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关键词： Binders  

摘要： Major histocompatibility complex class II (MHCII) bound to a peptide antigen mediates interactions between CD4+ T cells and antigen-presenting cells. Targeting peptide-MHCII with T cell antigen receptors (TCRs) and TCR-like antibodies has shown promise for autoimmune diseases and microbiome tolerance. To develop a general targeting approach, we introduce targeted recognition of antigen-MHC complex reporter for MHCII (TRACeR-II) for the rapid development of peptide-specific MHCII binders. TRACeR-II binders have a small helical bundle scaffold and use a single loop to recognize peptide-MHCII, which offers versatility and enables structural modeling of the interactions to target MHCII antigens. We demonstrate rapid generation of TRACeR-II binders to multiple molecules with affinities in the low-nanomolar to low-micromolar range, comparable to best-in-class TCRs and antibodies. Through computational protein design, we created specific binding sequences in silico from only the sequence of a severe acute respiratory syndrome coronavirus 2 peptide. TRACeR-II provides a straightforward approach to target antigen-MHCII without relying on combinatorial selection on complementarity-determining region loops.

关键词： pediatric   Crohn's disease   anti-TNF  

摘要： Background The 2021 ECCO-ESPGHAN guideline on the medical management of pediatric Crohn's disease promotes early risk stratification and top-down anti-TNF for patients deemed high risk of severe disease *** We aimed to objectively assess the risk-benefit profile of the guideline's risk stratification policy and guidance on top-down anti-TNF in a nationwide population-based cohort *** Using a prospectively identified nationwide cohort of all new pediatric patients (<17 years) diagnosed with Crohn's disease in Scotland between January 1, 2016 and December 31, 2020 and retrospectively applying the current management algorithm, we explored the guideline's ability to accurately risk stratify patients. Phenotypic and treatment data were retrospectively collected from electronic medical records with a maximum follow-up of 18 months *** Four hundred and eighteen children (258/418 [62%] male;median [interquartile range {IQR}] age at diagnosis: 13.2 [11.2-14.8] years) were included. High-risk phenotype was present in 224/418 (54%) with 53/224 (24%) of high-risk patients not requiring anti-TNF therapy within 18 months of diagnosis. Conversely, 78/194 (40%) of the low-risk group received anti-TNF within 18 months. High-risk patients were more likely to require anti-TNF (171/224 [76%] vs 78/194 [40%], P < .001) and had shorter median (IQR) time to anti-TNF start (5.0 [1.0-8.0] months vs 6.5 [3.3-13.0] months, P = .01).Conclusions Our data support the guideline's ability to identify patients more likely to require early treatment escalation. However, this approach would have led to potential over- and under-treatment in a substantial proportion of patients. This underscores the importance of frequent and comprehensive monitoring, along with flexible treatment strategies that adapt to changes in disease status. In a historic nationwide cohort of patients with pediatric Crohn's disease categorized as high or low risk using the 2021 ECCO-ESPGHAN

摘要： Depemokimab, the first ultra-long-acting anti-IL-5 monoclonal antibody, significantly reduced exacerbation rates in patients with severe eosinophilic asthma when administered biannually. While it offers potential benefits for patient adherence and convenience, the trials showed no improvement in symptoms and lung function. Further research is needed to determine its optimal place in therapy and identify patients who will benefit the most.

摘要： GLUT1 deficiency prevents glucose uptake in T cells resulting in lower intracellular ATP generation and IFNy production.

摘要： A method for designing high-affinity, specific binders to peptide–MHC complexes may improve the next generation of antigen-specific T cell-based therapeutics. © Springer Nature America, Inc. 2024.

关键词： IL-8   antibody against IL-8   heated molecular dynamic (MD) simulations   long simulations   MM-GBSA  

摘要： Elevated interleukin 8 (IL-8) expression has been linked to unfavorable outcomes in a range of inflammatory conditions, such as rheumatoid arthritis, psoriasis, and cancer. The human monoclonal antibody (HuMab) 10F8 and the hybridoma 35B11-B bind to an epitope on human IL-8, respectively. 10F8 inhibited interaction between IL-8 and neutrophils in eczema and pustulosis palmoplantaris patients while 35B11-B decreased size lesion in rat model. The binding interaction of monoclonal antibodies and IL-8, especially how complementarity-determining region (CDR) loops could bind the N-terminal of IL-8, has not been fully deliberated at molecular-level. Here, we used a combination of molecular docking, heated and long coarse-grained molecular dynamics simulations to identify key residues of established interaction. Based on heated MD simulation, docked pose of complexes generated by ClusPro showed good binding stability throughout of 70 ns simulation. Based on long molecular dynamic simulations, key residues for the binding were identified throughout of 1000 ns simulation. TYR-53, ASP-99, and ARG-100 of heavy chain CDR together with TYR-33 of light chain CDR are among the highest contributing energy residues within the binding interaction. Meanwhile, LYS11 and TYR13 of IL-8 are important for the determination of overall binding energy. Furthermore, the result of decomposition residues analysis is in good agreement with the interaction analysis data. Current study provides a list of important interacting residues and further scrutiny on these residues is essential for future development and design of a new and stable recombinant antibody against *** by Ramaswamy H. Sarma

关键词： Autoantibodies   Diagnosis   Endotype   Genetics   Genotype   Heterogeneity   HLA   Immunologic   Phenotype   Precision medicine   Preclinical   Prediction   Screening   TrialNet   Type 1 diabetes  

摘要： Aims/hypothesis Many studies of type 1 diabetes pathogenesis focus on individuals with high-risk HLA haplotypes. We tested the hypothesis that, among islet autoantibody-positive individuals, lacking HLA-DRB1*04-DQA1*03-DQB1*0302 (HLA-DR4-DQ8) and/or HLA-DRB1*0301-DQA1*0501-DQB1*0201 (HLA-DR3-DQ2) is associated with phenotypic differences, compared with those who have these high-risk HLA haplotypes. Methods We classified autoantibody-positive relatives of individuals with type 1 diabetes into four groups based on having both HLA-DR4-DQ8 and HLA-DR3-DQ2 (DR3/DR4;n=1263), HLA-DR4-DQ8 but not HLA-DR3-DQ2 (DR4/non-DR3;n=2340), HLA-DR3-DQ2 but not HLA-DR4-DQ8 (DR3/non-DR4;n=1607) and neither HLA-DR3-DQ2 nor HLA-DR4-DQ8 (DRX/DRX;n=1294). Group comparisons included demographics, metabolic markers and the prevalence of autoantibodies against GAD65 (GADA%), IA-2 (IA-2A%) or insulin (IAA%) at enrolment. A p value <0.01 was considered statistically significant. Results IA-2A% was lower in the DRX/DRX group (20.9%) than in the DR4/non-DR3 (38.5%, p<0.001) and DR3/DR4 (44.8%, p<0.001) groups, but similar to the DR3/non-DR4 group (20.0%). Conversely, IAA% was similar in the DRX/DRX (43.4%), DR4/non-DR3 (41.1%) and DR3/DR4 (41.0%) groups, but lower in the DR3/non-DR4 group (30.1%, p<0.001). Participants in the DRX/DRX group were older, with a lower prevalence of White participants and a higher prevalence of overweight/obesity, and higher preserved C-peptide (as measured by a lower Index60) than those in the DR3/DR4 group (all comparisons, p<0.005), a lower prevalence of White or non-Hispanic participants and a lower Index60 than those in the DR4/non-DR3 group, and younger age, a higher prevalence of Hispanic participants and a lower Index60 than those in the DR3/non-DR4 group (all comparisons, p<0.005). Among the 1292 participants who progressed to clinical type 1 diabetes, those in the DR3/non-DR4 group had higher GADA%, lower IA-2A% and lower IAA% than the other groups (all compa

关键词： 干扰素调节因子7   卵形鲳鲹   原核表达   多克隆抗体  

摘要： IRF7在免疫调节、抗病毒、抗细菌、细胞增殖和细胞凋亡等方面均发挥着重要作用。目前关于鱼类IRF7在抗病免疫应答方面的研究相对匮乏，本研究以海南深水网箱主要养殖鱼类卵形鲳鲹为研究对象，对卵形鲳鲹IRF7（Tro IRF7）进行原核表达、纯化和多克隆抗体制备。首先，构建了Tro IRF7的原核表达载体E. coli BL21（DE3）/pET32a-Tro IRF7，然后加入0.1 mmol·L-1的IPTG于20℃振荡培养24 h，诱导重组蛋白r Tro IRF7表达，其次，通过镍离子亲和层析柱对重组蛋白r Tro IRF7进行纯化，得到电泳纯的r Tro IRF7，最后将电泳纯的r Tro IRF7与弗氏（不）完全佐剂混合免疫小鼠，获得鼠抗r Tro IRF7的多克隆抗体，Elisa的实验结果显示所制备的多克隆抗体能与重组蛋白结合，抗体效价为1∶25 600。本研究为后续Tro IRF7在机体抗细菌免疫中的功能和机制研究提供了一定的基础。

关键词： IL-12   conventional dendritic cell   immunoglobulin A   immunomodulatory function   lactic acid bacteria  

摘要： In this study, we screened 308 lactic acid bacteria strains for high immunoglobulin A (IgA) production, dendritic cell activation, and IL-12 production using human derived cells. Among them, Lactobacillus helveticus GCL1815 demonstrated superior performance in all aspects, indicating its remarkable potential for immunomodulatory functions in both innate and adaptive immunity.