Understanding Of Immune Dysfunction Research Articles

Immune Dysfunction in Schizophrenia Spectrum Disorders.

Evidence from epidemiological, clinical, and biological research resulted in the immune hypothesis: the hypothesis that immune system dysfunction is involved in the pathophysiology of schizophrenia spectrum disorders (SSD). The promising implication of this hypothesis is the potential to use existing immunomodulatory treatment for innovative interventions for SSD. Here, we provide a selective historical review of important discoveries that have shaped our understanding of immune dysfunction in SSD. We first explain the basic principles of immune dysfunction, after which we travel more than a century back in time. Starting our journey with neurosyphilis-associated psychosis in the nineteenth century, we continue by evaluating the role of infections and autoimmunity in SSD and findings from assessment of immune function using new techniques, such as cytokine levels, microglia density, neuroimaging, and gene expression. Drawing from these findings, we discuss anti-inflammatory interventions for SSD, and we conclude with a look into the future.

Antiviral epithelial-macrophage crosstalk permits secondary bacterial infections.

Miscommunication of antiviral and antibacterial immune signals drives worsened morbidity and mortality during respiratory viral-bacterial coinfections. Extracellular vesicles (EVs) are a form of intercellular communication with broad implications during infection, and here we show that epithelium-derived EVs released during the antiviral response impair the antibacterial activity of macrophages, an innate immune cell crucial for bacterial control in the airway. Macrophages exposed to antiviral EVs display reduced clearance of Staphylococcus aureus as well as altered inflammatory signaling and anti-inflammatory metabolic reprogramming, thus revealing EVs as a source of dysregulated epithelium-macrophage crosstalk during coinfection. As effective epithelium-macrophage communication is critical in mounting an appropriate immune response, this novel observation of epithelium-macrophage crosstalk shaping macrophage metabolism and antimicrobial function provides exciting new insight and improves our understanding of immune dysfunction during respiratory coinfections.

Neutrophil Inhibitory Receptors Expression Is Distinct During Gram-Positive and -Negative Pneumonia and Affects Neutrophil Function

Abstract Rational: Despite effective antimicrobial therapy, morbidity and mortality from pneumonia remains high. Honing our understanding of immune dysfunction in pneumonia is now crucial for developing targeted therapeutics. Our objective is to understand how different lethal bacterial pneumonias affect neutrophil phenotype and function over time and identify regulators of neutrophil function. Methods: Mice were intratracheally instilled with E. colior S. pneumoniae(SP3) for 6, 24 or 48h and neutrophils were isolated from either bronchioloalveolar lavage fluid (BALF) or peripheral blood. Neutrophil surface marker expression (SME) was analyzed via 25-color panel run on a Cytek Aurora spectral flow cytometer (SFC). Data was analyzed in FlowJo and gated for live, single cell, CD45+Ly6G+ neutrophils, opt-SNE was run for data visualization, and Phenograph was run for unbiased clustering. For bacterial clearance assays, bone marrow neutrophils were isolated via Percoll, then incubated with blocking antibodies against inhibitor receptors (IRs) (PD-L1, SIRPα, VISTA, or CD200R), soluble ligands, or media only. Neutrophils were then cocultured with either SP3 or E. coli. Media from bacteria-neutrophil cultures was then plated on agar and the developing colonies were counted. Results and Conclusions: Using SFC, we identified pathogen- and timepoint-specific differences in SME of the IRs PD-L1, SIRPα, VISTA and CD200R. Modulating IR signaling by blocking or stimulating them impacts neutrophils’ ability to clear bacteria. In sum, our data suggests that neutrophils modulates their response to adapt to specific pathogens. IRs may play a role in regulating these dynamic neutrophil responses, making them a potential therapeutic target. NIH grants K08 HL130582 (KET) and R01 HL158732 (KET).

Uremic toxin indoxyl sulfate promotes proinflammatory macrophage activation by regulation of \u03b2-catenin and YAP pathways

Evidence has been shown that indoxyl sulfate (IS) could impair kidney and cardiac functions. Moreover, macrophage polarization played important roles in chronic kidney disease and cardiovascular disease. IS acts as a nephron-vascular toxin, whereas its effect on macrophage polarization during inflammation is still not fully elucidated. In this study, we aimed to investigate the effect of IS on macrophage polarization during lipopolysaccharide (LPS) challenge. THP-1 monocytes were incubated with phorbol 12-myristate-13-acetate (PMA) to differentiate into macrophages, and then incubated with LPS and IS for 24 h. ELISA was used to detect the levels of TNFα, IL-6, IL-1β in THP-1-derived macrophages. Western blot assay was used to detect the levels of arginase1 and iNOS in THP-1-derived macrophages. Percentages of HLA-DR-positive cells (M1 macrophages) and CD206-positive cells (M2 macrophages) were detected by flow cytometry. IS markedly increased the production of the pro-inflammatory factors TNFα, IL-6, IL-1β in LPS-stimulated THP-1-derived macrophages. In addition, IS induced M1 macrophage polarization in response to LPS, as evidenced by the increased expression of iNOS and the increased proportion of HLA-DR+ macrophages. Moreover, IS downregulated the level of β-catenin, and upregulated the level of YAP in LPS-stimulated macrophages. Activating β-catenin signaling or inhibiting YAP signaling suppressed the IS-induced inflammatory response in LPS-stimulated macrophages by inhibiting M1 polarization. IS induced M1 macrophage polarization in LPS-stimulated macrophages via inhibiting β-catenin and activating YAP signaling. In addition, this study provided evidences that activation of β-catenin or inhibition of YAP could alleviate IS-induced inflammatory response in LPS-stimulated macrophages. This finding may contribute to the understanding of immune dysfunction observed in chronic kidney disease and cardiovascular disease.

CD4:CD8 ratio as a frontier marker for clinical outcome, immune dysfunction and viral reservoir size in virologically suppressed HIV-positive patients.

IntroductionAbsolute CD4 T cell count and plasma viral load have been established as predictors of HIV disease progression, and CD4 T cell count is used as an indicator for initiation of antiretroviral therapy. Following long-term therapy, patients generally present with significant CD4 T cell recovery contrasting with persistently elevated CD8 T cell counts, which leads to a partial restoration of CD4:CD8 ratio. This review focuses on the relevance of the CD4:CD8 ratio on clinical outcomes, immune dysfunction and HIV reservoir size in long-term treated patients.MethodWe conducted a comprehensive literature review of publications in English language using major electronic databases. Our search was focused on factors contributing to CD4:CD8 T cell ratio and clinical outcome in adult HIV-positive patients in the context of treated infection.DiscussionLow CD4:CD8 ratio has been linked to ageing and acts as a predictor of mortality in the general population. This ratio may represent the combined effects of inflammation and immunological changes called “inflammaging.” Although the mechanisms underlying partial correction of the CD4:CD8 ratio and persistently elevated CD8 T cell count in long-term treated patients remain poorly understood, it has been recently indicated that patients with optimal CD4 T cell recovery and low CD4:CD8 ratio still harbour increased immune activation, an immune senescent phenotype and have a higher risk of non-AIDS morbidity and mortality. This review reconsiders CD4:CD8 ratio in the light of advances in the understanding of immune dysfunction and examines its pathophysiological features and implications on clinical outcome and HIV reservoir size in long-term treated HIV-positive adults.ConclusionThe CD4:CD8 ratio can contribute to the immunological evaluation of treated patients in a long-term follow-up and may be applied for monitoring both immune dysfunction and viral reservoir size in immune-based clinical trials.

‘Immunogenetics of Aging’: report on the activities of the 15th International HLA and Immunogenetics Working Group and 15th International HLA and Immunogenetics Workshop

'Immunogenetics of Aging' is a component that was first included in the 14th International HLA and Immunogenetics Workshop (IHIWS) and developed further within the 15th Workshop. The aim of this component was to assess the impact of human leukocyte antigen (HLA) genes, cytokine genes, and some innate immunity genes such as killer-cell immunoglobulin-like receptors (KIRs) and mannose-binding lectin 2 (MBL2) in successful aging and their contribution to the better understanding of immune dysfunction in old age. Within the 15th IHIWS new populations were included in the analysis. Additional cytokine gene polymorphisms were assessed and innate immunity genes were analyzed for possible relevance in longevity. The results showed that longevity might be associated with anti-inflammatory cytokine gene profiles, decreased frequency of interleukin-10 (IL-10) and transforming growth factor-B1 haplotypes associated with a low level of gene expression, and increased frequency of haplotypes determining a high level of expression. Extended tumor necrosis factor-A and IL-12B genotypes were also likely relevant to longevity. Data also showed that innate immunity genes are associated with susceptibility to infections in the elderly and showed that these genes might be an important genetic marker in aging. Decreased frequencies of KIR2DS5 and A1B10 haplotypes, and an increased proportion of MBL2-deficient haplotypes were found in the group with higher cytomegalovirus-specific IgG antibody levels. Together, these studies emphasize the relevance of genes regulating immune functions in maintaining human longevity and stress the importance of further clarifying their impact on successful aging.

CASPASE-3, BCL-2 AND SOLUBLE FAS-LIGAND IN WHOLE BLOOD INDICATE APOPTOSIS AS AN IMPORTANT PLAYER IN THE COURSE OF SEPSIS AND SEPTIC SHOCK

Objective: We asked whether the analysis of pro- or antiapoptosis contribute to our understanding of immune dysfunction, hyperinflammation and/or resolution of sepsis and septic shock. Patients: Twenty intensive care unit (ICU) patients were analyzed daily: 2 had SIRS, 5 suffered from sepsis (2 died), and 13 had septic shock (5 died). Methods: EDTA-blood was lysed with cell lysis buffer containing protease inhibitors. The lysate was stored at - 20?C. Active caspase-3, soluble CD95-L (sCD178) and Bcl-2 were measured by ELISAs (R&D Systems, Chemicon International, or Bender-Systems). Alternatively, we used the CBA Apoptosis® (BD-Biosciences). Cytokines and active metallo-proteinases (MMPs) were quantified by using the bead-based Luminex technology (Beadlyte® Upstate USA). Patients' courses were documented according to (i) clinical scores, (ii) diagnostic and therapeutic interventions, and (iii) complications such as bleeding, infections, positive blood cultures, etc. Results: Data obtained from whole blood lysates as well as plasma measurements demonstrate that active caspase-3 is high when leukocyte counts consecutively decline. In 2 patients with favourable outcome, these caspase 3 peaks follow plasma peaks of sCD178 and precede elevations of Creactive protein (CRP) and IL-6. High Bcl-2 contents in blood lysates accompany increased leukocyte counts and appear to be linked to higher TNF-α. Patients with prolonged phases of septic shock lacked apoptosis markers as well as elevated cytokines. Conclusions: The present study shows that quantification of apoptosis relevant factors is feasible in whole blood on a daily basis.

Altered CD46-mediated T cell co-stimulation in haemodialysis patients

While most of our understanding of immune dysfunction in dialysis patients involves alterations in CD28-CD80/86 signalling, nothing is known of CD46-mediated co-stimulation of T cells in these patients. Because C3b/C4b bind to CD46 and complement activation occurs during haemodialysis (HD), we addressed whether CD46-mediated T cell activation is altered in HD (n = 9), peritoneal dialysis (PD) (n = 10) and predialysis patients (n = 8) compared to healthy controls (HC) (n = 8). T cell surface markers, T cell proliferation and interleukin (IL)-10 production were studied in CD4(+)T cells. In addition, CD46 splice-variants and IL-10 promoter gene polymorphisms were studied by reverse transcription (RT) or amplification refractory mutation system-polymerase chain reaction (ARMS-PCR), respectively. In all uraemic patients, irrespective of the stage of renal insufficiency or dialysis modality, a significant increase in the percentage of CD25 positivity in naive CD4(+)T cells was found (64% +/- 21%versus 23% +/- 18%, P < 0.001). Lymphocytes of HD patients proliferated in greater numbers and produced more IL-10 after co-stimulation with anti-CD46 than after co-stimulation with anti-CD28. This was also found in CD4(+)T cells of PD patients, albeit to a lesser extent. In contrast, with T cells of predialysis patients and of HC, co-stimulation via CD28 was more efficient. The observed alterations in T cell proliferation and IL-10 production were associated neither with CD46 splice variants nor with IL-10 promoter gene polymorphisms. Lymphocytes of HD patients show an increased response on CD46 co-stimulation. These data suggest that ongoing complement activation in HD patients may lead to alterations in acquired immunity.