Broadly neutralizing antibodies target the coronavirus fusion peptide

The potential for future coronavirus outbreaks highlights the need to develop strategies and tools to broadly target this group of pathogens. Here, using an epitope-agnostic approach, we identified six monoclonal antibodies that bound to spike proteins from all seven human-infecting coronaviruses. Epitope mapping revealed that all six antibodies target the conserved fusion peptide region adjacent to the S2 cleavage site. Two antibodies, COV44-62 and COV44-79, broadly neutralize a range of alpha and beta coronaviruses, including SARS-CoV-2 Omicron subvariants BA.1 and BA.2, albeit with lower potency than RBD-specific antibodies. In crystal structures of Fabs COV44-62 and COV44-79 with the SARS-CoV-2 fusion peptide, the fusion peptide epitope adopts a helical structure and includes the arginine at the S2 cleavage site. Importantly, COV44-79 limited disease caused by SARS-CoV-2 in a Syrian hamster model. These findings identify the fusion peptide as the target of the broadest neutralizing antibodies in an epitope-agnostic screen, highlighting this site as a candidate for next-generation coronavirus vaccine development. One-Sentence SummaryRare monoclonal antibodies from COVID-19 convalescent individuals broadly neutralize coronaviruses by targeting the fusion peptide.

Polymorphisms of TAP2 Gene in Schizophrenia / 신경정신의학

OBJECTIVES: The genes for transporters associated with antigen processing (TAP) are located near to HLA class II coding regions and related to antigen presentation. Therefore polymorphisms of TAP might alter the T-cell mediated immune response and influence susceptibility to schizophrenia, which is known to have alterations in T-cell immunity. The aim of this study was to verify the relationship between schizophrenia and polymorphisms of TAP2 genes. METHODS: 257 patients with schizophrenia and 184 normal controls participated in this study. TAP2 polymorphic residues at positions 379, 565 and 665 were typed using amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and single-strand conformation polymorphism (SSCP). The resulted products, TAP2379, TAP2565 and TAP2665 were assessed. RESULTS: The frequency of TAP2 alleles did not differ between patients with schizophrenia and controls. The polymorphic sites TAP2379, TAP2565 and TAP2665 did not show any difference in their amino acid substitution frequencies. CONCLUSION: This study did not show the association of the TAP2 gene with schizophrenia in Korean population. Further studies are needed to test the informative value of haplotypes including other polymorphic sites.

Investigation of IL-1B (-511, +3954) and IL-1RN Gene Polymorphisms in Korean Psoriasis Patients

BACKGROUND: Psoriasis is an inflammatory skin disorder that is characterized by a marked proliferation of keratinocytes, vascular dilation and leukocyte infiltration. Cytokines play important roles in the pathogenesis of inflammatory disorders. An overexpression of proinflammatory cytokines was characterized in psoriasis plaque. Among these cytokines, IL-1beta is major pro-inflammatory cytokine synthesized during the infection and inflammatory process. The IL-1 receptor antagonist (IL-1Ra) competes for the same IL-1 receptor for IL-1alpha and -1beta, which prevents activation of the target cells. Three single nucleotide polymorphisms (SNPs) in the IL-1beta gene have been reported at position-31, -511 and +3954. Within the IL-1Ra gene (IL-1RN), there is a variable number of tandem repeats (VNTR) of an 86 bp length in intron 2. These polymorphisms related to cytokine production and associated with various diseases. METHODS: We investigated the polymorphisms of IL-1B (promoter -511 and +3954) and IL-1RN on 114 psoriasis patients and -311 healthy normal controls in Korean. We performed PCR-RFLP on single nucleotide polymorphisms (SNPs) of IL-1B (promoter -511 and +3954) and fragment analysis on IL-1RN 86 bp VNTR polymorphism. RESULTS: The frequency of IL-1B-511*1 allele (patients vs. controls; 50.0% vs. 42.3%, RR=1.4) was significantly increased and IL-1B -511*2 allele (patients vs. controls; 50.0% vs. 57.7%, RR=0.7) decreased in psoriasis patients compared to normal controls. We also analyzed the IL-1B -511 polymorphism according to patients' characters (age of onset, sex and family history). The IL-1B -511 alleles were significantly associated in patients with male and family history than health normal controls. There were no significant associations of IL-1B +3954 and IL-1RN polymorphisms with psoriasis patients. CONCLUSION: These results suggest that the polymorphism of IL-1B -511 could be genetic susceptibility to psoriasis in Koreans.

Associations of Moyamoya Patients with HLA Class I and Class II Alleles in the Korean Population

Moyamoya disease is characterized by progressive cerebrovascular occlusion at the peripheral internal carotid artery and development of abnormal collateral circulation at the cerebral basal region. Although abnormal thrombogenesis, inflammation and autoimmune process might be involved in the etiology, the genetic pathogenesis of Moyamoya disease is still unknown. To evaluate the association of Moyamoya disease with HLA alleles in the Korean population, we investigated HLA class I and class II alleles in 28 Moyamoya patients and 198 unrelated healthy controls. The frequency of HLA-B35 allele was significantly increased in the patients compared to the controls (32.1% vs. 10.1%, RR=4.2, p<0.008). Further analysis of HLA-B35 on onset age and sex showed that this allele was significantly increased compared to the controls in both late-onset and female group. Especially, HLA-B35 was the most significantly increased in female of late-onset group compared to the controls. These results suggest that HLA-B35 may be an useful genetic marker for Moyamoya disease, and particularly in females of late onset group in the Korean population.

Distribution of HLA-DQA1*01, *03, *05 and DQB1*02 Subtypes and the Associated Haplotypes in the Korean Population

BACKGROUND: As all HLA class II genes, the DQ genes show their polymorphic variation mainly in the second exon, which encodes the first extracellular domain of the molecule. PCR-SSOP (Polymerase chain reaction-Sequence specific oligonucleotide probe) techniques were frequently used for HLA-DQA1 and DQB1 typing but certain alleles, DQA1*0101/0104/0105, *0302/0303, *0501/0505 and DQB1*0201/*0202, which differ from each other in segment other than exon 2, could not be unequivocally assigned. METHODS: To overcome this problem, we applied additional PCR-SSP (PCR-Sequence specific primer) method to analyze DQA1 exons 1, 3 and 4 and DQB1 exon 3. And we investigated the distributions and haplotypes of HLA-DRB1, DQA1 and DQB1 alleles in 406 unrelated Korean healthy individuals. RESULTS: Using this method the indistinguishable alleles of DQA1 and DQB1 in PCR-SSOP were typed definitively. We also found several important associations between DQA1 and DQB1 alleles in the Korean population; DQA1*0101-DQB1*0501, DQA1*0104-DQB1*0502 or -*0503, DQA1 *0105-DQB1*0501, DQA1*0302-DQB1*0303, DQA1*0303-DQB1*0401 or -*0402, DQA1 *0501-DQB1*0201, DQA1*0505-DQB1*0301, and DQA1*0201-DQB1*0202. The haplotypes of DRB1-DQA1-DQB1 associated with DQA1*01, *03, *05, and DQB1*02 subtypes were investigated. Several haplotypes associated with these alleles were observed in the Korean population. CONCLUSION: Our results can be helpful to find potential unrelated donors for bone marrow registries and study the HLA-associated disease and anthropology at high-resolution allelic level.

Associations of HLA Alleles with Chronic Infection and Prophylaxis in Vertical Transmission of Hepatitis B Virus

Perinatal transmission and infection of hepatitis B virus (HBV) in early childhood were observed in the offsprings of hepatitis B surface antigen (HBsAg)-positive mothers who had been vaccinated against HBV immediately after giving birth. This prophylaxis failure of perinatal HBV infection is likely due to the interplay of the virus and host immune response. To investigate whether the HLA polymorphism affected the outcome of the perinatal prophylaxis, HLA class I (HLA-A, B and Cw) and class II (HLA-DRB1, DQA1, DQB1 and DPB1) were typed using serology, PCR-SSOP (polymerase chain reaction-sequence specific oligonucleotide probe), and PCR-ARMS (amplification refractory modification system) methods in 22 HBeAg-positive mothers and their 10 prophylaxis-succeeded and 12 prophylaxis- failed children. The HLA types of the mothers and their children were compared with 198 HBsAg-negative healthy controls in a Korean population. HLA-B35 (relative risk=4.2, p<0.01), B51 (relative risk=3.2, p<0.02), DRB1*07 (relative risk=3.8, p<0.03), and DQA1*02 (relative risk=3.8, p<0.03) alleles were more frequent in HBeAg-positive mothers than in the controls. Also, HLA-DRB1*13 (relative risk=0.1, p<0.02) and DPB1*0401 (relative risk=0.1, p<0.02) alleles were less frequent in HBeAg-positive mothers. However, HLA alleles did not affect the outcome of the perinatal prophylaxis against HBV. These results suggest that the reported influences of some HLA alleles on the natural chronic HBV infections may not operate in the HBV infections in children received perinatal prophylaxis.

Association of HIV infection with MICA (MHC class I chain-related A) gene alleles

BACKGROUND: A large number of diseases occur in association with specific HLA-B or-C alleles. Recently a new gene, termed maj or histocompatibility complex class I chain-related gene A (MICA), has been identified in close proximity to HLA-B. The function of this gene is still unknown. However, it is structurally similar to HLA class I genes. MICA gene is polymorphic and is potentially associated with several diseases. METHODS: To evaluate the association of MICA gene in Korean patient s with human immunodeficiency virus 1 (HIV-1) infections, Polymerase chain reaction-Sequence specific primer (PCR-SSP) was done for MICA alleles in the extracellular exons, and a microsatellite analysis for GCT repeat polymorphisms in the TM exon was also completed. RESULTS: In 199 Korean healthy controls, 7 alleles were observed and the frequencies for each allele were MICA008 (44.7%), MICA0 10 (34.2%), MICA002 (31.7%), MICA004 (23.6%), MICA0 12 (2 1.6%), MICA009 (19.6%), and MICA007 (6.5%). When 65 HIV seropositive patients were analyzed, MICA007 allele frequency was significantly higher than in controls (15.4% vs 6.5 %, RR=2.6, p<0.04). In contrast, the frequencies of other MICA alleles and microsatellite alleles in the transmembrane region of MICA gene were not significantly different between HIV seropositive patients and controls. The tight linkage between MICA alleles in the extracellular exons and GCT repeat polymorphisms in the TM exon was observed as follows; MICA002/A9, MICA004/A6, MICA007/A4, MICA008/A5. 1, MICA0 10/A5, and MICA0 12/A4 in both groups. No significant difference between patient s and controls was observed in the haplotype frequencies of MICA alleles in the extracellular exons and GCT repeat polymorphisms in the TM exon. CONCLUSION: The data suggest that immune functions related with MICA gene may affect a HIV infections.

The Distribution of CTLA-4 Alleles in Korean Patients with SLE / 대한면역학회지

No abstract available.