From Hypoxia to Buoyancy: Serotonin and Oxygen Deprivation Rewire Neutrophils.

Herein, we describe a method to purify higher buoyancy neutrophils after exposure of whole blood to brief hypoxia and reoxygenation in combination with platelet-derived serotonin. These higher buoyancy neutrophils display enhanced ability to form neutrophil extracellular traps and increment the tryptamine-protein adducts. Similar changes are identified in neutrophils isolated from patients with systemic lupus erythematosus.

Improved Mitochondrial Metabolism and Reduced Inflammation Following Attenuation of Murine Lupus With Coenzyme Q10 Analog Idebenone.

Objective: A role for mitochondrial dysfunction has been proposed in the immune dysregulation and organ damage characteristic of systemic lupus erythematosus (SLE). Idebenone is a coenzyme Q10 synthetic quinone analog and an antioxidant that has been used in humans to treat diverse diseases in which mitochondrial function is impaired. This study was undertaken to assess whether idebenone ameliorates lupus in murine models.

Peptidylarginine deiminases 2 and 4 modulate innate and adaptive immune responses in TLR-7-dependent lupus.

The peptidylarginine deiminases PAD2 and PAD4 are implicated in the pathogenesis of several autoimmune diseases. PAD4 may be pathogenic in systemic lupus erythematosus (SLE) through its role in neutrophil extracellular trap (NET) formation that promotes autoantigen externalization, immune dysregulation, and organ damage. The role of this enzyme in mouse models of autoimmunity remains unclear, as pan-PAD chemical inhibitors improve clinical phenotype, whereas PAD4-KO models have given conflicting results.

Metabolic abnormalities and oxidative stress in lupus.

Purpose Of Review: Upon antigen exposure, immune cells rely on cell-specific metabolic pathways to mount an efficient immune response. In autoimmunity, failure in critical metabolic checkpoints may lead to immune cell hyperactivation and tissue damage. Oxidative stress in autoimmune patients can also contribute to immune dysregulation and injury to the host.

Disentangling the role of neutrophil extracellular traps in rheumatic diseases.

Purpose Of Review: A breakdown of immune tolerance to self-antigens in a genetically predisposing background, precipitated by environmental triggers, contributes to the development of systemic autoimmune diseases. Renewed interest in the immunomodulatory capabilities of neutrophils in systemic autoimmunity has identified neutrophil extracellular trap (NET) formation as a distinguishing action of neutrophils in afflicted hosts.

Recent Findings: Oxidation of nucleic acids and posttranslational modifications of proteins distinctly occur during NET formation and may promote enhanced immunogenicity.

Acute Versus Progressive Onset of Diabetes in NOD Mice: Potential Implications for Therapeutic Interventions in Type 1 Diabetes.

Most natural history models for type 1 diabetes (T1D) propose that overt hyperglycemia results after a progressive loss of insulin-secreting β-cell mass and/or function. To experimentally address this concept, we prospectively determined morning blood glucose measurements every other day in multiple cohorts (total n = 660) of female NOD/ShiLtJ mice starting at 8 weeks of age until diabetes onset or 26 weeks of age. Consistent with this notion, a majority of mice that developed diabetes (354 of 489 [72%]) displayed a progressive increase in blood glucose with transient excursions >200 mg/dL, followed by acute and persistent hyperglycemia at diabetes onset.

SIGNR3-dependent immune regulation by Lactobacillus acidophilus surface layer protein A in colitis.

Intestinal immune regulatory signals govern gut homeostasis. Breakdown of such regulatory mechanisms may result in inflammatory bowel disease (IBD). Lactobacillus acidophilus contains unique surface layer proteins (Slps), including SlpA, SlpB, SlpX, and lipoteichoic acid (LTA), which interact with pattern recognition receptors to mobilize immune responses.

Colonic immune suppression, barrier dysfunction, and dysbiosis by gastrointestinal bacillus anthracis Infection.

Gastrointestinal (GI) anthrax results from the ingestion of Bacillus anthracis. Herein, we investigated the pathogenesis of GI anthrax in animals orally infected with toxigenic non-encapsulated B. anthracis Sterne strain (pXO1+ pXO2-) spores that resulted in rapid animal death.

Epithelial CaSR deficiency alters intestinal integrity and promotes proinflammatory immune responses.

The intestinal epithelium is equipped with sensing receptor mechanisms that interact with luminal microorganisms and nutrients to regulate barrier function and gut immune responses, thereby maintaining intestinal homeostasis. Herein, we clarify the role of the extracellular calcium-sensing receptor (CaSR) using intestinal epithelium-specific Casr(-/-) mice. Epithelial CaSR deficiency diminished intestinal barrier function, altered microbiota composition, and skewed immune responses towards proinflammatory.

Impaired colonic B-cell responses by gastrointestinal Bacillus anthracis infection.

Ingestion of Bacillus anthracis spores causes gastrointestinal (GI) anthrax. Humoral immune responses, particularly immunoglobulin A (IgA)-secreting B-1 cells, play a critical role in the clearance of GI pathogens. Here, we investigated whether B.

Activation of B cells by a dendritic cell-targeted oral vaccine.

Production of long-lived, high affinity humoral immunity is an essential characteristic of successful vaccination and requires cognate interactions between T and B cells in germinal centers. Within germinal centers, specialized T follicular helper cells assist B cells and regulate the antibody response by mediating the differentiation of B cells into memory or plasma cells after exposure to T cell-dependent antigens. It is now appreciated that local immune responses are also essential for protection against infectious diseases that gain entry to the host by the mucosal route; therefore, targeting the mucosal compartments is the optimum strategy to induce protective immunity.

Microbiota impact on the epigenetic regulation of colorectal cancer.

Mechanisms of colorectal cancer (CRC) development can be generally divided into three categories: genetic, epigenetic, and aberrant immunologic signaling pathways, all of which may be triggered by an imbalanced intestinal microbiota. Aberrant gut microbial composition, termed 'dysbiosis', has been reported in inflammatory bowel disease patients who are at increased risk for CRC development. Recent studies indicate that it is feasible to rescue experimental models of colonic cancer by oral treatment with genetically engineered beneficial bacteria and/or their immune-regulating gene products.

Tailoring gut immune responses with lipoteichoic acid-deficient Lactobacillus acidophilus.

As highlighted by the development of intestinal autoinflammatory disorders when tolerance is lost, homeostatic interactions between gut microbiota, resident immune cells, and the gut epithelium are key in the maintenance of gastrointestinal health. Gut immune responses, whether stimulatory or regulatory, are dictated by the activated dendritic cells (DCs) that first interact with microorganisms and their gene products to then elicit T and B cell responses. Previously, we have demonstrated that treatment with genetically modified Lactobacillus acidophilus is sufficient to tilt the immune balance from proinflammatory to regulatory in experimental models of colitis and colon cancer.

Colonic immune stimulation by targeted oral vaccine.

Background: Currently, sufficient data exist to support the use of lactobacilli as candidates for the development of new oral targeted vaccines. To this end, we have previously shown that Lactobacillus gasseri expressing the protective antigen (PA) component of anthrax toxin genetically fused to a dendritic cell (DC)-binding peptide (DCpep) induced efficacious humoral and T cell-mediated immune responses against Bacillus anthracis Sterne challenge.

Methodology/principal Finding: In the present study, we investigated the effects of a dose dependent treatment of mice with L.

Targeting aberrant colon cancer-specific DNA methylation with lipoteichoic acid-deficient Lactobacillus acidophilus.

Pathogenic autoinflammatory responses triggered by dysregulated microbial interactions may lead to intestinal disorders and malignancies. Previously, we demonstrated that a lipoteichoic acid (LTA)-deficient Lactobacillus acidophilus strain, NCK2025, ameliorated inflammation-induced colitis, significantly reduced the number of polyps in a colonic polyposis cancer model and restored physiological homeostasis in both cases. Nonetheless, the regulatory signals delivered by NCK2025 to reprogram the gastrointestinal microenvironment, and thus resist colonic cancer progression, remain unknown.

Oxidative stress and beta cell dysfunction.

Autoimmune Type 1 A Diabetes (T1D) is characterized by dependence on exogenous insulin consequential to the autoimmune attack and destruction of insulin-producing islet beta cells. Pancreatic islet cell inflammation, or insulitis, precedes beta cell death and T1D onset. In the insulitic lesion, innate immune cells produce chemokines and cytokines that recruit and activate adaptive immune cells (Eizirik D et al.

Immune-mediated β-cell death in type 1 diabetes: lessons from human β-cell lines.

Type 1 diabetes (T1D) is a chronic, multifactorial disorder that results from a contretemps of genetic and environmental factors. Autoimmune attack and functional inhibition of the insulin-producing β cells in the pancreas lead to the inability of β cells to metabolize glucose, and thus results the hallmark clinical symptom of diabetes: abnormally high blood glucose levels. Treatment and protection from T1D require a detailed knowledge of the molecular effectors and the mechanism(s) of cell death leading to β-cell demise.

Role of the mitochondria in immune-mediated apoptotic death of the human pancreatic β cell line βLox5.

Mitochondria are indispensable in the life and death of many types of eukaryotic cells. In pancreatic beta cells, mitochondria play an essential role in the secretion of insulin, a hormone that regulates blood glucose levels. Unregulated blood glucose is a hallmark symptom of diabetes.

Progressive erosion of β-cell function precedes the onset of hyperglycemia in the NOD mouse model of type 1 diabetes.

Objective: A progressive decline in insulin responses to glucose was noted in individuals before the onset of type 1 diabetes. We determined whether such abnormalities occurred in prediabetic NOD mice-the prototypic model for human type 1 diabetes.

Research Design And Methods: Morning blood glucose was measured every other day in a cohort of NOD females.