Seroconversion rates following 2 doses of measles- mumps- rubella vaccination given at the ages 12 and 18 months: data for possible additional dose at older age

Background Despite high rate of vaccination coverage with 2-doses of measles containing vaccine among Iranian children, outbreaks of measles occurred among different age groups and fully vaccinated subjects. Although the main reason for these outbreaks is unknown, however, vaccine failure was supposed to be an important cause. This study was designed to determine the seroconversion rates to measles- mumps- rubella (MMR) vaccine currently in use among Iranian children. Methods This prospective study was conducted among healthy children older than 12 months who were candidates of scheduled MMR vaccination. Blood samples were obtained from each mother- infant pair just before vaccination, and from infants 4–6 weeks after MMR1 and MMR2 immunization. Collected sera were tested for specific lgG antibodies against MMR agents using ELISA method. The proportion of seroprotected subjects among mother- infant pairs before vaccination as well as the prevalence rates of seroconversion after MMR1 and MMR2 vaccination were calculated. Collected data were analyzed using descriptive statistical methods. Results During 22-months study period, 92 mother- infant pairs were participated. Seroimmunity rates against MMR viruses were 85.8%, 84.7% and 86.9% for mothers, and 3.2%, 2.1% and 1.0% for children, respectively. After MMR1 vaccination from 52 seronegative children, 80.7%, 78.8% and 75% were seroconverted. These rates increased to 94.8%, 89.7% and 94.8% after the MMR2 vaccination. Also, the specific immunity was enhanced among seropositive children. Conclusion Majority of the mothers and few infants were immune to MMR viruses prior to MMR1 vaccination. Immune responses detected after MMR1 injection, and overall seroconversion rates achieved after 2-doses of MMR vaccination were less than expected and inadequate to preserve long-term protection against MMR agents.

Membrane tension sensing molecule-FNBP1 is a prognostic biomarker related to immune infiltration in BRCA, LUAD and STAD

Background Formin-binding protein 1/17 (FNBP1/FBP17), as a membrane-bound protein, is wildly expressed in eukaryotic cells and performs a critical role in tumor tumorigenesis and progression. However, the relationship between FNBP1 and immune infiltrating cells, prognostic value in patients still require comprehensive understanding. We purposed to explore the correlations of FNBP1 expression, prognosis and immune infiltration levels in various cancers. Method The expression and survival data of FNBP1 were collected from Oncomine, TIMER, GEPIA, Kaplan–Meier Plotter and PrognoScan databases. Correlations between FNBP1 and immune infiltrates were analyzed in TIMER and GEPIA databases. Results Compared with normal tissues, FNBP1 is significantly differentially expressed in a variety of tumor tissues. FNBP1 has significant and complex effects on the prognosis of kinds of cancers. High-expression was obviously correlated with better prognosis in breast carcinoma and lung adenocarcinoma, while worse prognosis in stomach adenocarcinoma. Besides, FNBP1 had a correlation with various immune infiltrating cells and diverse immune gene markers in breast invasive carcinoma (BRCA), lung adenocarcinoma (LUAD), and stomach adenocarcinoma (STAD). FNBP1 was also positively correlated with the adjustment of CD8+ cells, T cells, M2 macrophage, neutrophils, monocyte, Th1 cells, T regulatory cells (Treg) and Tumor-associated macrophages (TAMs). The expression level of FNBP1 is closely positively correlated with the expression level of multiple immune checkpoints in the three cancers. In addition, FNBP1 is significantly positively correlated with the expression levels of a variety of immunosuppressive molecules. Conclusion Our findings reveal FNBP1 can serve as a significant biomarker to influence the prognosis and the immune infiltrating levels in different cancers. The differential expression of FNBP1 might not only contribute to the judgment of metastatic and non-metastatic tumors but also in the immune escape by upregulating the expression of immune checkpoints.

Adalimumab and anti-adalimumab LISA-TRACKER immunoassays performance criteria for therapeutic drug monitoring of adalimumab-amgen biosimilar (ABP501)

Background ABP501 is a biosimilar to Reference Adalimumab (HUMIRA®) produced by AMGEN. Adalimumab (ADA) has a marketing authorization for Crohn's disease, ulcerative colitis and other inflammatory or autoimmune diseases. The aim of this study was to evaluate the LISA-TRACKER assays developed by Theradiag (France), for the monitoring of ABP501 and anti-ABP501 antibodies in human serum. Results 68 ABP501 clinical samples were measured with the LISA TRACKER Duo Adalimumab assay. LISA TRACKER has been validated as suitable for quantification of ABP501 in human serum samples. Accuracy of the LISA-TRACKER was measured using 3 human serum matrices spiked with known levels of biosimilar, 3 levels spanning the dynamic range. Percentages of recovery were ranged from 90 to 120% for biosimilar batch1, and between 93 and 105% for biosimilar batch2. The acceptance criteria (CV < 20%) were met for intra-run (from 3.8 to 16.5%) and inter-run imprecision (from 4.4 to 13.9%) including the two batches. All results were comprised within ± 20% from results, obtained with the kit and sample unexposed in order to evaluate stability of the sample, stability of the kit and consistency of the results. In any case, but two, all percentages of inhibition were > 50% for specificity. Specificity was tested with Biosimilar spiked samples, Biosimilar with Humira® spiked samples, and clinical samples from patients treated with adalimumab biosimilar. All of these samples were spiked with polyclonal antibodies directed against Humira®. Specificity inhibition and specificity detection steps were also part of the validation parameters. Reagents made with ABP501 gave similar results than reagents made with Humira® meeting acceptance criteria. Conclusions LISA-TRACKER ADA and anti-ADA assays are reliable for the monitoring of patients treated with ABP501.

Immunogenicity profile in African green monkeys of a vaccine candidate based on a mutated form of human Interleukin-15

Background Interleukin (IL)-15 is a proinflammatory T-cell growth factor overexpressed in several autoimmune diseases such as rheumatoid arthritis. Our initial strategy to neutralize the increased levels of IL-15 consisted in a vaccine candidate based on the recombinant modified human IL-15 (mhIL-15) mixed with the alum adjuvant. A previous study in non-human primates Macaca fascicularis has shown that vaccination induces neutralizing antibodies against native IL-15, without affecting animal behavior, clinical status, or the percentage of IL-15-dependent cell populations. However, the mhIL-15 used as an antigen was active in the IL-2-dependent cytotoxic T-cell line CTLL-2, which could hinder its therapeutic application. The current article evaluated the immunogenicity in African green monkeys of a vaccine candidate based on IL-15 mutant D8SQ108S, an inactive form of human IL-15. Results IL-15 D8SQ108S was inactive in the CTLL-2 bioassay but was able to competitively inhibit the biological activity of human IL-15. Immunization with 200 µg of IL-15 mutant combined with alum elicited anti-IL-15 IgG antibodies after the second and third immunizations. The median values of anti-IL-15 antibody titers were slightly higher than those generated in animals immunized with 200 µg of mhIL-15. The highest antibody titers were induced after the third immunization in monkeys vaccinated with 350 µg of IL-15 D8SQ108S. In addition, sera from immunized animals inhibited the biological activity of human IL-15 in CTLL-2 cells. The maximum neutralizing effect was observed after the third immunization in sera of monkeys vaccinated with the highest dose of the IL-15 mutant. These sera also inhibited the proliferative activity of simian IL-15 in the CTLL-2 bioassay and did not affect the IL-2-induced proliferation of the aforementioned T-cell line. Finally, it was observed that vaccination neither affects the animal behavior nor the general clinical parameters of immunized monkeys. Conclusion Immunization with inactive IL-15 D8SQ108S mixed with alum generated neutralizing antibodies specific for human IL-15 in African green monkeys. Based on this fact, the current vaccine candidate could be more effective than the one based on biologically active mhIL-15 for treating autoimmune disorders involving an uncontrolled overproduction of IL-15.

Repression of the expression of proinflammatory genes by mitochondrial transcription factor A is linked to its alternative splicing regulation in human lung epithelial cells

Background Mitochondrial transcription factor A (TFAM) is associated with a number of neurodegenerative diseases and also with asthma. TFAM deficiency-induced mitochondrial DNA stress primes the antiviral innate immune response in mouse embryonic fibroblasts. However, the role of TFAM in asthma related inflammation remains obscure. The purpose of this study was to investigate the regulatory mechanism of TFAM in asthma. Results In this study, we overexpressed TFAM in human lung epithelial cells (A549), then obtained the TFAM-regulated transcriptome by Illumina sequencing technology. Transcriptome analysis revealed that TFAM overexpression down-regulated and up-regulated the expression of 642 and 169 differentially expressed genes (DEGs), respectively. The TFAM-repressed genes were strongly enriched in cytokine-mediated signaling pathway, type I interferon- and INF-γ-mediated signaling pathways, and viral response pathways. We also revealed that 2563 alternative splicing events in 1796 alternative splicing genes (ASGs) were de-regulated upon TFAM overexpression. These TFAM-responding ASGs were enriched in DNA repair, nerve growth factor receptor signaling pathway, and also transcription regulation. Further analysis revealed that the promoters of TFAM-repressed DEGs were enriched by DNA binding motifs of transcription factors whose alternative splicing was regulated by TFAM. Conclusions These findings suggest that TFAM regulates not only immune response gene expression in human lung epithelial cells, but also pre-mRNA alternative splicing which may mediate transcriptional regulation; this TFAM-centered gene regulation network could be targeted in developing therapies against various diseases.

Clinical relevance of glomerular IgM deposition in patients with lupus nephritis

Background The aim of the study was to investigate the clinical relevance of IgM deposition in patients with lupus nephritis (LN) in a large cohort. Results 217 patients with renal biopsy-proven active LN were enrolled. The associations between glomerular IgM deposition and clinicopathological parameters were further analyzed. IgM deposition was positively correlated with glomerular C1q and C3 deposition moderately (r = 0.436, P < 0.001; r = 0.408, P < 0.001, respectively), and inversely correlated with plasma levels of C3 and CFH mildly (r = − 0.138, P = 0.043; r = − 0.147, P = 0.037, respectively). By multivariate analysis, we found that glomerular IgM deposition independently contributed to glomerular C3 deposition in patients with LN (OR = 2.002, 95% CI 1.295–3.094, P = 0.002). In addition, we also found that patients with IgM 0–2+ had similar plasma CFH levels, but in patients with IgM3+–4+, plasma CFH levels were significantly lower (300.4 ± 155.8 μg/mL vs. 429.9 ± 187.5 μg/mL, P < 0.001). Furthermore, patients with high density of glomerular IgM and low levels of CFH had heavier proteinuria, higher serum creatinine and lower plasma C3 levels (5.7 ± 3.1 g/d vs. 4.7 ± 3.5 g/d, P = 0.037; 150.1 ± 121.0 μmol/L vs. 105.6 ± 97.1 μmol/L, P = 0.005; 0.3 ± 0.2 μg/L vs. 0.4 ± 0.2 μg/L, P = 0.04, respectively), comparing with those with low density of glomerular IgM and low levels of CFH. Conclusions Our results suggested the involvement of glomerular deposited IgM in complement activation and renal injury in LN.

Transmembrane signaling molecules play a key role in the pathogenesis of IgA nephropathy: a weighted gene co-expression network analysis study

Background Immunoglobulin A nephropathy (IgAN) is one of the most common primary glomerulonephritis and a serious health concern worldwide; though still the underlying molecular mechanisms of IgAN are yet to be known and there is no efficient treatment for this disease. The main goal of this study was to explore the IgAN underlying pathogenic pathways, plus identifying the disease correlated modules and genes using the weighted gene co-expression network analysis (WGCNA) algorithm. Results GSE104948 dataset (the expression data from glomerular tissue of IgAN patients) was analyzed and the identified differentially expressed genes (DEGs) were introduced to the WGCNA algorithm for building co-expression modules. Genes were classified into six co-expression modules. Genes of the disease’s most correlated module were mainly enriched in the immune system, cell–cell communication and transmembrane cell signaling pathways. The PPI network was constructed by genes in all the modules and after hub-gene identification and validation steps, 11 genes, mostly transmembrane proteins (CD44, TLR1, TLR2, GNG11, CSF1R, TYROBP, ITGB2, PECAM1), as well as DNMT1, CYBB and PSMB9 were identified as potentially key players in the pathogenesis of IgAN. In the constructed regulatory network, hsa-miR-129-2-3p, hsa-miR-34a-5p and hsa-miR-27a-3p, as well as STAT3 were spotted as top molecules orchestrating the regulation of the hub genes. Conclusions The excavated hub genes from the hearts of co-expressed modules and the PPI network were mostly transmembrane signaling molecules. These genes and their upstream regulators could deepen our understanding of IgAN and be considered as potential targets for hindering its progression.

Chemokine CXCL1 as a potential marker of disease activity in systemic lupus erythematosus

Objectives The chemokine CXCL1, known as growth-related oncogene α (GRO-α), is a potent chemoattractant and regulator of neutrophils. The purpose of our study was to evaluate the regulatory response of CXCL1 in the serum of patients with systemic lupus erythematosus (SLE) in the active stage of disease and to assess whether it was implicated in the pathogenesis/inflammatory process in lupus. Methods CXCL1 serum concentrations were examined in 90 SLE patients, 56 other autoimmune diseases (OADs) patients and 100 healthy controls using enzyme-linked immunosorbent methodology. Results SLE patients exhibited significant increases in serum CXCL1 concentrations [1492.86 (735.47–2887.34) pg/ml] compared with OADs patients [155.88 (10.77–366.78) pg/ml] and healthy controls [13.58 (8.46–37.22) pg/ml] (p < 0.001). Moreover, the level of CXCL1 decreased as the level of anti-dsDNA IgG decreased after treatment between the anti-dsDNA-positive SLE patients and the anti-dsDNA-negative SLE patients. Additionly, serum CXCL1 concentrations were related to different disease activity levels in SLE and lupus nephritis (LN) and high avidity of IgG ANAs (HA IgG ANAs) (p < 0.05). Furthermore, CXCL1 serum concentrations were significantly correlated with the SLE Disease Activity Index(SLEDAI) score, relative avidity index (RAI) of HA IgG ANAs and the levels of anti-dsDNA IgG, CRP, ESR, albumin, C3 and C4.Additionally, Statistical analysis revealed that positivity for IgG ANA (p < 0.001), the presence of HA IgG ANAs (p = 0.001) and the logarithmic level of anti-dsDNA IgG (p = 0.021) were significantly associated with the logarithmic level of CXCL1 with standard partial regression coefficients (95% CI) of 2.371 (1.734–3.009), 1.231 (0.52–1.937) and 0.409 (0.062–0.755), respectively. Finally, using cutoff points of 1182.17 pg/mL and 1500.31 pg/mL, serum CXCL1 levels had a similar sensitivity of 76% and specificity of 100% and 75% for the diagnosis of active SLE and LN, respectively. Conclusions Serum CXCL13 concentrations might represent a potential marker of disease activity in systemic lupus erythematosus.

Reference ranges of T lymphocyte subsets by single-platform among healthy population in southwest China

Background Appropriate reference ranges of T lymphocyte subsets are essential for immune status evaluation of patients with immunological diseases. We aim to establish the age- and sex-related reference intervals of T lymphocyte subsets by single-platform for the southwest China population using the indirect method with the data resulting from 53,822 cases of periodic health examination individuals in the Laboratory Information System (LIS) of West China Hospital from 2018 to 2020. Methods We used the Box-Cox conversion combined with the Tukey method to normalize the data and eliminate the outliers, and the nonparametric method to estimate the 95% distribution reference intervals. Results We initially established the reference ranges of T lymphocyte subsets by single-platform among healthy population in southwest China by indirect method (See text for details). Using the standard normal deviate test (z-test) suggested by Harris and Boyd according to CLSI EP28-A3C, which is more scientific, we found the reference ranges of T lymphocyte subsets should be differentiated by ages and genders since the reference ranges of T lymphocyte subsets by single-platform in different ages and genders are significantly different. Conclusions We further demonstrated the absolute count of CD3 + T cell, CD3 + CD4 + T cell, CD3 + CD8 + T cell decreased with aging, which is more marked in men and CD3 + CD8 + T cell count, and the obtained reference intervals were superior to the reference intervals derived from the reagent specification currently in use.

Reduction of peripheral regulatory T cells in active rheumatoid arthritis patients with coronary artery disease

Objective To identify lymphocyte and CD4 + T cell subset characteristics, particularly regulatory T cells (Tregs), in active rheumatoid arthritis (RA) patients with coronary artery disease (CAD). Methods A total of 54 RA patients with CAD (RA-CAD group), 43 RA patients without CAD (pure RA group), and 43 healthy controls (HC group) were enrolled. The absolute number and frequency of lymphocyte subpopulations and CD4 + T cell subsets were analyzed by flow cytometry. Serum levels of cytokines were analyzed using a cytometric bead array. Clinical and laboratory data were collected retrospectively and their correlation with CD4 + T subsets were analyzed. Results There was a significant decrease in the absolute number of Treg cells (CD4 + CD25 + Foxp3 + T cells) in the RA-CAD group compared to the pure RA group (p < 0.001). Similarly, both the absolute number (p = 0.001) and frequency (p = 0.011) of Tregs in the RA-CAD group were decreased compared to the HCs, causing a Th17/Treg imbalance (p = 0.044). No difference was found in the absolute number and frequency of Treg cells between the pure RA and HC groups. However, the absolute Th17 cell count was increased in the pure RA group (p = 0.032). The serum level of cytokine IL-17 was lower in the RA-CAD group than in the pure RA group (p = 0.023). In the RA-CAD group, the Treg number was negatively correlated with the RA disease activity score and ESR value, and LDL and ApoB100 levels were negatively correlated with the number of Th17 cells. Conclusions Active RA patients with CAD sustain more severe immune tolerance damage and Th17/Treg disorder. Monitoring of lymphocyte and CD4 + T cell subsets, particularly Treg cells, is crucial to understanding immune status in this group. Focusing on RA activity and CAD risk control, immune-regulatory therapy based on the Treg level may be more beneficial for RA patients with CAD.