Ageing on the impact of distribution about preformed anti-HLA and anti-MICA antibody specificities in recipients prior to initial HSCT from East China.

BACKGROUND: With the development of Hematopoietic Stem Cell Transplantation (HSCT) technology, increasing numbers of elderly patients were undergoing allogeneic HSCT and elderly patients with hematologic malignancies could benefit most from it. Preformed donor-specific human leukocyte antigen (HLA) antibodies (DSA) were associated with graft failure in HLA-mismatched allogeneic HSCT and the absence of DSA was the main criterion of selecting the donor. Except for sensitization events such as transfusion, pregnancy or previous transplantation, ageing affects the humoral immune response both quantitatively and qualitatively. To evaluate the prevalence and distribution of anti-HLA and antibodies of MHC class I chain related antigens A (MICA) specificities in different age groups before initial HSCT would provide HLA and MICA specific antibody profiles under the impact of ageing, which could provide meaningful information in the process of selecting suitable HLA-mismatched donors by avoiding preformed DSA. RESULTS: There were no significant differences in the distribution of anti-HLA class I, class II and anti-MICA antibodies among the three age groups in this study except that a significant lower negative ratio of anti-HLA class I, class II antibodies and higher positive rate of MICA antibodies with maximum mean fluorescent intensity (MFI) > 5000 in the elderly than in young age group. The distribution of antibody specificities against HLA -A, -B, -C, -DR, -DQ, -DP and MICA antigens in the three age groups were generally consistent. The anti-HLA class I antibody specificities with higher frequencies were A80,A68;B76,B45;Cw17, which were unlikely to become DSA in Chinese. Anti-HLA class II antibody specificities were more likely to become potential DSA than class I.DR7, DR9, DQ7, DQ8 and DQ9 were most likely to become potential DSA. CONCLUSIONS: The prevalence of anti-HLA and anti-MICA antibodies increased slightly as age increased. While ageing had a small impact on the distribution of antibody specificity frequencies against HLA-A, -B, -C, -DR,-DQ, -DP and MICA antigens in recipients awaiting initial HSCT from East China. The risk of developing preformed DSA was basically consistent in the three age groups and the elderly group might be more favorable in HLA-mismatched HSCT due to higher positive rate of anti-MICA antibody.

The novel HLA-DRB1*12:108 allele identified by next-generation sequencing.

HLA-DRB1*12:108 differs from HLA-DRB1*12:02:01:01 by one nucleotide in exon 2.

The impact of preformed and de novo HLA-DP antibodies in renal transplantation, a meta-analysis.

The impact of preformed and de novo HLA-DP antibodies after renal transplantation remains controversial and unclear. To address the clinical relevance of HLA-DP antibodies on the outcomes in renal transplantation, we performed a random effect model meta-analysis through a systematic review from inception to December 31, 2021. The outcome was graft loss or acute rejection. Finally five articles were identified as our inclusion criteria. The study which reported 1166 patients included in the final meta-analysis of de novo HLA-DP antibodies after transplantation showed an increased risk of graft loss or acute rejection (OR = 3.6, 95% CI = 1.6-8.10, P = 0.002, I2  = 52%). In the subgroup study, we established that patients with HLA-DP DSA after renal transplantation had a 8.85-fold increased risk of graft loss or acute rejection compared with patients without HLA-DP DSA (p = 0.003).While as for HLA-DP NDSA after renal transplantation, 2.73-fold increased risk of graft loss or acute rejection compared with patients without HLA-DP antibodies (p = 0.04). Besides, the studies which reported 487 patients included in the final meta-analysis of preformed HLA-DP antibodies did not show an increased risk of graft loss or acute rejection (OR = 4.55, 95% CI = 0.79-26.16, P = 0.09, I2  = 57%). The results of our meta-analysis suggested that de novo HLA-DP antibodies especially de novo HLA-DP DSA had a significant deleterious impact on the renal transplant risk of graft loss or acute rejection, while preformed HLA-DP antibodies had a no significant deleterious impact on the risk. The routine detection of HLA-DP antibodies after renal transplantation seems to be very important and may be as one of noninvasive biomarker-guided risk stratification.

Inhaled Corticosteroids and Mycobacterial Infection in Patients with Chronic Airway Diseases: A Systematic Review and Meta-Analysis.

BACKGROUND: Inhaled corticosteroids (ICSs) have been widely used in chronic airway diseases, such as asthma, chronic obstructive pulmonary disease (COPD), and bronchiectasis. However, whether ICS use causes mycobacterial infection is uncertain. Some conclusions of published studies were inconsistent. OBJECTIVE: We aimed to investigate the association between the use of ICSs and mycobacterial infections in patients with chronic airway diseases. METHODS: This review was registered on PROSPERO (CRD42021284607). We focused on examining the association between ICS use and mycobacterial infection (nontuberculous mycobacterial [NTM] infection as well as tuberculosis [TB]). We searched PubMed (MEDLINE), Sciencenet, Cochrane, and EMBASE databases for studies up to 2021 to retrieve articles. The enrollment conditions included gender, enrollment diagnosis and ICS use in chronic airway disease patients, and so on. Preclinical studies, review articles, editorials, reviews, conference abstracts, and book chapters were excluded. Methodologically, the study was assessed using the Newcastle Ottawa Scale, and Rev-man5 was used for statistical analysis. RESULTS: Ten studies (including 4 NTM and 6 TB articles) with 517,556 patients met the inclusion criteria and were included in this meta-analysis. From the NTM pooled analyses, ICS use was associated with increased odds of NTM infection in patients with chronic airway diseases (odds ratio [OR] = 3.93, 95% confidence interval [CI] 2.12-7.27), subgroup analysis showed that high-dose ICS use (OR = 2.27, 95% CI 2.08-2.48) and fluticasone use (OR = 2.42, 95% CI 2.23-2.63) were associated with increased odds of NTM infection risk in patients with chronic respiratory diseases. The TB pooled analyses showed a significant association between ICS use and risk of TB infection in patients with chronic respiratory diseases (OR = 2.01, 95% CI 1.23-3.29). Subgroup analysis showed that in chronic respiratory diseases, ICS use increased odds of TB infection in high-dose ICS use (OR = 1.70, 95% CI 1.56-1.86) and in COPD patients (OR = 1.45, 95% CI 1.29-1.63). CONCLUSION: Our meta-analysis indicated that ICS use may increase the odds of mycobacterial infection in chronic respiratory disease patients, and this conclusion is more applicable to patients with high dose of ICS or fluticasone in NTM infection subgroups. In addition, high-dose ICS use may have higher risk of TB infection in patients with chronic respiratory diseases, especially COPD. Therefore, we should be vigilant about the application of ICS use in chronic respiratory diseases to avoid infection.

Blood Eosinophils and Clinical Outcome of Acute Exacerbations of Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Numerous studies have shown the association between eosinophilia and clinical outcomes of patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). But the evidences are lack of consensus. OBJECTIVE: The aim of this meta-analysis was to conduct a pooled analysis of outcome comparing eosinophilic (EOS) AECOPD and non-EOS AECOPD patients. METHODS: We included PubMed, EMBASE, Web of Science, and Cochrane databases up to 2020 to retrieve articles. Randomized controlled trials and quasi-experimental studies about patients with and without EOS AECOPD in terms of in-hospital mortality, length of hospital stay, comorbidities, forced expiratory volume in 1 s (FEV1), gender, and BMI were included preclinical studies, review articles, editorials, commentaries, conference abstracts, and book chapters were excluded. The methodologic assessment of studies was performed with the Newcastle-Ottawa Scale and Cochran scale. Comprehensive Rev Man 5 was used for the statistical analysis. RESULTS: Twenty-one studies with 18,041 patients fulfilled the inclusion criteria and were used in this meta-analysis. Comparing to the non-EOS group, those with EOS AECOPD patients had a lower risk for in-hospital mortality (odds ratio (OR) = 0.59, 95% confidence interval [CI] 0.36-0.95, p = 0.03), shorter length of hospital stay (OR = -0.72, 95% CI -1.44 to -0.00, p = 0.05), better FEV1 (mean difference = 0.14, 95% CI 0.08-0.20, p < 0.00001), and a lower risk of arrhythmias (OR = 1.50, 95% CI 1.01-2.21, p = 0.04). In addition, the non-EOS group had a higher percentage of male (OR = 1.34, 95% CI 1.15-1.56, p = 0.0002) than EOS group. The rate of steroid use (OR = 0.82, 95% CI 0.47-1.42, p = 0.48) and BMI (mean difference = 0.43, 95% CI -0.18 to 1.05, p = 0.17] had no difference between 2 groups. CONCLUSION: The results of our meta-analysis suggest that EOS AECOPD patients have a better clinical outcome than non-EOS AECOPD patients in terms of length of hospital stay, in-hospital mortality, FEV1, and risk of arrhythmias. In addition, the non-EOS AECOPD patients have higher percentage of male than EOS AECOPD patients.

Modeling coupled kinetics of arsenic adsorption/desorption and oxidation in ferrihydrite-Mn(II)/manganese (oxyhydr)oxides systems.

The speciation and mobility of As are controlled by both Fe and Mn (oxyhydr)oxides through a series of surface complexation and redox reactions occurring in the environment, which is also complicated by the solution chemistry conditions. However, there is still a lack of quantitative tools for predicting the coupled kinetic processes of As reactions with Fe and Mn (oxyhydr)oxides. In this study, we developed a quantitative model for the coupled kinetics of As adsorption/desorption and oxidation in ferrihydrite-Mn (oxyhydr)oxides and ferrihydrite-Mn(II)-O2 systems. This model also accounted for the variations in solution chemistry conditions and binding site heterogeneity. Our model suggested that Mn (oxyhydr)oxide and ferrihydrite mainly served as an oxidant and an adsorbent, respectively, when they coexisted. Among the three types of binding sites of ferrihydrite, the adsorbed As(V) was mainly distributed on the nonprotonated bidentate sites. Our model quantitatively showed that the oxidation rates of different reaction systems varied significantly. The rates of As(III) oxidation were enhanced with higher pH values and higher molar ratios of Mn(II)/As(III) in the ferrihydrite-Mn(II)-O2 system. This study provides a modeling framework for predicting the kinetic behavior of As when multiple adsorption/desorption and oxidation reactions are coupled in the environment.

A single center study of protective and susceptible HLA alleles and haplotypes with end-stage renal disease in China.

Chronic kidney disease (CKD) is becoming a global public health problem and usually cause End-Stage Renal Disease (ESRD) in the end of progression. To analyze the associations of HLA-A, -B, -C, -DRB1 and -DQB1 alleles at high resolution with ESRD in Jiangsu province of China, a total of 499 unrelated patients with ESRD from the First Affiliated Hospital with Nanjing Medical University and 1584 healthy controls from Jiangsu Branch of Chinese Marrow Donor Program (CMDP) were genotyped at HLA-A, -B, -C, -DRB1 and -DQB1 loci. Statistical analysis was applied to compare the differences of HLA allele frequencies between patients with ESRD and healthy controls. As results, no protective allele at A locus was found and the susceptible alleles were A*11:01 and A*31:01. At B locus, B*15:01, B*55:02 and B*39:05 emerged as susceptible alleles, whereas no protective allele was found. At C locus, C*06:02 and C*07:01 emerged as protective alleles and no susceptible allele was found. At DRB1 locus, six alleles including DRB1*03:01, DRB1*04:03, DRB1*04:04, DRB1*04:05, DRB1*11:01 and DRB1*12:02 emerged as susceptible alleles, while DRB1*15:01 emerged as a protective allele. At DQB1 locus, DQB1*02:01, DQB1*03:01, DQB1*03:02 and DQB1*04:01 emerged as susceptible alleles, while DQB1*06:02 and DQB1*06:09 emerged as protective alleles. Haplotype A*11:01-C*03:03-B*15:01-DRB1*11:01-DQB1*03:01 containing four susceptible alleles was regarded as the most susceptible haplotype. The susceptible alleles and haplotypes might be used as some important risk classification markers. Besides, in the consanguineous renal transplantation, it would be very beneficial for the long-term survival of renal transplant patients to avoid the susceptible alleles and haplotypes in selecting optimal donors.

Identification of Novel Epitopes with Agonistic Activity for the Development of Tumor Immunotherapy Targeting TRAIL-R1.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-1/2 (TRAIL-R1/R2), also known as death receptors, are expressed in a wide variety of tumor cells. Although TRAIL can induce cell apoptosis by engaging its cognate TRAIL-R1/R2, some tumor cells are or become resistant to TRAIL treatment. Monoclonal antibodies (mAbs) against TRAIL-R1/R2 have been developed to use as potential antitumor therapeutic agents instead of TRAIL. However, TRAIL-R1/R2-based tumor therapy has not yet been realized. We previously generated a series of fully human monoclonal antibodies against TRAIL-R1 (TR1-mAbs) that induced tumor cell apoptosis. In this study, we identified the antigenic binding sites of these TR1-mAbs and proposed two major epitopes on the extracellular domain of TRAIL-R1. The analysis revealed that the epitopes of some TR1-mAbs partially overlaps with the beginning of TRAIL-binding sites, and other epitopes are located within the TRAIL-binding region. Among these mAbs, TR1-422 and TR1-419 mAbs have two antigenic binding sites that bound to the same binding region, but they have different essential amino acid residues and binding site sizes. Furthermore, we investigated the apoptosis activity of TR1-419 and TR1-422 mAbs in the form of IgG and IgM. In contrast to the IgG-type TR1-419 and TR1-422 mAbs, which enhanced and inhibited TRAIL-induced apoptosis, respectively, both IgM-type TR1-419 and TR1-422 mAb strongly induced cell apoptosis with or without soluble TRAIL (sTRAIL). Moreover, the results showed that IgM-type TR1-419 and TR1-422 mAbs alone can sufficiently activate the extrinsic and intrinsic apoptosis signaling pathways and suppress tumor growth in vivo. Consequently, we identified two antigenic binding sites with agonistic activity, and their specific IgM-type mAbs exhibited strong cytotoxic activity in tumor cells in vitro and in vivo. Thus, these agonistic antigenic binding sites may be useful for the development of effective Ab-based drugs or Ab-based cell immunotherapy for various human solid tumors.