Tolerance to the Neuron-Specific Paraneoplastic HuD Antigen

Experiments dating back to the 1940's have led to the hypothesis that the brain is an immunologically privileged site, shielding its antigens from immune recognition. The paraneoplastic Hu syndrome provides a powerful paradigm for addressing this hypothesis; it is believed to develop because small cell lung cancers (SCLC) express the neuron-specific Hu protein. This leads to an Hu-specific tumor immune response that can develop into an autoimmune attack against neurons, presumably when immune privilege in the brain is breached. Interestingly, all SCLC express the onconeural HuD antigen, and clinically useful tumor immune responses can be detected in up to 20% of patients, yet the paraneoplastic neurologic syndrome is extremely rare. We found that HuD-specific CD8+ T cells are normally present in the mouse T cell repertoire, but are not expanded upon immunization, although they can be detected after in vitro expansion. In contrast, HuD-specific T cells could be directly activated in HuD null mice, without the need for in vitro expansion. Taken together, these results demonstrate robust tolerance to the neuronal HuD antigen in vivo, and suggest a re-evaluation of the current concept of immune privilege in the brain

Closing in on Asymmetric Dark Matter I: Model independent limits for interactions with quarks

It is argued that experimental constraints on theories of asymmetric dark matter (ADM) almost certainly require that the DM be part of a richer hidden sector of interacting states of comparable mass or lighter. A general requisite of models of ADM is that the vast majority of the symmetric component of the DM number density must be removed in order to explain the observed relationship $\Omega_B\sim\Omega_{DM}$ via the DM asymmetry. Demanding the efficient annihilation of the symmetric component leads to a tension with experimental limits if the annihilation is directly to Standard Model (SM) degrees of freedom. A comprehensive effective operator analysis of the model independent constraints on ADM from direct detection experiments and LHC monojet searches is presented. Notably, the limits obtained essentially exclude models of ADM with mass 1GeV$\lesssim m_{DM} \lesssim$ 100GeV annihilating to SM quarks via heavy mediator states. This motivates the study of portal interactions between the dark and SM sectors mediated by light states. Resonances and threshold effects involving the new light states are shown to be important for determining the exclusion limits.Comment: 18+6 pages, 18 figures. v2: version accepted for publicatio

Immune checkpoint blockade – how does it work in brain metastases?

Immune checkpoints restrain the immune system following its activation and their inhibition unleashes anti-tumor immune responses. Immune checkpoint inhibitors revolutionized the treatment of several cancer types, including melanoma, and immune checkpoint blockade with anti-PD-1 and anti-CTLA-4 antibodies is becoming a frontline therapy in metastatic melanoma. Notably, up to 60% of metastatic melanoma patients develop metastases in the brain. Brain metastases (BrM) are also very common in patients with lung and breast cancer, and occur in ∼20–40% of patients across different cancer types. Metastases in the brain are associated with poor prognosis due to the lack of efficient therapies. In the past, patients with BrM used to be excluded from immune-based clinical trials due to the assumption that such therapies may not work in the context of “immune-specialized” environment in the brain, or may cause harm. However, recent trials in patients with BrM demonstrated safety and intracranial activity of anti-PD-1 and anti-CTLA-4 therapy. We here discuss how immune checkpoint therapy works in BrM, with focus on T cells and the cross-talk between BrM, the immune system, and tumors growing outside the brain. We discuss major open questions in our understanding of what is required for an effective immune checkpoint inhibitor therapy in BrM

Central nervous system lymphatic unit, immunity, and epilepsy : Is there a link?

Summary The recent definition of a network of lymphatic vessels in the meninges surrounding the brain and the spinal cord has advanced our knowledge on the functional anatomy of fluid movement within the central nervous system (CNS). Meningeal lymphatic vessels along dural sinuses and main nerves contribute to cerebrospinal fluid (CSF) drainage, integrating the cerebrovascular and periventricular routes, and forming a circuit that we here define as the CNS-lymphatic unit. The latter unit is important for parenchymal waste clearance, brain homeostasis, and the regulation of immune or inflammatory processes within the brain. Disruption of fluid drain mechanisms may promote or sustain CNS disease, conceivably applicable to epilepsy where extracellular accumulation of macromolecules and metabolic by-products occur in the interstitial and perivascular spaces. Herein we address an emerging concept and propose a theoretical framework on: (a) how a defect of brain clearance of macromolecules could favor neuronal hyperexcitability and seizures, and (b) whether meningeal lymphatic vessel dysfunction contributes to the neuroimmune cross-talk in epileptic pathophysiology. We propose possible molecular interventions targeting meningeal lymphatic dysfunctions, a potential target for immune-mediated epilepsy.Peer reviewe

Income inequality and cardiovascular disease risk factors in a highly unequal country: a fixed-effects analysis from South Africa

Background: Chronic stress associated with high income inequality has been hypothesized to increase CVD risk and other adverse health outcomes. However, most evidence comes from high-income countries, and there is limited evidence on the link between income inequality and biomarkers of chronic stress and risk for CVD. This study examines how changes in income inequality over recent years relate to changes in CVD risk factors in South Africa, home to some of the highest levels of income inequality globally. Methods: We linked longitudinal data from 9356 individuals interviewed in the 2008 and 2012 National Income Dynamics Study to district-level Gini coefficients estimated from census and survey data. We investigated whether subnational district income inequality was associated with several modifiable risk factors for cardiovascular disease (CVD) in South Africa, including body mass index (BMI), waist circumference, blood pressure, physical inactivity, smoking, and high alcohol consumption. We ran individual fixed-effects models to examine the association between changes in income inequality and changes in CVD risk factors over time. Linear models were used for continuous metabolic outcomes while conditional Poisson models were used to estimate risk ratios for dichotomous behavioral outcomes. Results: Both income inequality and prevalence of most CVD risk factors increased over the period of study. In longitudinal fixed-effects models, changes in district Gini coefficients were not significantly associated with changes in CVD risk factors. Conclusions: Our findings do not support the hypothesis that subnational district income inequality is associated with CVD risk factors within the high-inequality setting of South Africa

Circulating Interferon-gamma and White Matter Brain Damage in Preterm Infants.

The fetal inflammatory response has been suggested as causal in neonatal morbidity. Serial levels of circulating cytokines were evaluated in 74 infants with a mean gestational age (GA) of 27.1 wk. Pro-inflammatory and modulatory (IL-4, IL-10) cytokines were analyzed from cord blood, and at 6, 24, and 72 h postnatal age. Measure of cytokine burden over time was assessed by calculating the area under curve (AUC) for analyzed levels (0-72 h). Premature rupture of membranes (PROM) was associated with higher levels of IL-2 at birth and at 6 h, of IFN-gamma at 6 and 24 h postnatal age and of TNF-alpha at 6 and 24 h. Levels of IFN-gamma at 6, 24, and 72 It were increased in infants developing white matter brain damage (WMD) compared with those without WMD. Infants with arterial hypotension requiring dopamine treatment had an increase in IL-6 with a peak at 6 It of age. Severe intraventricular hemorrhage (IVH) was associated with increase in AUC, whereas WMD was associated with increase in AUC. A fetal immune response with increased postnatal levels of IFN-gamma was associated with development of WMD. PROM was associated with a T-helper I cytokine response with increased levels of IFN-gamma. Type of inflammatory response appears of importance for subsequent morbidity