David A. Giles

Neutrophil-related factors as biomarkers in EAE and MS

Using a mouse model of multiple sclerosis (MS), the authors show that neutrophils expand in the bone marrow and accumulate in the circulation before clinical onset of disease. Early in disease development, neutrophils infiltrate the CNS, which is suppressed by G-CSF receptor deficiency and blockade of CXCL1 to ameliorate disease. In patients with MS, systemic expression of neutrophil-related mediators correlates with new lesion formation, lesion burden, and clinical disability.

IL-12-polarized Th1 cells produce GM-CSF and induce EAE independent of IL-23

CD4+ T‐helper (Th) cells reactive against myelin antigens mediate the mouse model experimental autoimmune encephalomyelitis (EAE) and have been implicated in the pathogenesis of multiple sclerosis (MS). It is currently debated whether encephalitogenic Th cells are heterogeneous or arise from a single lineage. In the current study, we challenge the dogma that stimulation with the monokine IL‐23 is universally required for the acquisition of pathogenic properties by myelin‐reactive T cells. We show that IL‐12‐modulated Th1 cells readily produce IFN‐γ and GM‐CSF in the CNS of mice and induce a severe form of EAE via an IL‐23‐independent pathway. Th1‐mediated EAE is characterized by monocyte‐rich CNS infiltrates, elicits a strong proinflammatory cytokine response in the CNS, and is partially CCR2 dependent. Conversely, IL‐23‐modulated, stable Th17 cells induce EAE with a relatively mild course via an IL‐12‐independent pathway. These data provide definitive evidence that autoimmune disease can be driven by distinct CD4+ T‐helper‐cell subsets and polarizing factors.

Intraventricular hemorrhage is associated with early hydrocephalus, symptomatic vasospasm, and poor outcome in aneurysmal subarachnoid hemorrhage.

OBJECTIVE We hypothesized that the subset of patients with early hydrocephalus following aneurysmal subarachnoid hemorrhage may represent a subset of patients with a more vehement inflammatory reaction to blood products in the subarachnoid space. We thus examined risk factors for early hydrocephalus and examined the relationship between early hydrocephalus and symptomatic vasospasm as well as clinical outcome. METHODS We retrospectively analyzed all patients presenting to our institution with subarachnoid hemorrhage over a 7-year period. We examined for risk factors, including early hydrocephalus, for poor clinical outcome and symptomatic vasospasm. RESULTS We found intraventricular hemorrhage to be strongly associated with the development of early hydrocephalus. In univariate analysis, early hydrocephalus was strongly associated with both poor functional outcome and symptomatic vasospasm. In multivariate analysis, intraventricular hemorrhage and tobacco use were associated with symptomatic vasospasm; intraventricular hemorrhage, intraparenchymal hemorrhage, and symptomatic vasospasm were associated with poor functional outcome. CONCLUSIONS We found that intraventricular hemorrhage was strongly associated with early hydrocephalus. Further exploration of the mechanistic explanation is needed, but we suggest this may be from a combination of obstruction of cerebrospinal fluid pathways by blood products and inflammation in the choroid plexus resulting in increased cerebrospinal fluid production. Further, we suggest that both early hydrocephalus and cerebral vasospasm may be parts of the overall inflammatory cascade that occurs with intraventricular hemorrhage and ultimately results in a poorer clinical outcome.

An emerging role for eotaxins in neurodegenerative disease.

Eotaxins are C-C motif chemokines first identified as potent eosinophil chemoattractants. They facilitate eosinophil recruitment to sites of inflammation in response to parasitic infections as well as allergic and autoimmune diseases such as asthma, atopic dermatitis, and inflammatory bowel disease. The eotaxin family currently includes three members: eotaxin-1 (CCL11), eotaxin-2 (CCL24), and eotaxin-3 (CCL26). Despite having only ~30% sequence homology to one another, each was identified based on its ability to bind the chemokine receptor, CCR3. Beyond their role in innate immunity, recent studies have shown that CCL11 and related molecules may directly contribute to degenerative processes in the central nervous system (CNS). CCL11 levels increase in the plasma and cerebrospinal fluid of both mice and humans as part of normal aging. In mice, these increases are associated with declining neurogenesis and impaired cognition and memory. In humans, elevated plasma levels of CCL11 have been observed in Alzheimers disease, amyotrophic lateral sclerosis, Huntingtons disease, and secondary progressive multiple sclerosis when compared to age-matched, healthy controls. Since CCL11 is capable of crossing the blood-brain barrier of normal mice, it is plausible that eotaxins generated in the periphery may exert physiological and pathological actions in the CNS. Here, we briefly review known functions of eotaxin family members during innate immunity, and then focus on whether and how these molecules might participate in the progression of neurodegenerative diseases.

Endovascular treatment for aneurysmal subarachnoid hemorrhage in the ninth decade of life and beyond

Objective As the population ages, clinicians will be faced with difficult decisions regarding treatment of elderly patients presenting with aneurysmal subarachnoid hemorrhage (aSAH). Previous data have led to continued pessimism by some clinicians treating elderly and very elderly patients presenting with aSAH. The aim of this study was to present our experience in the very elderly treated with endovascular coiling after presentation with aSAH. Methods Retrospective review of all patients 80 years of age or older presenting with aSAH who underwent coil embolization. Primary outcomes of interest were functional outcome, as assessed by the Glasgow Outcome Scale score, and inhospital mortality. Results During the study period, 16 patients aged 80 years or older presenting with aSAH underwent coil embolization; nine (56%) had a poor outcome at the 6 month follow-up while seven (44%) had a good outcome. The inhospital mortality rate was 50%. Of those patients alive at discharge, seven out of eight (88%) patients had a good outcome. Variables associated with poor outcome included higher Hunt and Hess score (p=0.010), use of balloon assistance/remodeling (p=0.025), and presence of coronary artery disease (p=0.006). Conclusions Not surprisingly, we found that very elderly patients presenting with aSAH have a high inhospital mortality rate. However, those patients who survive to discharge have a surprisingly robust chance at good functional recovery when treated with coil embolization. We believe these results support offering endovascular coil embolization, when feasible, to very elderly patients presenting with aSAH.

Myeloid cell plasticity in the evolution of central nervous system autoimmunity

Myeloid cells, including macrophages and dendritic cells, are a prominent component of central nervous system (CNS) infiltrates during multiple sclerosis (MS) and the animal model experimental autoimmune encephalomyelitis (EAE). Although myeloid cells are generally thought to be proinflammatory, alternatively polarized subsets can serve noninflammatory and/or reparative functions. Here we investigate the heterogeneity and biological properties of myeloid cells during central nervous system autoimmunity.

Management of recurrent aneurysms following endovascular therapy

The aim of the current study is to describe the complication rates and clinical outcomes in patients who either underwent repeat intervention or conservative management with radiographic surveillance when presenting with aneurysmal recurrence after endovascular treatment. Since publication of the international subarachnoid aneurysm trial (ISAT), an increasing number of patients are treated with endovascular therapy. However, recurrence after endovascular therapy continues to pose a challenge, and there is minimal evidence to guide its management. We performed a retrospective review of all patients who underwent endovascular treatment of an intracranial aneurysm from January 2005 to February 2013. The patients who had an aneurysmal recurrence following the initial endovascular treatment were identified and divided into two groups: those followed with conservative management (n=24), and those who underwent reintervention (n=65). The groups were compared for complications and clinical outcomes. When a reintervention was undertaken, microsurgical clip ligation was associated with a higher rate of occlusion than additional endovascular therapy (p<0.001). When comparing conservative treatment and reintervention, there was no statistically significant difference in complications or clinical outcomes. Reintervention was more common in patients who were younger, had presented with subarachnoid hemorrhage, or had a greater degree of recurrence. We conclude that clinical outcomes and repeat subarachnoid hemorrhage are similar in patients who underwent retreatment versus those who had conservative management for their recurrent cerebral aneurysms.

An IFNγ/CXCL2 regulatory pathway determines lesion localization during EAE

BackgroundMyelin oligodendrocyte glycoprotein (MOG)-reactive T-helper (Th)1 cells induce conventional experimental autoimmune encephalomyelitis (cEAE), characterized by ascending paralysis and monocyte-predominant spinal cord infiltrates, in C57BL/6 wildtype (WT) hosts. The same T cells induce an atypical form of EAE (aEAE), characterized by ataxia and neutrophil-predominant brainstem infiltrates, in syngeneic IFNγ receptor (IFNγR)-deficient hosts. Production of ELR+ CXC chemokines within the CNS is required for the development of aEAE, but not cEAE. The cellular source(s) and localization of ELR+ CXC chemokines in the CNS and the IFNγ-dependent pathways that regulate their production remain to be elucidated.MethodsThe spatial distribution of inflammatory lesions and CNS expression of the ELR+ CXC chemokines, CXCL1 and CXCL2, were determined via immunohistochemistry and/or in situ hybridization. Levels of CXCL1 and CXCL2, and their cognate receptor CXCR2, were measured in/on leukocyte subsets by flow cytometric and quantitative PCR (qPCR) analysis. Bone marrow neutrophils and macrophages were cultured with inflammatory stimuli in vitro prior to measurement of CXCL2 and CXCR2 by qPCR or flow cytometry.ResultsCNS-infiltrating neutrophils and monocytes, and resident microglia, are a prominent source of CXCL2 in the brainstem of IFNγRKO adoptive transfer recipients during aEAE. In WT transfer recipients, IFNγ directly suppresses CXCL2 transcription in microglia and myeloid cells, and CXCR2 transcription in CNS-infiltrating neutrophils. Consequently, infiltration of the brainstem parenchyma from the adjacent meninges is blocked during cEAE. CXCL2 directly stimulates its own expression in cultured neutrophils, which is enhanced by IL-1 and suppressed by IFNγ.ConclusionsWe provide evidence for an IFNγ-regulated CXCR2/CXCL2 autocrine/paracrine feedback loop in innate immune cells that determines the location of CNS infiltrates during Th1-mediated EAE. When IFNγ signaling is impaired, myeloid cell production of CXCL2 increases, which promotes brainstem inflammation and results in clinical ataxia. IFNγ, produced within the CNS of WT recipients, suppresses myeloid cell CXCR2 and CXCL2 production, thereby skewing the location of neuroinflammatory infiltrates to the spinal cord and the clinical phenotype to an ascending paralysis. These data reveal a novel mechanism by which IFNγ and CXCL2 interact to direct regional recruitment of leukocytes in the CNS, resulting in distinct clinical presentations.

CNS resident classical DCs play a critical role in CNS autoimmune disease

Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disease of the central nervous system (CNS), induced by the adoptive transfer of myelin-reactive CD4+ T cells into naive syngeneic mice. It is widely used as a rodent model of multiple sclerosis (MS). The development of EAE lesions is initiated when transferred CD4+ T cells access the CNS and are reactivated by local antigen-presenting cells (APCs) bearing endogenous myelin peptide/MHC class II complexes. The identity of the CNS-resident, lesion-initiating APCs is widely debated. Here we demonstrate that classical dendritic cells (cDCs) normally reside in the meninges, brain, and spinal cord in the steady state. These cells are unique among candidate CNS APCs in their ability to stimulate naive, as well as effector, myelin-specific T cells to proliferate and produce proinflammatory cytokines directly ex vivo. cDCs expanded in the meninges and CNS parenchyma in association with disease progression. Selective depletion of cDCs led to a decrease in the number of myelin-primed donor T cells in the CNS and reduced the incidence of clinical EAE by half. Based on our findings, we propose that cDCs, and the factors that regulate them, be further investigated as potential therapeutic targets in MS.