups among 56 types of EVs. CONCLUSIONS: This study is the report of epidemiology, serotype distribution and clinical manifestations of children with EV infection in Incheon. This data will be helpful for further study about the epidemiology of EV infection in Korea.
Asymptomatic Infections ; Child ; Enterovirus* ; Epidemiology* ; Exanthema ; Fever ; Genotype ; Humans ; Incheon* ; Inpatients* ; Korea ; Meningitis ; Meningitis, Aseptic ; Sex Ratio ; Siblings ; Trees

BACKGROUND AND OBJECTIVES: We sought to determine whether an elevated homocysteine (Hcy) level is associated with a worse prognosis in Korean patients with coronary artery disease (CAD). SUBJECTS AND METHODS: A total of 5839 patients (60.4% male, mean age 61.3±11.2 years) with CAD were enrolled from 2000 to 2010 at Gangnam Severance Hospital. CAD was diagnosed by invasive coronary angiography. Laboratory values including Hcy level were obtained on the day of coronary angiography and analyses were performed shortly after sampling. Patients were divided into two groups according to their Hcy levels. Baseline risk factors, coronary angiographic findings, length of follow-up, and composite endpoints including cardiac death (CD) and non-fatal myocardial infarction (NFMI) were recorded. 1:1 propensity score matched analysis was also performed. RESULTS: Over a mean follow-up period of 4.4±2.5 years, there were 132 composite endpoints (75 CD and 57 NFMI) with an event rate of 2.3%. Mean Hcy level was 9.9±4.3 µmol/L (normal Hcy 7.9±1.5 µmol/L and elevated Hcy 13.9±5.1 µmol/L). Kaplan-Meier survival analysis showed an association of elevated Hcy level with worse prognosis (p<0.0001). In addition, a multivariate Cox regression analysis showed an association of elevated Hcy level with worse prognosis for both the entire cohort (hazard ratio [HR] 2.077, 95% confidence interval [CI] 1.467-2.941, p<0.0001) and the propensity score matched cohort (HR 1.982, 95% CI 1.305-3.009, p=0.001). CONCLUSION: Elevated Hcy level is associated with worse outcomes in Korean patients with CAD.
Cohort Studies ; Coronary Angiography ; Coronary Artery Disease* ; Coronary Vessels* ; Death ; Follow-Up Studies ; Homocysteine* ; Humans ; Male ; Myocardial Infarction ; Prognosis ; Propensity Score* ; Risk Factors

Our previous study has demonstrated that there is a significant delay of Balb/c cardiac allograft rejection in the C57BL/6 4-1BB-deficient knockout recipient. In this study, we examined the effect of combined blockade of the 4-1BB and CD28 costimulatory pathways on cardiac allograft rejection in the C57BL/6-->Balb/c model. A long-term cardiac allograft survival was induced in CD28/4-1BB- deficient mice (>100 days survival in 3 of 4 mice), which was comparable with CD28-deficient mice (>100 days survival in 2 of 5 mice; P<0.2026). There was no long-term cardiac allograft survival in either wild-type (WT) or 4-1BB-deficient mice, even though 4-1BB-deficient recipients showed a significant delay of cardiac allograft rejection than WT mice. An in vitro mixed leukocyte reaction (MLR) assay showed that 4-1BB-deficient and WT mouse T cells had a similar responsiveness to allostimulation, whereas CD28- and CD28/4-1BB-deficient mouse T cells had a defective responsiveness to allostimulation. Furthermore, 4-1BB-deficient mice showed a similar CTL but an elevated Ab response against alloantigens as compared to WT mice, and the alloimmune responses of 4-1BB-deficient mice were abrogated in the CD28-deficient background. Overall, these results indicate that the CD28 costimulatory pathway plays a major role in the alloimmune response and that 4-1BB signals are dependent upon CD28 signals.
Transplantation, Homologous/immunology ; Signal Transduction/*immunology ; Mice, Knockout ; Mice ; Isoantigens/immunology ; Heart Transplantation/immunology ; Graft Survival/immunology ; Cytotoxicity Tests, Immunologic ; Antigens, CD28/genetics/*immunology/metabolism ; Antibodies/immunology ; Animals ; 4-1BB Ligand/deficiency/genetics/*immunology/metabolism

The present study in angulated coronary stenosis used human in vivo hemodynamic parameters and computed simulation, both qualitatively and qualitatively, to evaluate the influence of flow velocity and wall shear stress (WSS) on coronary atherosclerosis, the changes of hemodynamic indices following coronary stenting, and their effect on evolving in-stent restenosis. Initial and follow-up coronary angiographies in patients with angulated coronary stenosis were performed (n=60). The optimal degree of coronary stenting for angulated coronary stenosis had two models, the less than 50% angle changed group (model 1, n=33) and the more than 50% angle changed group (model 2, n=27). This angle change was based on the percentage change of vascular angle between pre- and post-intracoronary stenting. The flow-velocity wave obtained from in vivo intracoronary Doppler study data was used for in vitro numerical simulation. Spatial and temporal patterns of the flow-velocity vector and recirculation area were drawn throughout the selected segment of coronary models. WSS of pre- and post-intracoronary stenting was calculated from three-dimensional computer simulation. As results, follow-up coronary angiogram demonstrated significant difference in the percentage of diameter stenosis between the two groups (group 1: 40.3 +/- 30.2 vs. group 2: 25.5 +/- 22.5%, p < 0.05). Negative shear area on 3D simulation, which is consistent with the re-circulation area of flow vector, was noted on the inner wall of the post-stenotic area before stenting. The negative WSS disappeared after stenting. High spatial and temporal WSS before stenting fell within the range of physiologic WSS after stenting. This finding was more prominent in model 2 (p < 0.01). The present study suggests that hemodynamic forces exerted by pulsatile coronary circulation, termed WSS, might affect the evolution of atherosclerosis within the angulated vascular curvature. Moreover, geometric characteristics, such as the angular difference between pre- and post- intracoronary stenting might define optimal rheologic properties for vascular repair after stenting.
Adult ; Aged ; Biomechanics ; *Coronary Circulation ; Coronary Stenosis/*physiopathology/therapy ; Female ; *Hemodynamics ; Human ; Male ; Middle Age ; *Stents ; Stress, Mechanical

OBJECTIVE: To know whether HPV Oligonucleotide Microarray (HPVDNAChip) can detect the HPV DNA in the urine and, if it can, to compare the results with Pap smear, biopsy, and cervix HPVDNAChip. METHODS: The authors had done Pap smear, cervix HPVDNAChip and colposcopy-guided punch biopsy as well as detailed information to those who visited Dept. of Ob. And Gyn. during 1st of April to 31st of May in 2003 for their uterine cervical problems related to the neoplasia. When they were determined to admit for treatment, urine had been collected to be tested by HPVDNAChip. RESULTS: Among 25 patients enrolled in this study, there were 10 whose urine HPVDNAChip test turned out positive (40%). Among 10 positive results, 9 patients had HPV 16 subtypes. Among 10 urine HPVDNAChip positive patients, there were 5 HSIL, 4 squamous cell cancer (SCC), and 1 ASCUS cell types on the Pap smears. Among 15 urine HPVDNAChip negative patients, there were 7 HSIL, 5 SCC, 1 ASCUS, 1 LSIL, and 1 AGUS. Among 10 urine HPVDNAChip there are 5 CIN3, and 4 invasive SCC, and 1 adenocarcinoma at the biopsy. Among 15 urine HPVDNAChip negative patients, there are 7 CIN3, 6 invasive SCC, 1 adenocarcinoma in situ, and 1 CIN1 patient. Whenever there were a urine HPVDNAChip 16 subtype positive, there were always cervix HPVDNAChip 16 subtype positive, but among the 12 urine HPVDNAChip negative patients, 5 had HPV 16 subtype positive and 4 had another subtypes and 3 had negative on cervix HPVDNAChip tests. CONCLUSION: Using HPVDNAChip, we verified that 40% of patients had the HPV DNA in their urine who had admitted for the treatment of their cervical neoplasm. And HPV 16 subtype was the most common type in the urine. If we can extend this data more widely, we might use it as an auxiliary tool for cervical HPV infection.
Adenocarcinoma ; Biopsy ; Cervix Uteri* ; DNA ; Female ; Human papillomavirus 16 ; Humans ; Neoplasms, Squamous Cell ; Oligonucleotide Array Sequence Analysis* ; Uterine Cervical Neoplasms*