SARS‑CoV‑2 Omicron variant causes brain infection with lymphoid depletion in a mouse COVID‑19 model / 한국실험동물학회지

Background@#The Omicron variant has become the most prevalent SARS-CoV-2 variant. Omicron is known to induce milder lesions compared to the original Wuhan strain. Fatal infection of the Wuhan strain into the brain has been well documented in COVID-19 mouse models and human COVID-19 cases, but apparent infections into the brain by Omicron have not been reported in human adult cases or animal models. In this study, we investigated whether Omicron could spread to the brain using K18-hACE2 mice susceptible to SARS-CoV-2 infection. @*Results@#K18-hACE2 mice were intranasally infected with 1 × 105 PFU of the original Wuhan strain and the Omicron variant of SARS-CoV-2. A follow-up was conducted 7 days post infection. All Wuhan-infected mice showed > 20% body weight loss, defined as the lethal condition, whereas two out of five Omicron-infected mice (40%) lost > 20% body weight. Histopathological analysis based on H&E staining revealed inflammatory responses in the brains of these two Omicron-infected mice. Immunostaining analysis of viral nucleocapsid protein revealed severe infection of neuron cells in the brains of these two Omicron-infected mice. Lymphoid depletion and apoptosis were observed in the spleen of Omicron-infected mice with brain infection. @*Conclusion@#Lethal conditions, such as severe body weight loss and encephalopathy, can occur in Omicron-infected K18-hACE2 mice. Our study reports, for the first time, that Omicron can induce brain infection with lymphoid depletion in the mouse COVID-19 model.

Laboratory information management system for COVID-19 non-clinical efficacy trial data / 한국실험동물학회지

Background@#As the number of large-scale studies involving multiple organizations producing data has steadily increased, an integrated system for a common interoperable format is needed. In response to the coronavirus disease 2019 (COVID-19) pandemic, a number of global efforts are underway to develop vaccines and therapeutics. We are therefore observing an explosion in the proliferation of COVID-19 data, and interoperability is highly requested in multiple institutions participating simultaneously in COVID-19 pandemic research. @*Results@#In this study, a laboratory information management system (LIMS) approach has been adopted to systemically manage various COVID-19 non-clinical trial data, including mortality, clinical signs, body weight, body temperature, organ weights, viral titer (viral replication and viral RNA), and multiorgan histopathology, from multiple institutions based on a web interface. The main aim of the implemented system is to integrate, standardize, and organize data collected from laboratories in multiple institutes for COVID-19 non-clinical efficacy testings. Six animal biosafety level 3 institutions proved the feasibility of our system. Substantial benefits were shown by maximizing collaborative high-quality non-clinical research. @*Conclusions@#This LIMS platform can be used for future outbreaks, leading to accelerated medical product development through the systematic management of extensive data from non-clinical animal studies.

Inflammasome-Dependent Peroxiredoxin 2 Secretion Induces the Classical Complement Pathway Activation

Peroxiredoxins (Prxs) are ubiquitously expressed peroxidases that reduce hydrogen peroxide or alkyl peroxide production in cells. Prxs are released from cells in response to various stress conditions, and they function as damage-associated molecular pattern molecules. However, the secretory mechanism of Prxs and their roles have not been elucidated. Thus, we aimed to determine whether inflammasome activation is a secretory mechanism of Prxs and subsequently identify the effect of the secreted Prxs on activation of the classical complement pathway. Using J774A.1, a murine macrophage cell line, we demonstrated that NLRP3 inflammasome activation induces Prx1, Prx2, Prx5, and Prx6 secretion in a caspase-1 dependent manner. Using HEK293T cells with a transfection system, we revealed that the release of Prx1 and Prx2 relies on gasdermin-D (GSDMD)-mediated secretion. Next, we confirmed the binding of both Prx1 and Prx2 to C1q; however, only Prx2 could induce the C1q-mediated classical complement pathway activation. Collectively, our results suggest that inflammasome activation is a secretory mechanism of Prxs and that GSDMD is a mediator of their secretion. Moreover, secreted Prx1 and Prx2 bind with C1q, but only Prx2 mediates the classical complement pathway activation.

Association Analysis of Interleukin-1β, Interleukin-6, and HMGB1 Variants with Postictal Serum Cytokine Levels in Children with Febrile Seizure and Generalized Epilepsy with Febrile Seizure Plus

BACKGROUND AND PURPOSE: Febrile seizure (FS) is a unique type of seizure that only occurs during childhood. Genelized epilepsy with febrile seizure plus (GEFS+) is a familial epilepsy syndrome associated with FS and afebrile seizure (AFS). Both seizure types are related to fever, but whether genetic susceptibility to inflammation is implicated in them is still unclear. To analyze the associations between postictal serum cytokine levels and genetic variants in the cytokine genes interleukin (IL)-1β, IL-6, and high mobility group box-1 (HMGB1) in FS and GEFS+. METHODS: Genotyping was performed in 208 subjects (57 patients with FS, 43 patients with GEFS+, and 108 controls) with the SNaPshot assay for IL-1β-31 (rs1143627), IL-1β-511 (rs16944), IL-6-572 (rs1800796), and HMGB1 3814 (rs2249825). Serum IL-1β, IL-6, and HMGB1 levels were analyzed within 2 hours after seizure attacks using the ELISA in only 68 patients (38 FS, 10 GEFS+, and 20 controls). The allele distribution, genotype distribution, and correlations with serum cytokine levels were analyzed. RESULTS: Near-complete linkage disequilibrium exists between IL-1β-31 and IL-1β-511 variants. CT genotypes of these variants were associated with significantly higher postictal serum IL-1β levels than were CC+TT genotypes in FS (both p<0.05). CT genotypes of IL-1β-31 and IL-1β-511 variants were more strongly associated with FS than were CC+TT genotypes (odds ratio=1.691 and 1.731, respectively). For GEFS+, serum IL-1β levels after AFS for CT genotypes of IL-1β-31 and IL-1β-511 were also higher than for CC+TT genotypes. No significant associations were found for IL-6 and HMGB1. CONCLUSIONS: Genetic variants located in IL-1β-31 and IL-1β-511 promotor regions are correlated with higher postictal IL-1β levels in FS. These results suggest that IL-1 gene cluster variants in IL-1β-31 and IL-1β-511 are a host genetic factor for provoking FS in Korean children.

Association of Tumor Necrosis Factor-α Gene Promotor Variant, Not Interleukin-10, with Febrile Seizures and Genetic Epilepsy with Febrile Seizure Plus / 대한소아신경학회지

PURPOSE@#Cytokines demonstrate active roles in the occurrence of febrile seizures (FS). However, whether a genetic predisposition to inflammation is implicated in FS, febrile seizure plus (FS+) or genetic epilepsy with febrile seizure plus (GEFS+) are still unclear. Therefore we perform this study to find the association of promotor variants in pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) genes and anti-inflammatory cytokine interleukin 10 (IL-10) genes either with FS, FS+, and GEFS+ in Korean children.@*METHODS@#Fifty-seven children with FS, 32 FS+, and 12 GEFS+ patients were compared with 108 controls. The allelic and genotypic distributions were compared for TNF-α-238 (rs361525), −308 (rs1800629), −857 (rs1799724), −863 (rs1800630), and IL-10-592 (rs1800872), −819 (rs1800871), −1082 (rs1800896), and −1352 (rs1800893).@*RESULTS@#Allelic and genotypic frequencies of TNF-α and IL-10 promotor variants showed no significant differences between FS, FS+, and GEFS+ versus controls. However, AA genotypes at TNF-α-863 were present only in controls. TNF-α-863 (rs1800630) promoter variants showed an association with FS, FS+, and GEFS+ in a recessive mode of inheritance pattern (P<0.05).@*CONCLUSION@#Our results suggest that AA genotypes at TNF-α-863 may be associated with FS, FS+, and GEFS+, implicating protective roles against to development of FS, FS+, and GEFS+.

NOD-Like Receptors in Infection, Immunity, and Diseases

Nucleotide-binding and oligomerization domain (NOD)-like receptors (NLRs) are pattern-recognition receptors similar to toll-like receptors (TLRs). While TLRs are transmembrane receptors, NLRs are cytoplasmic receptors that play a crucial role in the innate immune response by recognizing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). Based on their N-terminal domain, NLRs are divided into four subfamilies: NLRA, NLRB, NLRC, and NLRP. NLRs can also be divided into four broad functional categories: inflammasome assembly, signaling transduction, transcription activation, and autophagy. In addition to recognizing PAMPs and DAMPs, NLRs act as a key regulator of apoptosis and early development. Therefore, there are significant associations between NLRs and various diseases related to infection and immunity. NLR studies have recently begun to unveil the roles of NLRs in diseases such as gout, cryopyrin-associated periodic fever syndromes, and Crohn's disease. As these new associations between NRLs and diseases may improve our understanding of disease pathogenesis and lead to new approaches for the prevention and treatment of such diseases, NLRs are becoming increasingly relevant to clinicians. In this review, we provide a concise overview of NLRs and their role in infection, immunity, and disease, particularly from clinical perspectives.

The Effect of Bortezomib on Expression of Inflammatory Cytokines and Survival in a Murine Sepsis Model Induced by Cecal Ligation and Puncture

PURPOSE: Although the proteasome inhibitor known as bortezomib can modulate the inflammatory process through the nuclear factor-kappa B signaling pathway, the immunomodulatory effect of pre-incubated bortezomib has not been fully evaluated for inflammation by infectious agents. Therefore, we evaluated the effect of bortezomib on the expression of inflammatory cytokines and mediators in macrophage cell lines and on survival in a murine peritonitis sepsis model. MATERIALS AND METHODS: Bortezomib was applied 1 hr before lipopolysaccharide (LPS) stimulation in RAW 264.7 cells. The cecal ligation and puncture (CLP) experiments were performed in C57BL/6J mice. RESULTS: Pre-incubation with bortezomib (25 nM or 50 nM) prior to LPS (50 ng/mL or 100 ng/mL) stimulation significantly recovered the number of viable RAW 264.7 cells compared to those samples without pre-incubation. Bortezomib decreased various inflammatory cytokines as well as nitric oxide production in LPS-stimulated cells. The 7-day survival rate in mice that had received bortezomib at 0.01 mg/kg concentration 1 hr prior to CLP was significantly higher than in the mice that had only received a normal saline solution of 1 mL 1 hr prior to CLP. In addition, the administration of bortezomib at 0.01 mg/kg concentration 1 hr before CLP resulted in a significant decrease in inflammation of the lung parenchyma. Collectively, pretreatment with bortezomib showed an increase in the survival rate and changes in the levels of inflammatory mediators. CONCLUSION: These results support the possibility of pretreatment with bortezomib as a new therapeutic target for the treatment of overwhelming inflammation, which is a characteristic of severe sepsis.

The Role of High Mobility Group Box 1 in Innate Immunity

With growing accounts of inflammatory diseases such as sepsis, greater understanding the immune system and the mechanisms of cellular immunity have become primary objectives in immunology studies. High mobility group box 1 (HMGB1) is a ubiquitous nuclear protein that is implicated in various aspects of the innate immune system as a damage-associated molecular pattern molecule and a late mediator of inflammation, as well as in principal cellular processes, such as autophagy and apoptosis. HMGB1 functions in the nucleus as a DNA chaperone; however, it exhibits cytokine-like activity when secreted by injurious or infectious stimuli. Extracellular HMGB1 acts through specific receptors to promote activation of the NF-kappaB signaling pathway, leading to production of cytokines and chemokines. These findings further implicate HMGB1 in lethal inflammatory diseases as a crucial regulator of inflammatory, injurious, and infectious responses. In this paper, we summarize the role of HMGB1 in inflammatory and non-inflammatory states and assess potential therapeutic approaches targeting HMGB1 in inflammatory diseases.

Current Understanding of HMGB1-mediated Autophagy

Reactive oxygen species (ROS) is an oxidative stress to which cells respond by activating various defense mechanisms or cell death. Autophagy associated with oxidative stress response is a process to degrade and recycle macro-molecule as well as organelles in eukaryotic cells. HMGB1, a ubiquitous nuclear protein, is actively released in eukaryotic cells under oxidative stress. HMGB1 plays an important role as regulator of autophagy in nuclear, cytosolic and extracellular level. Nuclear HMGB1 regulates the expression of heat shock protein beta-1 (HSPB1), which is critical for dynamic intracellular trafficking during autophagy and mitophagy. Cytoplasmic HMGB1 can bind to a beclin 1 by the intramolecular disulfide bridge using cysteine 23 and 45, which dissociates its inhibitory partner Bcl-2 and induces autophagy. Extracellular HMGB1 binds to receptor for advanced glycation endproducts (RAGE) which inhibits mammalian target of rapamycin (mTOR) and then promotes the formation of the belin1-Ptdlns3KC3 complex. Furthermore, endogenous HMGB1 is an intrinsic regulator of autophagy, and it enhances chemoresistance in diverse cancer cells. Here, we review recent reports suggesting a novel mechanism of diverse cancer cell resistance to therapy facilitated by HMGB1-mediated autophagy.

CKD-712, (S)-1-(alpha-naphthylmethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, Inhibits the NF-kappaB Activation and Augments Akt Activation during TLR4 Signaling

Since CKD-712 has been developed as an anti-inflammatory agent, we examined the effect of CKD-712 during TLR4 signaling. Using HEK293 cells expressing TLR4, CKD-712 was pre-treated 1 hr before LPS stimulation. Activation of NF-kappaB was assessed by promoter assay. The activation of ERK, JNK, p38, IRF3 and Akt was measured by western blotting. CKD-712 inhibited the NF-kappaB signaling triggered by LPS. The activation of ERK, JNK, p38 or IRF3 was not inhibited by CKD-712. On the contrary the activation of these molecules was augmented slightly. The activation of Akt with stimulation of LPS was also enhanced with CKD-712 pre-treatment at lower concentration, but was inhibited at higher concentration. We suggest that during TLR4 signaling CKD-712 inhibits NF-kappaB activation. However, CKD-712 augmented the activation of Akt as well as Map kinases. Therefore, we suggest that CKD-712 might have a role as an immunomodulator.

Development of Monoclonal Antibodies Against Human IRF-5 and Their Use in Identifying the Binding of IRF-5 to Nuclear Import Proteins Karyopherin-alpha1 and -beta1

PURPOSE: IRF-5 is a direct transducer of virus-mediated and TLR-mediated signaling pathways for the expression of cytokines and chemokines which form homodimers or heterodimers with IRF-7. However, direct IRF-5-specific monoclonal antibodies (mAbs) are not available at present. These could be used to further evaluate the functions of IRF-5. In this study, we produced and characterized three mouse mAbs to human IRF-5. The binding of IRF-5 to nuclear import proteins was first identified using a mAb. MATERIALS AND METHODS: His-tagged human IRF-5 protein spanning amino acid residues 193- 257 was used as an antigen and three mAbs were produced. The mAbs were tested with ELISA, Western blot analysis (WB), immunofluorescent staining (IF), and immunoprecipitation (IP). In addition, the nuclear import protein which carried phosphorylated IRF-5 was identified using one of these mAbs. RESULTS: MAbs 5IRF8, 5IRF10 and 5IRF24 which reacted with the recombinant His-IRF-5(193-257) protein were produced. All mAbs bound to human IRF-5, but not to IRF-3 or IRF-7. They could be used for WB, IF, and IP studies. The binding of phosphorylated IRF-5 to karyopherin-alpha1 and -beta1 was also identified. CONCLUSION: Human IRF-5-specific mAbs are produced for studying the immunologic roles related to IRF-5. Phosphorylated IRF-5 is transported to the nucleus by binding to nuclear import proteins karyopherin-alpha1 and -beta1.

Serotype and Antimicrobial Susceptibility of Streptococcus pneumoniae

BACKGROUND: Pneumococcus is the most common cause of acute otitis media, community acquired pneumonia and invasive bacterial diseases in children. Ninety serotypes have been identified, and the distribution differs according to geographic area and ages. The 7 valent pneumococcal protein conjugate vaccine is used widely. To evaluate the efficacy of the vaccine, it is essential to investigate the distribution of the pneumococcal serotypes. MATERIALS AND METHODS: The serotypes and antibiotic resistance of the pneumococcus isolated from 308 patients at Shinchon Severance hospital from September of 2001 to July of 2005 were analyzed. RESULTS: The pneumococcci were isolated mostly from sputum and blood, and ear discharge in the descending order. Serotyping was possible in 265 cases, and the distribution of serotypes were 19F (16.2%), 19A (12.8%), 23F (8.7%), 6B (7.9%), and 6A (7.2%). Fifty two cases were isolated from those patients less than 16 years of age and the distribution of serotypes was 19F, 19A, 23F, 14, 6B, 6A and 4. Resistance to penicillin was 64.6% in all cases and 67.3% in children. The more common serotype showed the higher rate of penicillin resistance. Multi-drug resistance was demonstrated in 64.7%. Forty three percent of the total identified serotypes were included in the 7 valent pneumococcal conjugate vaccine. And 61.5% of the serotypes identified in children were included in the vaccine. CONCLUSION: The 7 valent vaccine may be used effetively in Korea. But, further study is needed to address serotype switching after the use of the protein conjugated vaccine, which has been reported in other countries.

Serotype and Antimicrobial Susceptibility of Streptococcus pneumoniae

BACKGROUND: Pneumococcus is the most common cause of acute otitis media, community acquired pneumonia and invasive bacterial diseases in children. Ninety serotypes have been identified, and the distribution differs according to geographic area and ages. The 7 valent pneumococcal protein conjugate vaccine is used widely. To evaluate the efficacy of the vaccine, it is essential to investigate the distribution of the pneumococcal serotypes. MATERIALS AND METHODS: The serotypes and antibiotic resistance of the pneumococcus isolated from 308 patients at Shinchon Severance hospital from September of 2001 to July of 2005 were analyzed. RESULTS: The pneumococcci were isolated mostly from sputum and blood, and ear discharge in the descending order. Serotyping was possible in 265 cases, and the distribution of serotypes were 19F (16.2%), 19A (12.8%), 23F (8.7%), 6B (7.9%), and 6A (7.2%). Fifty two cases were isolated from those patients less than 16 years of age and the distribution of serotypes was 19F, 19A, 23F, 14, 6B, 6A and 4. Resistance to penicillin was 64.6% in all cases and 67.3% in children. The more common serotype showed the higher rate of penicillin resistance. Multi-drug resistance was demonstrated in 64.7%. Forty three percent of the total identified serotypes were included in the 7 valent pneumococcal conjugate vaccine. And 61.5% of the serotypes identified in children were included in the vaccine. CONCLUSION: The 7 valent vaccine may be used effetively in Korea. But, further study is needed to address serotype switching after the use of the protein conjugated vaccine, which has been reported in other countries.

Human Brain Astrocytes Mediate TRAIL-mediated Apoptosis after Treatment with IFN-gamma

TNF-related apoptosis inducing ligand (TRAIL) expressions were studied in primary human brain astrocytes in response to pro-inflammatory cytokines. When astrocytes were treated with IL-1beta TNF-alphaor IFN-gamma TRAIL was induced in cultured fetal astrocytes. In particular, IFN-gammainduced the highest levels of TRAIL in cultured astrocytes. When astrocytes were pre-reated with IFN-gamma they induced apoptosis in TRAIL-sensitive Peer cells. Our results suggest that IFN-gamma modulates the expression of TRAIL in astrocytes, which may enhance cytotoxic sensitivity of infiltrating immune cells or brain cells other than astrocytes during inflammation of brain.

Human Brain Astrocytes Mediate TRAIL-mediated Apoptosis after Treatment with IFN-gamma

TNF-related apoptosis inducing ligand (TRAIL) expressions were studied in primary human brain astrocytes in response to pro-inflammatory cytokines. When astrocytes were treated with IL-1beta TNF-alphaor IFN-gamma TRAIL was induced in cultured fetal astrocytes. In particular, IFN-gammainduced the highest levels of TRAIL in cultured astrocytes. When astrocytes were pre-reated with IFN-gamma they induced apoptosis in TRAIL-sensitive Peer cells. Our results suggest that IFN-gamma modulates the expression of TRAIL in astrocytes, which may enhance cytotoxic sensitivity of infiltrating immune cells or brain cells other than astrocytes during inflammation of brain.

Association between CCR5 Promoter Polymorphisms and Hepatitis B Virus Infection / 대한간학회지

BACKGROUND/AIMS: Immunogenetic factors may play a role in determining the susceptibility of an individual to viral infection. CCR5 promoter polymorphisms are known to be associated with HIV infection. However, there has been no report on the association between CCR5 promoter polymorphism and HBV infection. Therefore, we investigated the relationship between the CCR5 promoter polymorphism and HBV infection. METHODS: A total of 377 patients were classified into two groups according to their HBV infection status: (1)he spontaneous clearance group (SC); HBsAg (-), anti-HBc (+), anti-HBs (+) (2)he chronic HBsAg (+) carrier group (CC); HBsAg (+), anti-HBc (+), anti-HBs (-). CCR5 polymorphisms were detected by employing matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS)- based SNP scoring assay, termed Restriction Fragment Mass Polymorphism (RFMP), which exploits the differences in molecular masses between the common allele and rare allele bases of interest. RESULTS: We found that the genotype frequencies of CCR5 A59029G significantly differed between the SC group (n=138) and CC group (n=239) (P<0.05). The CCR5 59029A allelic genotype was associated with an increased risks of chronic infection rather than spontaneous clearance (P=0.002), and the presence of the CCR5 59029G allele was significantly associated with the spontaneous clearance of HBV (P=0.001). Strong linkage disequilibrium between the CCR5-59029 and the CCR5-59353 polymorphic variants was identified. None of the 377 subjects had the CCR5-32 bp deletion mutation. CONCLUSIONS: The CCR5 promoter polymorphisms at position 59029 might play a role in the clearance of HBV infection. This primary experimental evidence needs further studies to clarify the clinical usefulness of CCR5 promoter polymorphisms as a target for the screening or treatment of HBV infection.

Cloning of TLR3 Isoform

Toll-like receptor (TLR) 3 is a member of the TLR family that confers innate immunity by recognizing viral pathogens. Herein, we report that the TLR3 isoform is expressed on human primary cells and cell lines. This isoform has 2, 520 bp cDNAs compared to the 2, 712 bp of full cDNA, is produced by deletion of an intron-like sequence within exon 4 and is co-expressed with wild type TLR3 in primary human astrocytes and glioblastoma cell lines. This finding suggests the TLR3 isoform in astrocytes may have a different immunological role for binding ligands during the immune response in brain.

Peptide Mimotopes of Neisseria meningitidis Group B Capsular Polysaccharide

The antigenic similarity between Neisseria meningitidis group B (NMGB) capsular polysaccharide (PS) and human polysialic acid (PSA) has hampered the development of a NMGB PS-based vaccine. But the possibility of a safe vaccine based on NMGB PS has been demonstrated by the existence of the NMGB PS-associated nonautoreactive epitope, which is distinct from those present on human PSA. To obtain peptide mimotopes of NMGB PS, we used HmenB3, a protective and nonautoreactive monoclonal antibody, to screen a phage library with 12 amino acids. We obtained 23 phage clones that bound to HmenB3 but not in the presence of E. coli K1 PS [which is alpha (2-8) -linked PSA like NMGB PS]. The clones contained 3 mimotopes and differed from previously described NMGB PS mimotopes. Immunization with a synthetic peptide of one mimotope elicited anti-NMGB antibodies in BALB/c mice. These mimotopes may be useful in the development of group B meningococcal vaccines.

Modulation of the Surface Expression of CD158 Killer Cell Ig-like Receptor by Interleukin-2 and Transforming Growth Factor-beta

Killer cell Ig-like receptor (KIR) binds to HLA class I molecules on the surface of target cells, and it confers inhibitory signals to NK cells. Although NK cytotoxicity can be affected by the change of the surface expression of KIR on NK cells, the effect of cytokines on the regulation of KIR expression has not been thoroughly investigated. Here in our study, we investigated the effect of several cytokines, including IL-2, TGF-beta, IFN-gamma, IL-12 and IL-18, on the surface expression of CD158 KIR, which binds to HLA-C, by the use of FACS analysis. In the isolated NK cells, IL-2 obviously increased the surface expression of CD158 KIR after 72 hr in vitro culture, and this was evidenced by the increased percentage of CD158+ NK cells and the increased mean fluorescence intensity of CD158 in CD158+ NK cells. In contrast, TGF-beta decreased the surface expression of CD158 KIR after 72 hr culture. However, IFN-gamma, IL-12 and IL-18 did not change the expression of CD158 KIR. The modulated expression of KIR by IL-2 and TGF-beta can be associated with the changed NK-cytotoxic target-discriminating ability of NK cells upon their exposure to IL-2 and TGF-beta.

Tumor Necrosis Factor-alpha Levels and Promoter Polymorphism in Patients with Kawasaki Disease in Korea

Tumor necrosis factor (TNF) -alpha plays a major role in the pathogenesis of Kawasaki disease (KD), a systemic vasculitis primarily affecting young children. We performed this study to examine the serum levels of TNF-alpha and to investigate a possible relation to promoter polymorphism at positions -238 and -308 in KD patients in Korea. We obtained 48 paired serum samples from 24 patients in the acute and subacute stages of KD, and control sera from 12 age-matched children who were having routine blood samples taken before elective surgical procedures. Our studies showed a significant increase in serum levels of TNF-alpha measured in the acute stage of KD (24.1+/-9.4 pg/mL) compared to those in the subacute stage (11.8+/-5.8 pg/mL; p < 0.01) and normal controls (10.4+/-4.9 pg/mL; p < 0.01). Previous studies report that the presence of the A allele at positions -308 and -238 may be associated with higher TNF-alpha levels. However, our results showed that the frequency of the A allele at position -308 in the KD patients was the same as the controls (2 out of 24, 8.3% vs. 8.3%, odds ratio (OR) = 1.00), while the frequency of the A allele at position -238 in the KD patients was lower than the controls (0/24, 0% vs. 8.3%, OR=0.00) ; this difference though was not statistically significant. We concluded that although TNF-alpha levels were significantly elevated in the acute stage of KD, there was no significant difference in the frequency of the A allele at positions -238 and -308 between the KD and control groups in Korean patients.