Intrastriatal injection of interleukin-1 beta triggers the formation of neuromyelitis optica-like lesions in NMO-IgG seropositive rats

BACKGROUND: Neuromyelitis optica (NMO) is a severe, disabling disease of the central nervous system (CNS) characterized by the formation of astrocyte-destructive, neutrophil-dominated inflammatory lesions in the spinal cord and optic nerves. These lesions are initiated by the binding of pathogenic aquaporin 4 (AQP4)-specific autoantibodies to astrocytes and subsequent complement-mediated lysis of these cells. Typically, these lesions form in a setting of CNS inflammation, where the blood–brain barrier is open for the entry of antibodies and complement. However, it remained unclear to which extent pro-inflammatory cytokines and chemokines contribute to the formation of NMO lesions. To specifically address this question, we injected the cytokines interleukin-1 beta, tumor necrosis factor alpha, interleukin-6, interferon gamma and the chemokine CXCL2 into the striatum of NMO-IgG seropositive rats and analyzed the tissue 24 hours later by immunohistochemistry. RESULTS: All injected cytokines and chemokines led to profound leakage of immunoglobulins into the injected hemisphere, but only interleukin-1 beta induced the formation of perivascular, neutrophil-infiltrated lesions with AQP4 loss and complement-mediated astrocyte destruction distant from the needle tract. Treatment of rat brain endothelial cells with interleukin-1 beta, but not with any other cytokine or chemokine applied at the same concentration and over the same period of time, caused profound upregulation of granulocyte-recruiting and supporting molecules. Injection of interleukin-1 beta caused higher numbers of blood vessels with perivascular, cellular C1q reactivity than any other cytokine tested. Finally, the screening of a large sample of CNS lesions from NMO and multiple sclerosis patients revealed large numbers of interleukin-1 beta-reactive macrophages/activated microglial cells in active NMO lesions but not in MS lesions with comparable lesion activity and location. CONCLUSIONS: Our data strongly suggest that interleukin-1 beta released in NMO lesions and interleukin-1 beta-induced production/accumulation of complement factors (like C1q) facilitate neutrophil entry and BBB breakdown in the vicinity of NMO lesions, and might thus be an important secondary factor for lesion formation, possibly by paving the ground for rapid lesion growth and amplified immune cell recruitment to this site

Distinct Stromal Cell Factor Combinations Can Separately Control Hematopoietic Stem Cell Survival, Proliferation, and Self-Renewal

SummaryHematopoietic stem cells (HSCs) are identified by their ability to sustain prolonged blood cell production in vivo, although recent evidence suggests that durable self-renewal (DSR) is shared by HSC subtypes with distinct self-perpetuating differentiation programs. Net expansions of DSR-HSCs occur in vivo, but molecularly defined conditions that support similar responses in vitro are lacking. We hypothesized that this might require a combination of factors that differentially promote HSC viability, proliferation, and self-renewal. We now demonstrate that HSC survival and maintenance of DSR potential are variably supported by different Steel factor (SF)-containing cocktails with similar HSC-mitogenic activities. In addition, stromal cells produce other factors, including nerve growth factor and collagen 1, that can antagonize the apoptosis of initially quiescent adult HSCs and, in combination with SF and interleukin-11, produce >15-fold net expansions of DSR-HSCs ex vivo within 7 days. These findings point to the molecular basis of HSC control and expansion

Psychological Well-Being of Parents of Very Young Children With Type 1 Diabetes – Baseline Assessment

Background: Type 1 diabetes in young children is a heavy parental burden. As part of pilot phase of the KIDSAP01 study, we conducted a baseline assessment in parents to study the association between hypoglycemia fear, parental well-being and child behavior. Methods: All parents were invited to fill in baseline questionnaires: hypoglycemia fear survey (HFS), WHO-5, Epworth Sleepiness Scale and Strength and Difficulties Questionnaire (SDQ). Results: 24 children (median age: 5-year, range 1-7 years, 63% male, mean diabetes duration: 3 ± 1.7 years) participated. 23/24 parents filled out the questionnaires. We found a higher score for the hypoglycemia fear behavior 33.9 ± 5.6 compared to hypoglycemia worry 34.6 ± 12.2. Median WHO-5 score was 16 (8 - 22) with poor well-being in two parents. Median daytime sleepiness score was high in five parents (>10). For six children a high total behavioral difficulty score (>16) was reported. Pro social behavior score was lower than normal in six children (<6). Parental well-being was negatively associated with HFS total (r = - 0.50, p <.05) and subscale scores (r = - 0.44, p <.05 for HFS-Worry and HFS-Behavior), child behavior (r = - 0.45, p = .05) and positively with child age and diabetes duration (r = 0.58, p <.01, r = 0.6, p <.01). HFS, parental well-being nor daytime sleepiness are associated with the HbA1c. Conclusion: Regular screening of parental well-being, hypoglycemia fear and child behavior should be part of routine care to target early intervention

Psychological Well-Being of Parents of Very Young Children With Type 1 Diabetes – Baseline Assessment

Background: Type 1 diabetes in young children is a heavy parental burden. As part of pilot phase of the KIDSAP01 study, we conducted a baseline assessment in parents to study the association between hypoglycemia fear, parental well-being and child behavior. Methods: All parents were invited to fill in baseline questionnaires: hypoglycemia fear survey (HFS), WHO-5, Epworth Sleepiness Scale and Strength and Difficulties Questionnaire (SDQ). Results: 24 children (median age: 5-year, range 1-7 years, 63% male, mean diabetes duration: 3 ± 1.7 years) participated. 23/24 parents filled out the questionnaires. We found a higher score for the hypoglycemia fear behavior 33.9 ± 5.6 compared to hypoglycemia worry 34.6 ± 12.2. Median WHO-5 score was 16 (8 - 22) with poor well-being in two parents. Median daytime sleepiness score was high in five parents (>10). For six children a high total behavioral difficulty score (>16) was reported. Pro social behavior score was lower than normal in six children (<6). Parental well-being was negatively associated with HFS total (r = - 0.50, p <.05) and subscale scores (r = - 0.44, p <.05 for HFS-Worry and HFS-Behavior), child behavior (r = - 0.45, p = .05) and positively with child age and diabetes duration (r = 0.58, p <.01, r = 0.6, p <.01). HFS, parental well-being nor daytime sleepiness are associated with the HbA1c. Conclusion: Regular screening of parental well-being, hypoglycemia fear and child behavior should be part of routine care to target early intervention

Crop pests and predators exhibit inconsistent responses to surrounding landscape composition

The idea that noncrop habitat enhances pest control and represents a win–win opportunity to conserve biodiversity and bolster yields has emerged as an agroecological paradigm. However, while noncrop habitat in landscapes surrounding farms sometimes benefits pest predators, natural enemy responses remain heterogeneous across studies and effects on pests are inconclusive. The observed heterogeneity in species responses to noncrop habitat may be biological in origin or could result from variation in how habitat and biocontrol are measured. Here, we use a pest-control database encompassing 132 studies and 6,759 sites worldwide to model natural enemy and pest abundances, predation rates, and crop damage as a function of landscape composition. Our results showed that although landscape composition explained significant variation within studies, pest and enemy abundances, predation rates, crop damage, and yields each exhibited different responses across studies, sometimes increasing and sometimes decreasing in landscapes with more noncrop habitat but overall showing no consistent trend. Thus, models that used landscape-composition variables to predict pest-control dynamics demonstrated little potential to explain variation across studies, though prediction did improve when comparing studies with similar crop and landscape features. Overall, our work shows that surrounding noncrop habitat does not consistently improve pest management, meaning habitat conservation may bolster production in some systems and depress yields in others. Future efforts to develop tools that inform farmers when habitat conservation truly represents a win–win would benefit from increased understanding of how landscape effects are modulated by local farm management and the biology of pests and their enemies

Persistence of foodborne pathogens and their control in primary and secondary food production chains

International audienc

Antibody production using a ciliate generates unusual antibody glycoforms displaying enhanced cell-killing activity

Antibody glycosylation is a key parameter in the optimization of antibody therapeutics. Here, we describe the production of the anti-cancer monoclonal antibody rituximab in the unicellular ciliate, Tetrahymena thermophila. The resulting antibody demonstrated enhanced antibody-dependent cell-mediated cytotoxicity, which we attribute to unusual N-linked glycosylation. Detailed chromatographic and mass spectrometric analysis revealed afucosylated, oligomannose-type glycans, which, as a whole, displayed isomeric structures that deviate from the typical human counterparts, but whose branches were equivalent to fragments of metabolic intermediates observed in human glycoproteins. From the analysis of deposited crystal structures, we predict that the ciliate glycans adopt protein-carbohydrate interactions with the Fc domain that closely mimic those of native complex-type glycans. In addition, terminal glucose structures were identified that match biosynthetic precursors of human glycosylation. Our results suggest that ciliate-based expression systems offer a route to large-scale production of monoclonal antibodies exhibiting glycosylation that imparts enhanced cell killing activity.</p

Highly encephalitogenic aquaporin 4-specific T cells and NMO-IgG jointly orchestrate lesion location and tissue damage in the CNS

In neuromyelitis optica (NMO), astrocytes become targets for pathogenic aquaporin 4 (AQP4)-specific antibodies which gain access to the central nervous system (CNS) in the course of inflammatory processes. Since these antibodies belong to a T cell-dependent subgroup of immunoglobulins, and since NMO lesions contain activated CD4+ T cells, the question arose whether AQP4-specific T cells might not only provide T cell help for antibody production, but also play an important role in the induction of NMO lesions. We show here that highly pathogenic, AQP4-peptide-specific T cells exist in Lewis rats, which recognize AQP4268285 as their specific antigen and cause severe panencephalitis. These T cells are re-activated behind the bloodbrain barrier and deeply infiltrate the CNS parenchyma of the optic nerves, the brain, and the spinal cord, while T cells with other AQP4-peptide specificities are essentially confined to the meninges. Although AQP4268285-specific T cells are found throughout the entire neuraxis, they have NMO-typical “hotspots” for infiltration, i.e. periventricular and periaqueductal regions, hypothalamus, medulla, the dorsal horns of spinal cord, and the optic nerves. Most remarkably, together with NMO-IgG, they initiate large astrocyte-destructive lesions which are located predominantly in spinal cord gray matter. We conclude that the processing of AQP4 by antigen presenting cells in Lewis rats produces a highly encephalitogenic AQP4 epitope (AQP4268285), that T cells specific for this epitope are found in the immune repertoire of normal Lewis rats and can be readily expanded, and that AQP4268285-specific T cells produce NMO-like lesions in the presence of NMO-IgG.(VLID)484311