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Interferon-γ (IFNγ) is a pleiotropic cytokine with multiple effects on the inflammatory response and on innate and adaptive immunity. Overproduction of IFNγ underlies several, potentially fatal, hyperinflammatory or immune-mediated diseases. Several data from animal models and/or from translational research in patients point to a role of IFNγ in hyperinflammatory diseases, such as primary haemophagocytic lymphohistiocytosis, various forms of secondary haemophagocytic lymphohistiocytosis, including macrophage activation syndrome, and cytokine release syndrome, all of which are often managed by rheumatologists or in consultation with rheumatologists. Given the effects of IFNγ on B cells and T follicular helper cells, a role for IFNγ in systemic lupus erythematosus pathogenesis is emerging. To improve our understanding of the role of IFNγ in human disease, IFNγ-related biomarkers that are relevant for the management of hyperinflammatory diseases are progressively being identified and studied, especially because circulating levels of IFNγ do not always reflect its overproduction in tissue. These biomarkers include STAT1 (specifically the phosphorylated form), neopterin and the chemokine CXCL9. IFNγ-neutralizing agents have shown efficacy in the treatment of primary haemophagocytic lymphohistiocytosis in clinical trials and initial promising results have been obtained in various forms of secondary haemophagocytic lymphohistiocytosis, including macrophage activation syndrome. In clinical practice, there is a growing body of evidence supporting the usefulness of circulating CXCL9 levels as a biomarker reflecting IFNγ production., (© 2021. Springer Nature Limited.)

Objective: To assess antibody response to inactivated COVID-19 vaccine in patients with immune-mediated diseases (IMD) among hospital workers and people aged 65 and older., Methods: In this cross-sectional study, we studied 82 hospital workers with IMD (mean age: 42.2 ± 10.0 years) and 300 (mean age: 41.7 ± 9.9 years) controls. Among + 65 aged population, we studied 22 (mean age: 71.4 ± 4.5 years) patients and 47 controls (mean age: 70.9 ± 4.8 years). All study subjects had a negative history for COVID-19. Sera were obtained after at least 21 days following the second vaccination. Anti-spike IgG antibody titers were measured quantitatively using a commercially available immunoassay method., Results: Patients with IMD were significantly less likely to have detectable antibodies than healthy controls both among the hospital workers (92.7% vs 99.7%, p < 0.001) and elderly population (77.3% vs 97.9%, p = 0.011). Among patients with IMD, those using immunosuppressive or immune-modulating drugs (64/75, 85.3%) were significantly less likely to have detectable antibodies compared to those off treatment (29/29, 100%) (p = 0.029). Additionally, a negative association between age and the antibody titer categories among patients (r = - 0.352; p < 0.001) and controls (r = - 0.258; p < 0.001) were demonstrated., Conclusions: Among hospital workers, the vast majority of patients with IMD and immunocompetent controls developed a significant humoral response following the administration of the second dose of inactivated COVID-19 vaccine. This was also true for the elderly population, albeit with lower antibody titers. Immunosuppressive use, particularly rituximab significantly reduced antibody titers. Antibody titers were significantly lower among those aged ≥ 60 years both in patient and control populations. Whether these individuals should get a booster dose warrants further studies.

There are increasing evidences showing the contribution of somatic genetic variants to non-cancer diseases. However, their detection using massive parallel sequencing methods still has important limitations. In addition, the relative importance and dynamics of somatic variation in healthy tissues are not fully understood. We performed high-depth whole-exome sequencing in 16 samples from patients with a previously determined pathogenic somatic variant for a primary immunodeficiency and tested different variant callers detection ability. Subsequently, we explored the load of somatic variants in the whole blood of these individuals and validated it by amplicon-based deep sequencing. Variant callers allowing low frequency read thresholds were able to detect most of the variants, even at very low frequencies in the tissue. The genetic load of somatic coding variants detectable in whole blood is low, ranging from 1 to 2 variants in our dataset, except for one case with 17 variants compatible with clonal haematopoiesis under genetic drift. Because of the ability we demonstrated to detect this type of genetic variation, and its relevant role in disorders such as primary immunodeficiencies, we suggest considering this model of gene mosaicism in future genetic studies and considering revisiting previous massive parallel sequencing data in patients with negative results.

FOXP3 deficiency in mice and in patients with immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome results in fatal autoimmunity by altering regulatory T (T reg ) cells. CD4 + T cells in patients with IPEX syndrome and Foxp3-deficient mice were analyzed by single-cell cytometry and RNA-sequencing, revealing heterogeneous T reg -like cells, some very similar to normal T reg cells, others more distant. Conventional T cells showed no widespread activation or helper T cell bias, but a monomorphic disease signature affected all CD4 + T cells. This signature proved to be cell extrinsic since it was extinguished in mixed bone marrow chimeric mice and heterozygous mothers of patients with IPEX syndrome. Normal T reg cells exerted dominant suppression, quenching the disease signature and revealing in mutant T reg -like cells a small cluster of genes regulated cell-intrinsically by FOXP3, including key homeostatic regulators. We propose a two-step pathogenesis model: cell-intrinsic downregulation of core FOXP3-dependent genes destabilizes T reg cells, de-repressing systemic mediators that imprint the disease signature on all T cells, furthering T reg cell dysfunction. Accordingly, interleukin-2 treatment improved the T reg -like compartment and survival.

Context: Despite the pivotal role of calcium signaling in immune response, little is known about immune function in patients affected by hypoparathyroidism., Objective: This work aimed to evaluate immune function in hypoparathyroidism., Methods: The Evaluation of iMmune function in Postsurgical and AuToimmune HYpoparathyroidism (NCT04059380) is a case-control, cross-sectional study set in an Italian referral center. Participants included 20 patients with postsurgical hypoparathyroidism (12 females) and 20 age- and sex-matched controls. Main outcome measures included calcium metabolism assessment, peripheral blood mononuclear cells (PBMC) profiling via flow cytometry, parathyroid hormone receptor 1 (PTHr1) expression analysis using immunofluorescence and PrimeFlow RNA assay, gene expression analysis via real-time polymerase chain reaction, cytokine measurement, and evaluation of infectious disease frequency and severity., Results: Immune cell profiling revealed decreased monocytes, regulatory, naive, and total CD4+ T lymphocytes, which correlated with total calcium, ionized calcium, and PTH levels, in patients with hypoparathyroidism. Patients with hypoparathyroidism had a higher CD3-CD56+ natural killer (NK) cell count, which inversely correlated with calcium, PTH, and vitamin D levels. Furthermore, they exhibited decreased tumor necrosis factor (TNF) and granulocyte-macrophage colony-stimulating factor gene expression and decreased circulating TNF levels. Gene expression and immunofluorescence analysis confirmed PTHr1 expression in all PBMC lineages; however, the percentage of cells expressing PTHr1 was lower, whereas the intensity of PTHr1 expression in monocytes, total T lymphocytes, CD8+CD4+ and CD4+ T lymphocytes, and total NK cells was higher in patients with hypoparathyroidism., Conclusions: This study describes for the first time the immune alterations in patients with hypoparathyroidism receiving conventional therapies, supporting the immunoregulatory role of PTH and proposing an explanation for the increased susceptibility to infections observed in epidemiological studies., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Digital protein assays have great potential to advance immunodiagnostics because of their single-molecule sensitivity, high precision, and robust measurements. However, translating digital protein assays to acute clinical care has been challenging because it requires deployment of these assays with a rapid turnaround. Herein, we present a technology platform for ultrafast digital protein biomarker detection by using single-molecule counting of immune-complex formation events at an early, pre-equilibrium state. This method, which we term "pre-equilibrium digital enzyme-linked immunosorbent assay" (PEdELISA), can quantify a multiplexed panel of protein biomarkers in 10 µL of serum within an unprecedented assay incubation time of 15 to 300 seconds over a 104 dynamic range. PEdELISA allowed us to perform rapid monitoring of protein biomarkers in patients manifesting post-chimeric antigen receptor T-cell therapy cytokine release syndrome, with ∼30-minute sample-to-answer time and a sub-picograms per mL limit of detection. The rapid, sensitive, and low-input volume biomarker quantification enabled by PEdELISA is broadly applicable to timely monitoring of acute disease, potentially enabling more personalized treatment., (© 2021 by The American Society of Hematology.)

Gray platelet syndrome (GPS) is a rare recessive disorder caused by biallelic variants in NBEAL2 and characterized by bleeding symptoms, the absence of platelet α-granules, splenomegaly, and bone marrow (BM) fibrosis. Due to the rarity of GPS, it has been difficult to fully understand the pathogenic processes that lead to these clinical sequelae. To discern the spectrum of pathologic features, we performed a detailed clinical genotypic and phenotypic study of 47 patients with GPS and identified 32 new etiologic variants in NBEAL2. The GPS patient cohort exhibited known phenotypes, including macrothrombocytopenia, BM fibrosis, megakaryocyte emperipolesis of neutrophils, splenomegaly, and elevated serum vitamin B12 levels. Novel clinical phenotypes were also observed, including reduced leukocyte counts and increased presence of autoimmune disease and positive autoantibodies. There were widespread differences in the transcriptome and proteome of GPS platelets, neutrophils, monocytes, and CD4 lymphocytes. Proteins less abundant in these cells were enriched for constituents of granules, supporting a role for Nbeal2 in the function of these organelles across a wide range of blood cells. Proteomic analysis of GPS plasma showed increased levels of proteins associated with inflammation and immune response. One-quarter of plasma proteins increased in GPS are known to be synthesized outside of hematopoietic cells, predominantly in the liver. In summary, our data show that, in addition to the well-described platelet defects in GPS, there are immune defects. The abnormal immune cells may be the drivers of systemic abnormalities such as autoimmune disease., (© 2020 by The American Society of Hematology.)

Deep vein thrombosis (DVT) is a common complication in hematologic malignancies and immunologic disorders that coagulation and inflammatory factors play a crucial role in its occurrence. The content used in this article has been obtained by PubMed database and Google Scholar search engine of English-language articles (1980-2019) using the "Deep vein thrombosis," "Hematologic malignancies," "Immunologic disorders" and "Treatment." Increased levels of coagulation factors, the presence of genetic disorders, or the use of thrombotic drugs that stimulate coagulation processes are risk factors for the development of DVT in patients with hematologic malignancies. Inflammatory and auto-anti-inflammatory factors, along with coagulant factors, play an essential role in the formation of venous thrombosis in patients with immunological disorders by increasing the recruitment of inflammatory cells and adhesion molecules. Therefore, anti-coagulants in hematologic malignancies and immunosuppressants in immune disorders can reduce the risk of developing DVT by reducing thrombotic and inflammatory activity. Considering the increased risk of DVT due to impaired coagulation and inflammation processes, analysis of coagulation and inflammatory factors have prognostic values in patients with immunologic deficiencies and hematologic malignancies. Evaluation of these factors as diagnostic and prognostic biomarkers in the prediction of thrombotic events could be beneficial in implementing effective treatment strategies for DVT.

Objective: To capture the association of exposure to prolonged separation from both parents early in life and allostatic load (AL), a measure of biological multi-system dysregulation., Methods: We used data from 557 7-12-year-old children enrolled in rural area of Chizhou city, Anhui Province, China. We computed an AL score based on eleven biomarkers representing four regulatory systems: immune/inflammatory system (high sensitivity C-reactive protein); metabolic system (body mass index; high density lipoprotein; low density lipoprotein, total cholesterol; triglycerides; fasting glucose; glycated hemoglobin; insulin) and cardiovascular system (systolic and diastolic blood pressure). Child's experiences of parent-child separation were collected a brief online questionnaire by parents of children., Results: More than 1 in 3 of our participants separated with both parents at age 6 or younger and nearly 1 in 10 persistently separated from both parents after birth. The AL score was significantly higher among children separated from both parents during early childhood (3.25 ± 1.98) or persistently since birth (3.48 ± 1.92), compared with those who did not separated from both parents (2.34 ± 1.53, F = 12.992, P<0.001). After adjustment of demographic covariates, body mass index as well as parent frequency of communication and parental warmth, children who separated from both parents in early childhood (β = 0.84, 95%CI:0.40, 1.28, P < 0.001) or persistently into adolescence (β = 1.27, 95%CI:0.43, 2.12, P = 0.003) evinced the highest levels of AL., Conclusion: This study is the first to show an association between prolonged parent-child separation and physiological wear-and-tear as measured by AL, which provides potential insights into the biological mechanisms underpinning long-term health outcomes in contexts of parent-child separation., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Immunosuppressive drugs (ISD) are an essential tool in the treatment of transplant rejection and immune-mediated diseases. Therapeutic drug monitoring (TDM) for determination of ISD concentrations in biological samples is an important instrument for dose personalization for improving efficacy while reducing side effects. While currently ISD concentration measurements are performed at specialized, centralized facilities, making the process complex and laborious for the patient, various innovative technical solutions have recently been proposed for bringing TDM to the point-of-care (POC)., Content: In this review, we evaluate current ISD-TDM and its value, limitations, and proposed implementations. Then, we discuss the potential of POC-TDM in the era of personalized medicine, and provide an updated review on the unmet needs and available technological solutions for the development of POC-TDM devices for ISD monitoring. Finally, we provide concrete suggestions for the generation of a meaningful and more patient-centric process for ISD monitoring., Summary: POC-based ISD monitoring may improve clinical care by reducing turnaround time, by enabling more frequent measurements in order to obtain meaningful pharmacokinetic data (i.e., area under the curve) faster reaction in case of problems and by increasing patient convenience and compliance. The analysis of the ISD-TDM field prompts the evolution of POC testing toward the development of fully integrated platforms able to support clinical decision-making. We identify 4 major areas requiring careful combined implementation: patient usability, data meaningfulness, clinicians' acceptance, and cost-effectiveness., (© American Association for Clinical Chemistry 2020.)

Background: Polyclonal FLCs can be used as a biomarker of inflammation and immune activation in a range of diseases. This study evaluated the performance of new FLC ELISAs (Seralite FLC ELISA) for the quantitation of polyclonal κ and λ FLC, including comparisons to existing assays., Methods: Technical performance was assessed for the ELISA and reference ranges were generated using healthy donor serum (N = 91). Patients with a range of conditions associated with polyclonal FLC dysregulation (N = 164) were measured across platforms., Results: The ELISAs generated references ranges of: 8.72-23.0 mg/L κ FLC, and 8.52-25.24 mg/L for λ FLC. ELISAs demonstrated linearity across the calibration range and intra-assay (≤ 8.7%) and inter-assay (≤ 12.3%) imprecision was low. The limit of detection was 0.63 mg/L for κ and 0.57 mg/L for λ FLC. Minimal cross-reactivity was observed for interference agents, alternate FLC and whole immunoglobulin (median change ≤3.6 mg/L). Assays showed good batch-to-batch consistency. For patient samples, methods generated different κ and λ FLC concentrations and differences were seen between methods for the number of patients classified as below, with and above references ranges for κ and λ FLC. There was no significant difference in the FLC sum between the different techniques., Conclusions: The ELISAs displayed good analytical and technical performance. The quantification of individual κ and λ FLC appears inherently different between platforms. These differences are attenuated if using the FLC sum, which was similar between methods and provided agreement in relation to patients having normal or elevated FLCs., Competing Interests: Declaration of Competing Interest MS is an employee of Abingdon Health Ltd. MD has an advisory role with Abingdon Health Ltd. and reports personal fees from Abingdon Health Ltd. JC, MG, and TP own shares in Abingdon Health Ltd. CH is Chairman of Scientific & Medical Advisory Board of Abingdon Health Ltd., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: To explore the differences of immune disorders in peripheral blood between patients with early-onset Parkinson's disease (EOPD) and late-onset Parkinson's disease (LOPD)., Methods: We retrospectively reviewed medical records of Parkinson's disease (PD) patients and healthy controls between June 2002 and July 2017. At last, we included 117 PD patients who were divided into EOPD and LOPD according to whether onset age of PD was after 50 and 99 controls divided into E-Control (match for EOPD) and L-Control (match for LOPD) according to whether their age was after 53 which was onset age plus median of disease duration. We compared the ratios of cells between multiple groups and performed the multinominal logistic regression analysis to explore the relationship between ratios and subtypes of PD. We also carried out the receiver operating characteristic (ROC) curve analysis to estimate the diagnostic value of the variable., Results: Lymphocyte-red blood cell ratio (LRR) was lower in LOPD compared with that in EOPD or L-Control. LRR was also negatively associated with LOPD (OR: 0.623; 95% CI: 0.397-0.980; P =0.040). The ROC curve analysis showed the optimal cutoff value of 4.53 (×10 -4 ) of LRR for discrimination of LOPD versus L-Control (sensitivity: 0.596, specificity: 0.764). The area under curve (AUC) was 0.721. As for LOPD versus EOPD, the optimal threshold of LRR was 4.10 (×10 -4 ) (sensitivity: 0.516, specificity: 0.745). AUC was 0.641., Conclusions: Peripheral immune disorders might play an important part in the pathological progression of LOPD. Also, LRR has potential diagnostic value., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 Sen Jiang et al.)

Atherosclerotic cardiovascular disease (ACVD) is an inflammatory phenomenon that leads to structural abnormality in the vascular lumen due to the formation of atheroma by the deposition of lipid particles and inflammatory cytokines. There is a close interaction between innate immune cells (neutrophils, monocyte, macrophages, dendritic cells) and adaptive immune cells (T and B lymphocytes) in the initiation and progression of atherosclerosis. According to novel insights into the role of adaptive immunity in atherosclerosis, the activation of CD4 + T cells in response to oxidized low-density lipoprotein-antigen initiates the formation and facilitates the propagation of atheroma, whereas CD8 + T cells cause the rupture of a developed atheroma by their cytotoxic nature. Peripheral CD4 + and CD8 + T-cell counts were altered in patients with other cardiovascular risk factors. Furthermore, on evaluation of the feasibility of immune cells as a diagnostic tool, the blood CD4 + (helper), CD8 + (cytotoxic), and CD4 + CD25 + Foxp3 + (regulatory) T cells and the ratio of CD4 to CD8 cells hold promise as biomarkers of coronary artery disease and their subtypes. T cells also could be a therapeutic target for cardiovascular diseases. The goal of this review was therefore to summarize the available information regarding immune disorders in ACVD with a special focus on the clinical implications of circulating T-cell subsets as biomarkers.

Objectives: To quantify immunological dysfunction in surgical patients with presence/absence of sepsis using a droplet digital polymerase chain reaction (ddPCR) transcriptomic analysis. The study also aims to evaluate this approach for improving identification of sepsis in these patients., Background: Immune dysregulation is a central event in sepsis. Quantification of the expression of immunological genes participating in the pathogenesis of sepsis could represent a new avenue to improve its diagnosis., Methods: Expression of 6 neutrophil protease genes (MMP8, OLFM4, LCN2/NGAL, LTF, PRTN3, MPO) and also of 5 genes involved in the immunological synapse (HLA-DRA, CD40LG, CD3E, CD28, ICOS) was quantified in blood from 101 surgical patients with sepsis, 53 uninfected surgical patients, and 16 blood donors by using ddPCR. Areas under receiver operating characteristic curves (AUROC) and multivariate regression analysis were employed to test individual genes and gene ratios to identify sepsis, in comparison with procalcitonin., Results: Sepsis-induced overexpression of neutrophil protease genes and depressed expression of immunological synapse genes. MMP8/HLA-DRA, LCN2/HLA-DRA outperformed procalcitonin in differentiating between patients with sepsis and surgical controls in the AUROC analysis: LCN2/HLA-DRA: 0.90 (0.85-0.96), MMP8/HLA-DRA: 0.89 (0.84-0.95), procalcitonin: 0.80 (0.73-0.88) (AUROC, confidence interval 95%), and also in the multivariate analysis: LCN2/HLA-DRA: 8.57 (2.25-32.62); MMP8/HLA-DRA: 8.03 (2.10-30.76), procalcitonin: 4.20 (1.15-15.43) [odds ratio (confidence interval 95%)]. Gene expression levels of HLA-DRA were an independent marker of hospital mortality., Conclusions: Quantifying the transcriptomic ratios MMP8/HLA-DRA, LCN2/HLA-DRA by ddPCR is a promising approach to improve sepsis diagnosis in surgical patients.

Background: Infliximab (IFX) carries potential risk of immunogenicity with the production of anti-drug antibodies (ADA). ADA may belong to different isotypes and are usually measured by ELISA bridging assay. This test is not designed to detect IgG4 antibodies. The aim was to measure IgG4 anti-IFX antibodies in a cohort of IFX-treated patients and to evaluate their relationship with ADA and their clinical impact., Methods: Anti-drug antibodies were detected using a bridging ELISA in the serum of 222 treated patients with different clinical outcomes to IFX. The same samples were analyzed for IgG4 anti-IFX antibodies using an experimental ImmunoCAP assay with reduced serum IgG4 background levels. A longitudinal evaluation was performed in a subgroup of 38 patients to define the temporal evolution of IgG4 anti-IFX., Results: IgG4 anti-IFX was found in 26.6% of patients. Eighty of 222 patients were ADA+ (36%) and the majority (57/80, 71.3%) had IgG4 anti-IFX. Two IgG4-positive but ADA-negative patients were identified. IgG4 anti-IFX levels correlated with the serum levels of ADA. IgG4 anti-IFX was more common in both reactive and nonresponder patients than in tolerant/responder patients. Patients who had experienced IgE-mediated reactions displayed significantly higher IgG4 anti-IFX than IgE-negative reactive patients. The majority of patients tested positive for IgG4 anti-IFX after the first seven infusions., Conclusions: IgG4 anti-IFX is common in treated patients and a large part of ADA producing patients produce IgG4 antibodies. The IgG4 anti-IFX response does not prevent hypersensitivity reactions to IFX and correlates with the IgE anti-IFX response., (© 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

The immuno-inflammatory origin of schizophrenia in a subset of patients is viewed as a key element of an overarching etiological construct. Despite substantial research, the immune components exerting major effect are yet to be fully clarified. Disrupted T cell networks have consistently been linked to the pathogenesis of schizophrenia. Amongst the Th cell subsets, the Th17 cells have emerged as a paradigmatic lineage with significant functional implications in a vast number of immune mediated diseases including brain disorders such as schizophrenia. The present study was aimed at examining the functional role of the Th17 pathway in schizophrenia. To address this, genotyping of IL17A (rs2275913; G197A) Single Nucleotide Polymorphism was carried out by the PCR-RFLP method in 221 schizophrenia patients and 223 healthy control subjects. Gene expression of two transcription factors STAT3 and RORC was quantified in a subset of drug naïve schizophrenia patients (n = 56) and healthy controls (n = 52) by TaqMan assay. The plasma levels of fifteen cytokines belonging to Th17 pathway were estimated in a subset of drug naïve schizophrenia patients (n = 61) and healthy controls (n = 50) by using Bio-Plex Pro Human Th17 cytokine assays. The AA genotype was associated with higher total score of bizarre behaviour and apathy in female schizophrenia patients. A high gene expression level of RORC was observed in drug naïve schizophrenia patients. In addition, significantly elevated plasma levels of IL-6 and IL-22, and reduced levels of IL-1β and IL-17F were noted in schizophrenia patients. Taken together, these findings indicate a dysregulated Th17 pathway in schizophrenia patients., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Adsorptive granulocyte and monocyte apheresis (GMA) with the Adacolumn ® is an extracorporeal treatment, which uses cellulose acetate (CA) beads as adsorptive leukocytapheresis carriers designed to remove elevated and potentially activated myeloid lineage leukocytes. Reports on the clinical efficacy of GMA in patients with skin lesions have appeared in the published work. Dermatological diseases, which are known to respond to GMA, include pyoderma gangrenosum, skin lesions of Behçet's disease, rheumatoid arthritis, pustular psoriasis, psoriatic arthritis, adult-onset Still's disease, Sweet's syndrome, cutaneous allergic vasculitis and systemic lupus erythematosus rashes. In association with clinical studies, efforts to understand the mechanisms of GMA have made significant progress. GMA selectively depletes elevated myeloid lineage leukocytes through binding between blood immunoglobulin G or complement iC3b, which form on the surface of CA beads and the Fcγ receptors or complement receptors expressed on the myeloid lineage cells. However, GMA has immunomodulatory effects including down-modulation of inflammatory cytokine profile, changes in leukocyte surface receptors and induction of regulatory T cells. These actions render GMA a unique non-pharmacological treatment option for patients with chronic dermatoid conditions, which are difficult to treat with pharmacological preparations., (© 2018 Japanese Dermatological Association.)

IgG4-related disease (IgG4-RD) is a rare fibro-inflammatory condition that can affect almost any organ, characterized by tumefactive lesions and often by eosinophilia and elevated serum IgG4 concentrations. The aim of the study is to analyze in IgG4-RD patients the serum levels of a group of cytokines and growth factors potentially involved in the regulation of fibrotic processes. In the sera of 12 patients affected by IgG4-RD and of 15 normal healthy subjects (NHS), pro-fibrogenic mediators (TGF-β1 and periostin) and pro- (VEGF and angiogenin-1) and anti- (endostatin and thrombospondin-1) angiogenic mediators were measured by sandwich enzyme immunoassay. Among mediators regulating fibrosis and angiogenesis, endostatin levels were significantly higher in IgG4-RD patients compared to NHS (p < 0.0001). No differences in the levels of TGF-β1, periostin, VEGF, angiogenin-1 and thrombospondin-1 were observed between groups. Our study suggests that among the mediators mainly involved in fibrosis and angiogenesis endostatin might play a role in the pathogenetic processes of IgG4-RD.

Background: Although increased serum IgG4 level and tissue infiltration of IgG4-positive cells are key events in IgG4-related disease (IgG4RD), and nearly half of IgG4RD patients show hypocomplementemia, the role of IgG4 in the pathogenesis of IgG4RD remains unclear. Many reports show that altered IgG glycosylation, especially IgG with agalactosylated N-linked glycan (G0 N-glycan), have proinflammatory roles including complement activation, implicated in the pathogenesis of various inflammatory diseases. This study determined the concentration of N-linked glycans (N-glycan) released from serum IgG4 in IgG4RD patients and compared the difference of glycosylation changes to those in healthy controls. We also compared the concentration of each IgG4 glycoform between patients with and without hypocomplementemia and individual organ involvement (kidney, pancreas, lymph node) in IgG4RD., Methods: We collected sera from 12 IgG4RD patients and 8 healthy controls. IgG4 was isolated from sera via Melon™ Gel IgG Spin Purification Kit followed by Capture Select IgG4 (Hu) Affinity Matrix. IgG4 N-glycans were analyzed by S-BIO GlycanMap® Xpress methodology., Results: Significant increases of IgG4 G0 N-glycan and IgG4 fucosylated N-glycan (F1 N-glycan) concentrations were observed in IgG4RD compared with healthy controls. Although we observed decreased levels of IgG4 F0 glycan in IgG4RD with hypocomplementemia, there were no significant differences in the galactosylation and sialyation of IgG4 N-glycans. Furthermore, there were no significant differences in the glycosylation of IgG4 N-glycans between patients with and without individual organ involvement of IgG4RD., Conclusions: Although IgG4 has anti-inflammatory properties, IgG4 G0 and F1 glycans were increased in patients with IgG4RD. Our results suggest that decreased galactosylation of IgG4 is not related to complement activation and the differences of individual organ involvement in IgG4RD. IgG4 fucosylation change may be related to complement activation in IgG4RD. Further investigation is needed to clarify the role of IgG4 in IgG4RD.

Research has shown that a subset of the autism spectrum disorder (ASD) population presents with immune dysregulation. To explore this topic further, we investigated the efficacy and tolerability of intravenous immunoglobulin (IVIG) infusion in children with ASD. In this study, participants were recruited based on a diagnosis of autistic disorder, Asperger's disorder, or pervasive developmental disorder not otherwise specified. Participants also showed evidence of immune dysfunction based on abnormal levels of specific biomarkers, including CD40 ligand (CD154), lymphocyte stimulation, and T or B cell dysfunction. Of 17 screened patients, 14 completed the trial and received IVIG treatment (1 g/kg dose) for ten 21-day treatment cycles. The primary endpoint was disease improvement assessed using standardized cognitive and behavioral tests (Children's Communication Checklist [CCC-2], Social Responsiveness Scale [SRS], Aberrant Behavior Checklist [ABC], Clinical Global Impressions-Severity [CGI-S] and -Improvement [CGI-I], Autism Diagnostic Observation Schedule [ADOS], and Peabody Picture Vocabulary Test [PPVT]). Secondary endpoints included experimental biomarkers such as CD154, toll-like receptor-4, memory B cells, FOXP3, and lymphocyte stimulation. Significant improvements from baseline to study endpoint were observed in several subscales of the CCC-2, SRS, CGI-I, CGI-S, and ADOS, including Associated Maladaptive Behaviors (P ≤ .043), Reciprocal Social Interaction (P = .015), Communication (P < .001), and Stereotyped Behaviors and Repetitive Interests (P ≤ .013). Statistically significant reductions were also seen in numerous secondary outcomes of immunological biomarkers indicative of neuroinflammation. IVIG was well tolerated; no subjects withdrew due to an adverse event, and clinical data showed no evidence of thromboembolic events. Autism Res 2018, 11: 421-433. © 2018 International Society for Autism Research, Wiley Periodicals, Inc., Lay Summary: Since research has demonstrated a link between autism spectrum disorder (ASD) and immune dysfunction, this study investigated the efficacy and tolerability of intravenous immunoglobulin (IVIG) infusion in children with ASD. Fourteen patients received IVIG treatment and were assessed using standardized cognitive and behavioral tests. Following treatment with IVIG, significant improvement was observed across several subscales of the clinical tests and significant reductions were seen in the markers of neuroinflammation. These data suggest that inflammatory etiologies may play a role in select cases of autism, and IVIG treatment may exert a positive impact on behaviors and markers of inflammation in ASD., (© 2018 International Society for Autism Research, Wiley Periodicals, Inc.)

The rapidly increasing number of therapeutic biologics in development has led to a growing recognition of the need for improvements in immunogenicity assessment. Published data are often inadequate to assess the impact of an antidrug antibody (ADA) on pharmacokinetics, safety, and efficacy, and enable a fully informed decision about patient management in the event of ADA development. The recent introduction of detailed regulatory guidance for industry should help address many past inadequacies in immunogenicity assessment. Nonetheless, careful analysis of gathered data and clear reporting of results are critical to a full understanding of the clinical relevance of ADAs, but have not been widely considered in published literature to date. Here, we review visualization and modeling of immunogenicity data. We present several relatively simple visualization techniques that can provide preliminary information about the kinetics and magnitude of ADA responses, and their impact on pharmacokinetics and clinical endpoints for a given therapeutic protein. We focus on individual sample- and patient-level data, which can be used to build a picture of any trends, thereby guiding analysis of the overall study population. We also discuss methods for modeling ADA data to investigate the impact of immunogenicity on pharmacokinetics, efficacy, and safety.

Background: Sepsis is a leading cause of mortality and critical illness worldwide and is associated with an increased mortality rate in the months following hospital discharge. The occurrence of persistent or new organ dysfunction(s) after septic shock raises questions about the mechanisms involved in the post-sepsis status. The present study aimed to explore the immune profiles of patients one year after being discharged from the intensive care unit (ICU) following treatment for abdominal septic shock., Methods: We conducted a prospective, single-center, observational study in the surgical ICU of a university hospital. Eighty-six consecutive patients admitted for septic shock of abdominal origin were included in this study. Fifteen different plasma biomarkers were measured at ICU admission, at ICU discharge and at one year after ICU discharge. Three different clusters of biomarkers were distinguished according to their functions, namely: (1) inflammatory response, (2) cell damage and apoptosis, (3) immunosuppression and resolution of inflammation. The primary objective was to characterize variations in the immune status of septic shock patients admitted to ICU up to one year after ICU discharge. The secondary objective was to evaluate the relationship between these biomarker variations and patient outcomes., Results: At the onset of septic shock, we observed a cohesive pro-inflammatory profile and low levels of inflammation resolution markers. At ICU discharge, the immune status demonstrated decreased but persistent inflammation and increased immunosuppression, with elevated programmed cell death protein-1 (PD-1) levels, and a counterbalanced resolution process, with elevated levels of interleukin-10 (IL-10), resolvin D5 (RvD5), and IL-7. One year after hospital discharge, homeostasis was not completely restored with several markers of inflammation remaining elevated. Remarkably, IL-7 was persistently elevated, with levels comparable to those observed after ICU discharge, and PD-1, while lower, remained in the elevated abnormal range., Conclusions: In this study, protracted immune disturbances were observed one year after ICU discharge. The study results suggested the presence of long-lasting immune illness disorders following a long-term septic insult, indicating the need for long-term patient follow up after ICU discharge and questioning the use of immune intervention to restore immune homeostasis after abdominal septic shock.

A man aged 35 years presented with chronic headache and earache of 1-year duration. He had progressive vision loss and diplopia since last 9 months. He also had pain over the face and episodic profuse epistaxis. On examination, perception of light was absent in the right eye and hand movements were detected at 4 m distance in the left eye. Imaging revealed a lobulated mass in the nasopharynx extending into the bilateral cavernous sinuses and sphenoid sinus with bony erosions. Biopsy of the nasopharyngeal mass revealed pathological features which are characteristic of IgG4 disease. His serum IgG4 levels and acute inflammatory markers were also elevated. The patient was started on oral corticosteroid therapy. Fever, headache and earache resolved early and there was gradual improvement in the vision of the left eye. After 6 months, visual acuity in the left eye was 6/9, but right eye visual acuity had no change. Follow-up imaging revealed a significant reduction in the size of the mass., Competing Interests: Conflicts of Interest: None declared., (2016 BMJ Publishing Group Ltd.)

Recurrent pregnancy loss, depending on the definition, affects 1% to 3% of women aiming to have a child. Little is known about the direct causes of recurrent pregnancy loss, and the condition is considered to have a multifactorial and complex pathogenesis. The aim of this review was to summarize the evaluation and the management of the condition with specific emphasis on immunologic biomarkers identified as risk factors as well as current immunologic treatment options. The review also highlights and discusses areas in need of further research.

Background: IgG4-related disease (IgG4-RD) is a systemic condition of unknown cause characterized by highly fibrotic lesions with dense lymphoplasmacytic infiltrates. CD4(+) T cells constitute the major inflammatory cell population in IgG4-RD lesions., Objective: We used an unbiased approach to characterize CD4(+) T-cell subsets in patients with IgG4-RD based on their clonal expansion and ability to infiltrate affected tissue sites., Methods: We used flow cytometry to identify CD4(+) effector/memory T cells in a cohort of 101 patients with IgG4-RD. These expanded cells were characterized by means of gene expression analysis and flow cytometry. Next-generation sequencing of the T-cell receptor β chain gene was performed on CD4(+)SLAMF7(+) cytotoxic T lymphocytes (CTLs) and CD4(+)GATA3(+) TH2 cells in a subset of patients to identify their clonality. Tissue infiltration by specific T cells was examined by using quantitative multicolor imaging., Results: CD4(+) effector/memory T cells with a cytolytic phenotype were expanded in patients with IgG4-RD. Next-generation sequencing revealed prominent clonal expansions of these CD4(+) CTLs but not CD4(+)GATA3(+) memory TH2 cells in patients with IgG4-RD. The dominant T cells infiltrating a range of inflamed IgG4-RD tissue sites were clonally expanded CD4(+) CTLs that expressed SLAMF7, granzyme A, IL-1β, and TGF-β1. Clinical remission induced by rituximab-mediated B-cell depletion was associated with a reduction in numbers of disease-associated CD4(+) CTLs., Conclusions: IgG4-RD is prominently linked to clonally expanded IL-1β- and TGF-β1-secreting CD4(+) CTLs in both peripheral blood and inflammatory tissue lesions. These active, terminally differentiated, cytokine-secreting effector CD4(+) T cells are now linked to a human disease characterized by chronic inflammation and fibrosis., Competing Interests: The authors declare that they have no relevant conflict of interest., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

In October 2013, the International Life Sciences Institute - Health and Environmental Sciences Institute Immunotoxicology Technical Committee (ILSI-HESI ITC) held a one-day workshop entitled, "Workshop on Cytokine Release: State-of-the-Science, Current Challenges and Future Directions". The workshop brought together scientists from pharmaceutical, academic, health authority, and contract research organizations to discuss novel approaches and current challenges for the use of in vitro cytokine release assays (CRAs) for the identification of cytokine release syndrome (CRS) potential of novel monoclonal antibody (mAb) therapeutics. Topics presented encompassed a regulatory perspective on cytokine release and assessment, case studies regarding the translatability of preclinical cytokine data to the clinic, and the latest state of the science of CRAs, including comparisons between mAb therapeutics within one platform and across several assay platforms, a novel physiological assay platform, and assay optimization approaches such as determination of FcR expression profiles and use of statistical tests. The data and approaches presented confirmed that multiple CRA platforms are in use for identification of CRS potential and that the choice of a particular CRA platform is highly dependent on the availability of resources for individual laboratories (e.g. positive and negative controls, number of human blood donors), the assay through-put required, and the mechanism-of-action of the therapeutic candidate to be tested. Workshop participants agreed that more data on the predictive performance of CRA platforms is needed, and current efforts to compare in vitro assay results with clinical cytokine assessments were discussed. In summary, many laboratories continue to focus research efforts on the improvement of the translatability of current CRA platforms as well explore novel approaches which may lead to more accurate, and potentially patient-specific, CRS prediction in the future., (Copyright © 2016. Published by Elsevier Ltd.)

Background: The use of cyclophosphamide in cancer therapy is usually associated with challenging immunosuppression which exposes patients to increased risk of anemia and necessitating preventive measures during therapy. This study was carried out to investigate the efficacy of the hydro-ethanolic extract of the root of Z. zanthoxyloides in preventing and/or improving cyclophosphamide induced myelosuppression and oxidative stress in rats., Materials and Methods: Animals were divided into 6 groups of 6 rats each and were pretreated oral doses of 75, 150 and 225 mg/kg of the extract for 7 days and then co-administered with 2.5 mg/kg cyclophosphamide for 28 days., Results: The LD 50 of the extract was found to be 1682.3 mg/kg. Phytochemical analysis of the plant extract showed the presence of tannins, saponins, alkaloids and flavonoids, glycosides, terpenoids and phenols. In the anti-oxidant enzyme assay, CAT was significantly ( p < 0.05) increased for animals treated with 150 mg/kg+CP compared to 75 mg/kg+CP and 225 mg/kg+CP. GPx was significantly ( p < 0.01) increased in rats treated with 75 mg/kg+CP compared to 150 mg/kg+CP and control. SOD was significantly ( p < 0.01) increased in rats treated with 75 mg/kg+CP compared to the control. WBC was significantly ( p < 0.05) reduced for 225 mg/kg, 225 mg/kg+CP ( p < 0.001), 150 mg/kg+CP ( p < 0.001), 75 mg/kg+CP ( p < 0.001) and CP administered rats ( p < 0.001) respectively compared to the control. LDL and CHOL were significantly reduced ( p < 0.05) for rats treated with 75 mg/kg+CP, 225 mg/kg+CP and 225 mg/kg., Conclusion: Findings from this study demonstrates that the hydro-ethanolic root extract of Z. zanthoxyloides could be beneficial in hyperlipidemia and in cases of malignancies with abnormal cholesterol metabolism an effect which may be mediated via combating oxidative stress. List of Abbreviations: EDTA: Ethylenediamine-tetra acetate; MDA: Malondialdehyde; PCV: Packed cell volume; RBC: Red blood cell; HGB: Hemoglobin; WBC: White blood cell; ALT: Alanine transaminase; AST: Aspartate transaminase; CHOL: Cholesterol; LDL: Low density lipoprotein; HDL: High density lipoprotein; GSH: Reduced glutathione; SOD: Superoxide dismutase; CAT: Catalase; CP: Cyclophosphamide., Competing Interests: Conflict of interest The authors declare that there are no conflicts of interest in respect of this study.

Objective/background: Obstructive sleep apnea (OSA) is a common disorder, affecting over 100 million adults. Untreated OSA leads to serious health consequences and perturbations in endocrine, immune, inflammatory, and metabolic systems. Study objectives are to evaluate the association between OSA and biomarkers, and to test the hypothesis that a combination of markers may be useful in screening for OSA., Patients/methods: A multicenter trial was conducted enrolling symptomatic male patients with suspected OSA. All subjects underwent in-laboratory overnight polysomnography. A non-symptomatic control group was also obtained. Eleven biomarkers were tested: HbA1c, CRP, EPO, IL-6, uric acid, cortisol, hGH, prolactin, testosterone, DHEA (Beckman Coulter UniCel DxC 600i Synchron® Access® Clinical Systems), IGF-1., Results: 73 male subjects were enrolled; 26 had moderate/severe OSA. ROC curve analysis showed HbA1c, CRP, EPO, IL-6, and Uric Acid (AUCs: 0.76, 0.73, 0.65, 0.65, 0.61) were superior to the Epworth Sleepiness Scale (AUC: 0.52). Concurrent elevation of HbA1c and CRP provide even greater predictive power. A combination of elevated HbA1c, CRP, and EPO provided 0.08 increase in AUC (0.84 [0.75 - 0.94]) over individual markers (p<0.05), with high sensitivity (85%), and specificity (79%) for moderate/severe OSA., Conclusions: OSA induces characteristic endocrine, immune, inflammatory, and metabolic disturbances that can be detected with blood biomarkers. These biomarkers are superior to standard screening questionnaires. Various clusters of these biomarkers have an even greater association with OSA and thus may represent physiologic signatures of the disorder that may have value in initial screening for OSA as well as for follow-up of therapy response., (Copyright © 2016 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Objective: This study was performed to better know diagnosis associated with serum IgG4 concentration, and to explore the possibility for development of a serum IgG4 for IgG4-related disease (IgG4-RD) in Chinese populations., Methods: We studied retrospectively 497 IgG4 serum subclass measurements from Peking Union Medical College Hospital during the four-year period, including 242 IgG4-RD, 130 other diseases and 125 healthy individuals., Results: Serum IgG4 concentrations were significantly higher in IgG4-RD than in other pathologies (1662.9 ± 3760.9 mg/L, p < 0.001) and healthy individuals (538.2 ± 458.6 mg/L, p < 0.001). There were no significant differences in serum IgG4 level between other pathologies group and healthy individuals (p = 0.075). Among the 242 IgG4-RD patients analyzed, serum IgG4 concentrations were normal in 46 patients (19.0%). We found 32 patients (24.6%) with elevated serum IgG4 levels among the 130 patients who suffered from other pathologies. There were seven (5.6%) with serum IgG4 over 1350 mg/L in healthy individuals. The ROC curve analysis revealed that the optimal sensitivity and specificity were 80.0% and 88.2%, respectively, at the concentration of 1575 mg/L for Chinese patients., Conclusions: Our study demonstrated that serum IgG4 elevation was not specific of IgG4-RD. Further studies are needed to define the sensibility and specificity of IgG4 values for the diagnosis of IgG4-RD.

Background: Following the Chernobyl nuclear disaster of 1986, vast areas of Ukraine became contaminated with radionuclides. We examined health effects of school-based food intervention for children in a rural region Narodichi, Ukraine, exposed to low-level radiation through diet of locally produced foods. Until 1995, children received three daily meals with low content of artificial radionuclides which were subsequently reduced to two., Methods: Annual health screening data (1993-1998) were examined using a quasi-experimental regression discontinuity analysis (n = 947 children; 3,573 repeated measurements). Generalized Estimating Equation models evaluated effect of the food supplementation reduction on hematologic measures and prevalence of anemia, acute respiratory illnesses and diseases of immune system., Results: Prior improvement of several hematologic parameters diminished after food supplementation was reduced. From 1995 to 1996, levels of hemoglobin and erythrocytes decreased from 12.63 (95% CI: 12.56-12.71) to 12.46 g/dL (% CI: 12.39-12.52) and from 4.10 (95% CI: 4.07-4.12) to 4.02 (95% CI: 4.00-4.04) × 10(12)/L, respectively. In agreement, the prevalence ratio (PR) of previously declining anemia increased from 0.57 to 1.31 per year (p(interaction )< .0001). The relation between food supplementation and hemoglobin levels was modified by residential (137)Cs soil levels. After food supply reduction, PR of common cold and bronchitis increased from 1.27 to 2.32 per year (p(interaction) = 0.01) and from 1.09 to 1.24 per year (p(interaction) = 0.43), respectively., Conclusions: Food supplementation provided by the Ukrainian government likely prevented development of anemia in many of the children residing in the contaminated district. Food supplementation after the community exposure to radioactivity through a diet of locally grown foods should be considered as an effective approach to reduce adverse health effects of radiation.

Selective plasma exchange (SePE) using a selective membrane separator is a modified method of simple plasma exchange (PE). Immunoglobulin G (IgG) subclass distribution is one of the important immunological characteristics of IgG. However, there is little information regarding the removal characteristics of IgG subclasses by SePE and conventional PE. Here, we investigated the removal ratio of IgG subclasses by PE and SePE in seven patients with immunological disorders. When the mean processed volume was 0.88 plasma volume (PV) (corresponding to 2.12 L), the mean percent reductions by PE were as follows: IgG, 63.2%; IgG1, 64.5%; IgG2, 64.0%; IgG3, 61.4%; and IgG4, 69.5%. When the mean processed volume was 1.18 PV (corresponding to 2.98 L), the mean percent reductions by SePE were as follows: IgG, 51.6%; IgG1, 55.3%; IgG2, 52.0%; IgG3, 53.7%; and IgG4, 64.6%. In both PE and SePE, using albumin solution as the supplementary fluid, IgG was effectively eliminated regardless of IgG subclasses., (© 2015 International Society for Apheresis, Japanese Society for Apheresis, and Japanese Society for Dialysis Therapy.)

During infections or acute conditions high-density lipoproteins cholesterol (HDL-C) levels decrease very rapidly and HDL particles undergo profound changes in their composition and function. These changes are associated with poor prognosis following endotoxemia or sepsis and data from genetically modified animal models support a protective role for HDL. The same is true for some parasitic infections, where the key player appears to be a specific and minor component of HDL, namely apoL-1. The ability of HDL to influence cholesterol availability in lipid rafts in immune cells results in the modulation of toll-like receptors, MHC-II complex, as well as B- and T-cell receptors, while specific molecules shuttled by HDL such as sphingosine-1-phosphate (S1P) contribute to immune cells trafficking. Animal models with defects associated with HDL metabolism and/or influencing cell cholesterol efflux present features related to immune disorders. All these functions point to HDL as a platform integrating innate and adaptive immunity. The aim of this review is to provide an overview of the connection between HDL and immunity in atherosclerosis and beyond., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Isolated IgE deficiency is one of the most common primary immunodeficiency, which is still underestimated cause of health disorders of modern man. Recent genetic studies report that the cause of the IgE deficiency is immune dysregulation caused by polymorphisms of the gene, which is responsible for the synthesis of activation-induced cytidinedeaminase (AICDA). The Institute of Immunology and Allergology at Bogomolets NMU during the years 2012-2014 were examined 5298 patients with a range of different diseases, which could be suspected violations of immunity. All patients were conducted comprehensive immunological study, and 4476 of them were examined for content of total serum IgE. The criterion for the selection of patients for follow-up began serum IgE < 10 kIU/l. Serum immunoglobulin E was determined by ELISA. Serum IgE < 10 IU/ml was detected in 342 patients (7%). Average reduction in the study group made up (5.30 ± 1.31) IU/ml. Partial deficiency (5-10 kIU/l) was detected in 212 patients (4%), while the total--130 (3%). For follow-up, we are clinically selected group of patients with deficiency of IgE (n = 60) and control group (n = 30). All patients were distributed as per clinical syndromes, and the frequency of their manifestations: sinopulmonary syndrome (63%), gastrointestinal syndrome (13%), autoimmune manifestations (10%), allergic reactions (7%) and chronic fatigue syndrome (7%). The levels of serum IgG, IgA, IgM in the study group were within the age norm (IgG = 1160.00 mg/dl ± 2.88 mg/dl, IgA = 138 g/l ± 37 mg/dl, IgM = 114 mg/dl ± 30 mg/dl). However, only a small proportion of patients was observed decrease in other classes of immunoglobulins in 8 patients with IgG < 700 mg/dL in 16 patients with IgA < 90 mg/dl and 6 patients with decreased serum IgM < 90 mg/dl. These patients were examined the levels of serum IgG subclasses and sIgA levels in saliva. Significant violations by cellular immunity in determining lymphocyte subpopulations by flow cytometry using monoclonal antibodies also were found. Phagocytic indices were also no significant abnormalities. An important aspect of clinical deficiency of immunoglobulin E is its association with diseases of bacterial origin (H. influenza, M. catarrhalis, Str. pneumoniae), indicating a protective role of these antibodies in the mucosa of the respiratory tract. Thus, isolated IgE deficiency is associated with sustained decrease in serum concentrations of immunoglobulin E (< 10 kIU/l) in patients with normal immune status of other indicators that require dispensary and treatment. The results of their study indicate a high incidence of the IgE-deficiency among the population and its high incidence among the humoral defects.

Increasing evidence suggests that systemic inflammation is associated with many pathophysiological processes including frailty in older adults. We evaluated the relationships between white blood cell subtypes, geriatric assessment, and frailty syndrome and in particular, how they correlate with individual frailty criteria (involuntary loss of weight, low energy or exhaustion, slow mobility, muscle weakness, and low physical activity) in frail older women. There was a significant and positive correlation between the frailty score and neutrophil count, but a significantly negative correlation was found when this score was compared to the lymphocyte count. These associations were significant only for two frailty criteria: poor muscular strength and low physical activity. Further investigation into the role of white blood cell subtypes in ageing and its associated adverse outcomes in older adults is warranted, in particular in the loss of muscular strength and for poor physical activity., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Studies recently showed that intratracheal (IT) instillation of Libby amphibole (LA) increases circulating acute-phase proteins (APP; α-2 macroglobulin, A2M; and α-1 acid glycoprotein, AGP) and inflammatory biomarkers (osteopontin and lipocalin) in rats. In this study, objectives were to (1) compare changes in biomarkers of rats after instillation of different naturally occurring asbestos (NOA) minerals including LA, Sumas Mountain chrysotile (SM), El Dorado Hills tremolite (ED), and Ontario ferroactinolite cleavage fragments (ON), and (2) examine biomarkers after subchronic LA or amosite inhalation exposure. Rat-respirable fractions (aerodynamic diameter approximately 2.5 μm) prepared by water elutriation were delivered via a single IT instillation at doses of 0, 0.5, and 1.5 mg/rat in male F344 rats. Nose-only inhalation exposures were performed at 0, 1, 3.3, and 10 mg/m(3) for LA and at 3.3 mg /m(3) for amosite, 6h/d, 5 d/wk for 13 wk. Inflammation, metabolic syndrome, and cancer biomarkers were analyzed in the serum for up to 18 mo. IT instillation of some asbestos materials significantly increased serum AGP and A2M but to a varying degree (SM = LA > ON = ED). Numerical increases in interleukin (IL)-6 and osteopontin occurred in rats instilled with SM. SM and ED also elevated leptin and insulin at 15 mo, suggesting potential metabolic effects. LA inhalation tended to raise A2M at d 1 but not cytokines. Serum mesothelin appeared to elevate after 18 mo of LA inhalation. These results suggest that the lung injury induced by high levels of asbestos materials may be associated with systemic inflammatory changes and predisposition to insulin resistance.

Today is actively discussing the impact of the new adipocytokin visfatin on the processes of atherosclerosis and inflammation. In this regard, of particular interest is a contingent of patients with hypertension in combination with abdominal obesity (AO). According to the patient should receive an adequate selection of antihypertensive therapy in connection with common pathology. The aim of the study was improved the treatment of hypertensive patients combined with abdominal obesity, which based on determining the level of visfatin and markers of immune inflammation. There were 64 patients which separated on the 1st group of hypertensive patients (n=28), 2d hypertensive with AO (n=36) and the 3d group of 19 healthy individuals. Patients matched for age and sex. All patients were determined in serum the level of visfatin («RayBioteeh», USA) interleukin-6 (IL -6) ("Vector -Best", Russia) interleukin-4 (IL-4) ("Vector -Best ", Russian) and C -reactive protein (CRP) («DRG International Inc.», USA) - ELISA. The treatment was carrying out with a combination of antihypertensive therapy: angiotensin receptor blocker-II of olmesartan medoxomil (10-20 mg dose once daily) with a calcium antagonist amlodipine (5-10 mg once a day) as hypertensive patients with AO, and without. It was noted the achievement of target blood pressure in both groups. On the antihypertensive therapy the 1st group in serum the level of IL-6 and CRP was significantly decreased by 48.7% and 60,6% (p <0,05). Whereas in the 2nd group there were a statistically significant reduction in the level of IL-6 and CRP in serum by 43.6% and 63.4% and detected statistically significant change in the level of serum visfatin 37.3%, respectively (p <0,05). The level of IL-4 in serum was increased in the 1st and 2nd groups by 29.7% and 11.6%, respectively (p>0.05). Conducted combination of antihypertensive therapy reducing the level of visfatin in hypertensive patients with abdominal obesity. As well, as has contributed to the target blood pressure and reduce inflammation in both groups.

Circulating levels of adiponectin (APN) are reduced in obesity and associated comorbidities, with inflammation playing an important role in downregulating APN production. In contrast to obesity and metabolic disease, elevated systemic and local levels of APN are present in patients with inflammatory and immune-mediated diseases, including autoimmune and pulmonary conditions, heart and kidney failure, viral hepatitis, organ transplantation and perhaps critical illness. A positive association between inflammation and APN is usually reported in inflammatory/immune pathologies, in contrast with the negative correlation typical of metabolic disease. This review discusses the role of APN in modulation of inflammation and immunity and the potential mechanisms leading to increased levels of APN in inflammatory/immune diseases, including modification of adipose tissue physiology; relative contribution of different tissues and adipose depots; hormonal, pharmacological, nutritional and life style factors; the potential contribution of the microbiota as well as the role of altered APN clearance and release from T-cadherin-associated tissue reservoirs. Potential reasons for some of the apparently contradictory findings on the role of APN as a modulator of immunity and inflammation are also discussed, including a comparison of types of recombinant APN used for in vitro studies and strain-dependent differences in the phenotype of APN KO mice., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The sampling included 231 patient with hypertension disease of stage I-II. The hypertrophy of left ventricle of heart was established in 97 patients (group I) and 134 patients had no hypertrophy of left ventricle of heart (group II). The control group consisted of 25 healthy persons. The increase of tumor necrosis factor alpha and interleukin beta was established in group I as compared with group II and control group. In patients of group I the expressed dysfunction of endothelium was observed. The increase of endothelin I and number of desquamated endotheliocytes as compared with group II and healthy persons was established. The direct relationship between increase of concentration of analyzed cytokines and presence of hypertrophy of left ventricle of heart is revealed.

Introduction: Children and adolescents with a chronic illness have potential risk factors for vitamin D deficiency. An optimal vitamin D status might have multiple health effects. This study evaluated vitamin D status and its association with age, gender, and season in a large cohort of chronically ill Finnish patients at a tertiary pediatric outpatient clinic. A cross-sectional register-based study was carried out, involving altogether 1351 children (51% boys, age range 0.2-18 years), who visited the outpatient clinic during 2007-2010 and had their vitamin D status (S-25-OHD) determined. A post-doc analysis was conducted to identify predisposing and preventing factors for vitamin D deficiency., Results: Almost half (47%) of the S-25-OHD values were consistent with subnormal vitamin D status (S-25-OHD <50 nmol/L) while only 12% were >80 nmol/L. Age and season were the most important determinants for S-25-OHD concentration. Mean S-25-OHD concentration differed between age groups (Kruskal-Wallis; p<0.001), adolescents being at highest risk for vitamin D insufficiency. Young age and vitamin D supplementation were preventive factors for deficiency, while non-Finnish ethnic background was a predisposing factor. S-25-OHD showed significant seasonal variation in children older than 6 years. In the whole cohort, S-25-OHD was on average 13 nmol/L higher in summer than in winter, and the prevalence of vitamin D deficiency ( =  S-25-OHD <37.5 nmol/l) varied from 11% in summer to 29% in winter., Conclusions: The finding that almost half of the studied Finnish children with a chronic illness had suboptimal vitamin D status is alarming. Inferior vitamin D status was noted in adolescents compared with younger children, suggesting that imbalance between intake and requirement evolves with age. Although less common during summer, subnormal vitamin D status was still observed in 28% of those evaluated in summer. Clinicians should identify individuals at risk and actively recommend vitamin D supplementation.

Patients with a variety of systemic diseases may present with clinical indications of biliary tract disorders. This article describes a group of systemic conditions associated with bile duct abnormalities and the role of endoscopic therapy in their diagnosis and management., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Kidney dysfunction leads to disturbed renal metabolic activities and to impaired glomerular filtration, resulting in the retention of toxic solutes affecting all organs of the body. Cardiovascular disease (CVD) and infections are the main causes for the increased occurrence of morbidity and mortality among patients with chronic kidney disease (CKD). Both complications are directly or indirectly linked to a compromised immune defense. The specific coordinated roles of polymorphonuclear leukocytes (PMNLs), monocytes/macrophages, lymphocytes and antigen-presenting cells (APCs) in maintaining an efficient immune response are affected. Their normal response can be impaired, giving rise to infectious diseases or pre-activated/primed, leading to inflammation and consequently to CVD. Whereas the coordinated removal via apoptosis of activated immune cells is crucial for the resolution of inflammation, inappropriately high apoptotic rates lead to a diminished immune response. In uremia, the balance between pro- and anti-inflammatory and between pro- and anti-apoptotic factors is disturbed. This review summarizes the interrelated parameters interfering with the immune response in uremia, with a special focus on the non-specific immune response and the role of uremic toxins.

Objective: To define the relationship between worsening oxygenation status (worst PaO(2)/FiO(2) ratio in the first 24 hours after intensive care unit admission) and mortality in immunosuppressed and immunocompetent ICU patients in the presence and absence of mechanical ventilation., Design: Retrospective cohort study., Setting: Data were extracted from the Australian and New Zealand Intensive Care Society Adult Patient Database., Participants: Adult patients admitted to 129 ICUs in Australasia, 2000-2010., Main Outcome Measures: In hospital and ICU mortality; relationship between mortality and declining PaO(2)/FiO(2) ratio by ventilation status and immune status., Results: 457 750 patient records were analysed. Worsening oxygenation status was associated with increasing mortality in all groups. Higher mortality was seen in immunosuppressed patients than immunocompetent patients. After multivariate analysis, in mechanically ventilated patients, declining PaO(2)/FiO(2) ratio in the first 24 hours of ICU admission was associated with a more rapidly rising mortality rate in immunosuppressed patients than non-immunosuppressed patients. Immunosuppression did not affect the relationship between oxygenation status and mortality in non-ventilated patients., Conclusion: Immunosuppression increases the risk of mortality with progressively worsening oxygenation status, but only in the presence of mechanical ventilation. Further research into the impact of mechanical ventilation in immunosuppressed patients is required.