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关键词： antibodies   glutamate   interleukin-6   memory   aging  

摘要： Intranasal administration of antibodies to glutamate for 14 days improved passive avoidance conditioning and reduces the content of IL-6 within 7 days after their withdrawal in the prefrontal cortex and hippocampus of aging C57BL/6 mice.

关键词： Physiological root resorption   Deciduous dental pulp stem cells   alpha 7 nAChR   Mechanical stress   Autophagy   IL-1 beta  

摘要： Physiological root resorption of deciduous teeth is a normal phenomenon occurring during the developmental stages of children. Previous research has indicated the pivotal role of the inflammatory microenvironment in this process, although the specific mechanisms remain unclear. This study is aimed at elucidating the involvement of the alpha7 nicotinic acetylcholine receptors (alpha 7 nAChR)-autophagy axis in the regulation of the inflammatory microenvironment during physiological root resorption in deciduous teeth. Samples were collected from deciduous teeth at various stages of physiological root resorption, and deciduous dental pulp stem cells (DDPSCs) were isolated and cultured during the mid-phase of root resorption. The findings revealed a substantial infiltration of the pulp of deciduous teeth at the mid-phase of root resorption, characterized by elevated expression levels of alpha 7 nAChR and IL-1 beta. Significantly increased IL-1 beta and alpha 7 nAChR expressions were observed in DDPSCs during the mid-phase of root resorption, with alpha 7 nAChR demonstrating a regulatory effect on IL-1 beta. Moreover, evidence suggested that mechanical stress may act as a trigger, regulating autophagy and IL-1 expression via alpha 7 nAChR. In conclusion, mechanical stress was identified as a regulator of autophagy in DDPSCs through alpha 7 nAChR, influencing the expression of IL-1 beta and contributing to the formation of the inflammatory microenvironment. This mechanism plays a crucial role in the physiological root resorption of deciduous teeth. Key messages The pulp of deciduous teeth at mid-phase of root resorption was heavily infiltrated with high expression of alpha 7nAChR and IL-1 beta. alpha 7 nAChR acts as an initiating factor to regulate IL-1 beta through autophagy in DDPSCs. Mechanical stress can regulate autophagy of DDPSCs through alpha 7 nAChR and thus affect IL-1 beta expression and inflammatory microenvironment formation in physiological root resorption in

关键词： chronic obstructive pulmonary disease   COPD   IL-16   IL-25   survival analysis   immunopathology of COPD  

摘要： Background: Exacerbation of chronic obstructive pulmonary disease (ECOPD) significantly impact health status, hospitalization rates, and disease progression, and are linked to increased mortality. Predictive factors for ECOPD are therefore of considerable interest. The limited understanding of interleukin 16 (IL-16) and IL-25 role in ECOPD provided the rationale for this study. Methods: Fifty ex-smokers diagnosed with COPD (22 ECOPD and 28 patients in the stable phase of the disease) underwent prospective analysis to evaluate the role of I IL-25 as predictive markers of clinical outcomes in ECOPD. Results: We observed a significantly lower IL-16 and higher IL-25 concentrations among ECOPD patients (p = 0.002 and p = 0.01 respectively). We also detected a significant negative correlation between IL-16 and neutrophil-to-lymphocyte ratio (NLR) (p = 0.04) and a significant negative correlation between IL-25 concentration and absolute eosinophil count (p = 0.04). In the entire group, we observed a positive correlation between IL-16 and both FEV1 and FVC, both expressed as a percentage of reference value, (p = 0.002 and p = 0.0004 respectively). However, after stratification to ECOPD and stable COPD group, significance maintained for FVC (p = 0.045 for ECOPD and p = 0.02 for stable COPD). In survival analysis, we detected significantly lower all-cause mortality for 3rd tertile of IL-16 concentrations, with a hazard ratio of 0.33 (95%CI: 0.11-0.98;p = 0.04). Conclusions: Lower IL-16 levels among ECOPD patients may indicate a feedback mechanism linked to heightened Th1 response activation. Observed correlations with ventilatory parameters and survival also seems to reflect this mechanism. The higher IL-25 concentrations observed in ECOPD patients, along with the negative correlation with absolute eosinophil count and eosinopenia, suggest multifactorial regulation and independent functions of eosinophils and IL-25. Hypothetically, this paradox may be related to the Th1/Th2 i

关键词： Premature ovarian insufficiency   Methyltransferase like 3   Theca cells   Interleukin-1 beta   Granulosa cells apoptosis  

摘要： Premature ovarian insufficiency (POI) is a clinical syndrome characterised by a decline in ovarian function in women before 40 years of age and is associated with oestradiol deficiency and a complex pathogenesis. However, the aetiology of POI is still unclear and effective preventative and treatment strategies are still lacking. Methyltransferase like 3 (METTL3) is an RNA methyltransferase that is involved in spermatogenesis, oocyte development and maturation, early embryonic development, and embryonic stem cell differentiation and formation, but its role in POI is unknown. In the present study, METTL3 deficiency in follicular theca cells was found to lead to reduced fertility in female mice, with a POI -like phenotype, and METTL3 knockout promoted ovarian inflammation. Further, a reduction in METTL3 in follicular theca cells led to a decrease in the m 6 A modification of pri-miR-21, which further reduced pri-miR-21 recognition and binding by DGCR8 proteins, leading to a decrease in the synthesis of mature miR-21-5p. Decrease of miR-21-5p promoted the secretion of interleukin-1 beta (IL-1 beta) from follicular theca cells. Acting in a paracrine manner, IL-1 beta inhibited the cAMP -PKA pathway and activated the NF- kappa B pathway in follicular granulosa cells. This activation increased the levels of reactive oxygen species in granulosa cells, causing disturbances in the intracellular Ca 2 + balance and mitochondrial damage. These cellular events ultimately led to granulosa cell apoptosis and a decrease in oestradiol synthesis, resulting in POI development. Collectively, these findings reveal how METTL3 deficiency promotes the expression and secretion of IL-1 beta in theca cells, which regulates ovarian functions, and proposes a new theory for the development of POI disease.

关键词： HLA   HLA-B*51:01:44   novel allele   sequence-based typing   Taiwanese  

摘要： Nucleotide substitution in codon 221 of HLA-B*51:01:01:01 results in a novel allele, HLA-B*51:01:44.

关键词： Phenocopy   Multiple recurrent abscesses   Late onset   Teenage   Autoantibodies   Anti-cytokine   IL-12   IL-23   Inborn errors of immunity   Anti-CD20 monoclonal antibody  

摘要： More frequent among adults, phenocopies may be caused by somatic mutations or anti-cytokine autoantibodies, mimicking the phenotypes of primary immunodeficiencies. A fourteen-year-old girl was referred for a two-year history of weight loss and multiple recurrent abscesses, complicated recurrent pneumonia, pyelonephritis, osteomyelitis, and septic shock, without fever. She had started with nausea, hyporexia, and weight loss, then with abscesses in her hands, knee, ankle, and spleen. She also developed a rib fracture and left thoracic herpes zoster. The patient was cachectic, with normal vital signs, bilateral crackles on chest auscultation, tumefaction of the knee joint, and poorly healed wounds in hands and chest, oozing a yellowish fluid. Chest computed tomography revealed multiple bilateral bronchiectases. Laboratory workup reported chronic anemia, leukocytosis, neutrophilia, mild lymphopenia, thrombocytosis, pan-hypergammaglobulinemia, and elevated acute serum reactants. Lymphocyte subsets were low but present. Mycobacterium tuberculosis was detected via polymerase chain reaction in a bone biopsy specimen from ankle osteomyelitis. Whole-exome sequencing failed to identify a monogenic defect. Interleukin-12 was found markedly elevated in the serum of the patient. Phosphorylation of STAT4, induced by increasing doses of IL-12, was neutralized by patient serum, confirming the presence of antiIL12 autoantibodies. IL-12 and IL-23 are crucial cytokines in the defense against intracellular microorganisms, the induction of interferon-gamma production by lymphocytes, and other inflammatory functions. Patients who develop neutralizing serum autoantibodies against IL12 manifest late in life with weight loss, multiple recurrent abscesses, poor wound healing, and fistulae. Treatment with anti-CD20 monoclonal antibodies was effective.

关键词： COVID-19   Interleukin-17   Interleukin-22   IL-17/IL-22 ratio   Th17  

摘要： Background: The development of a cytokine storm in Coronavirus Disease 2019 (COVID-19) infection can make the disease fatal. We hypothesize that this excessive cytokine production impairs mucosal healing. IL-17 and IL-22 are cytokines that play a key role in protecting and regenerating mucosal tissues. IL-17 and IL-22 support each other, and the imbalance between them plays a role in the pathogenesis of many rheumatologic diseases. Objective: To investigate whether COVID-19 severity is related to IL17, IL-22, and the IL-17/IL-22 ratio. Methods: The study was planned prospectively and included 69 patients with active COVID-19 infection. Three groups were created: patients with upper respiratory tract infection, pneumonia, and cytokine storm. Blood samples were taken from the patients upon their first admission and serum levels of IL-17 and IL-22 were measured using the enzyme-linked immunosorbent assay (ELISA). We assessed the relationship between IL17, IL22, IL17/ IL22 ratio, clinical and lung involvement by comparing them with the healthy group. Results: The levels of IL-17 were significantly higher in COVID-19 patients with upper respiratory tract infection compared to the control group (p=0.027). p =0.027). IL17/IL-22 ratio significantly increased in patients with cytokine storm compared to the healthy controls (p=0.027). p =0.027). Serum levels of IL-22 were negatively correlated with the CO-RADS score (r=-0.31, p =0.004), while IL-17/IL-22 ratio was positively correlated with the CO-RADS score (r=0.29, p =0.008). Conclusion: Levels of IL-17, IL-22, and IL-17/IL-22 may provide valuable into the of COVID-19.

关键词： HLA   HLA-haploidentical haematopoietic cell transplantation with post-transplant cyclophosphamide   peptide-binding motif  

摘要： Peptide-binding motif (PBM) model, a hierarchical clustering of HLA class I based on their binding specificity, was developed to predict immunopeptidome divergence. The effect of PBM mismatches on outcomes is unknown in HLA-haploidentical haematopoietic cell transplantation with post-transplant cyclophosphamide (PTCy-haplo). We therefore conducted a retrospective study using national registry data in PTCy-haplo. Overall, 1352 patients were included in the study. PBM-A bidirectional mismatch was associated with an increased risk of overall mortality in multivariable analysis (hazard ratio, 1.26;95% confidence interval, 1.06 to 1.50;p = 0.010). None of relapse, non-relapse mortality (NRM) and graft-versus-host disease showed significant differences according to PBM-A bidirectional mismatch status in the entire cohort. The impact of PBM-A bidirectional mismatch on overall survival (OS) was preserved within the HLA-A genotype bidirectional mismatch population, and their lower OS stemmed from higher relapse rate in this population. The worse OS due to high NRM with PBM-A bidirectional mismatch was prominent in lymphoid malignancies receiving reduced-intensity conditioning. The PBM model may predict outcomes more accurately than HLA genotype mismatches. In conclusion, this study demonstrated that the presence of PBM-A bidirectional mismatch elevated the risk of mortality of PTCy-haplo. Avoiding PBM-A bidirectional mismatch might achieve better outcomes in PTCy-haplo.

摘要： Thrombotic thrombocytopenic purpura (TTP) is one of the rare group disorders classified as thrombotic microangiopathies (TMAs). Approximately 90% of TTP developed immune-mediation by the formation of antibodies against the enzyme ADAMTS-13. The exact cause is unknown. To establish an association between human leukocyte antigen (HLA) and autoimmune basis, as susceptibility or protection against the disease, we contributed a study aiming to evaluate the role of HLA in immune-mediated TTP (iTTP). Considering epidemiological factors such as age, sex, ethnicity, and geographical origins, we contributed the study in our country, Turkey, which consist of a very heterogeneous population. Patients' data collection was retrospectively from electronic database on two University hospitals having big therapeutic apheresis service. Control arm was healthy people registered as stem cell donors matched in terms of age and sex. The frequency of HLA-DRB1 and HLA-DQB1 alleles between acquired TTP and the control group was compared using the chi-square method. Yates correction and logistic regression were performed on these results. A total of 75 iTTP patients and 150 healthy individuals enrolled to the study. HLA-DRB1 & lowast;11, HLA-DQB1 & lowast;03, HLA-DRB1 & lowast;11:01, HLA-DRB1 & lowast;14:01, HLA-DRB1 & lowast;13:05, HLA-DRB1 & lowast;11 + HLA-DQB1 & lowast;03 allele pair and HLA-DRB1 & lowast;15 + HLA- DQB1 & lowast;06 were proved to be susceptibility allele pairs for iTTP. HLA-DRB1 & lowast;15, HLA-DRB1 & lowast;01:01, HLA-DRB1 & lowast;07:01, HLA-DRB1 & lowast;13:01, HLA-DRB1 & lowast;14:54, HLA-DQB1 & lowast;05:01, HLA-DQB1 & lowast;02:02 and HLA-DRB1 & lowast;07 + HLA-DQB1 & lowast;02 allele pair were found to be protective against iTTP. Our findings support an association with iTTP across very heterogenous populations in Turkey.