Pathogenic T cell responses against aquaporin 4

Inflammatory lesions in the central nervous system of patients with neuromyelitis optica are characterized by infiltration of T cells and deposition of aquaporin-4-specific antibodies and complement on astrocytes at the glia limitans. Although the contribution of aquaporin-4-specific autoantibodies to the disease process has been recently elucidated, a potential role of aquaporin-4-specific T cells in lesion formation is unresolved. To address this issue, we raised aquaporin-4-specific T cell lines in Lewis rats and characterized their pathogenic potential in the presence and absence of aquaporin-4-specific autoantibodies of neuromyelitis optica patients. We show that aquaporin-4-specific T cells induce brain inflammation with particular targeting of the astrocytic glia limitans and permit the entry of pathogenic anti-aquaporin-4-specific antibodies to induce NMO-like lesions in spinal cord and brain. In addition, transfer of aquaporin-4-specific T cells provoked mild (subclinical) myositis and interstitial nephritis. We further show that the expression of the conformational epitope, recognized by NMO patient-derived aquaporin-4-specific antibodies is induced in kidney cells by the pro-inflammatory cytokine gamma-interferon. Our data provide further support for the view that NMO lesions may be induced by a complex interplay of T cell mediated and humoral immune responses against aquaporin-4.     

Die Implantation der lumbalen Bandscheibenprothese vom Typ ProDisc®

OBJECTIVE: To eradicate treatment-resistant lower back pain caused by painful degeneration of the intervertebral disks. To avoid the disadvantages of alternative fusion surgery, especially degenerative wear and tear on adjacent segments, by maintaining the mobility of the affected motion segments. INDICATIONS: Treatment-resistant lower back pain due to painful degeneration of the intervertebral disks ("degenerative disk disease"). CONTRAINDICATIONS: Spondylolisthesis, scoliosis, osteoporosis, infection, spinal stenosis, degeneration of the vertebral articulations. SURGICAL TECHNIQUE: The intervertebral disk is excised through an anterior approach. It is essential to retain good mobility of the motion segment, if necessary, by resection of the posterior longitudinal ligament. After revitalization of the vertebral base and cover plates and chiseling of a groove for the keel of the prosthesis, the upper and lower prosthetic plates are inserted and the polyethylene inlay is locked into place. RESULTS: From April 2002 to May 2004, 36 ProDisc (Synthes Spine, West Chester, PA, USA) modular intervertebral disk prostheses were implanted in 34 patients (26 women, eight men, average age 44.3 years). Clinical evaluation was based on the visual analog scale (VAS), the Oswestry Disability Index (ODI), and the SF-36 Questionnaire. Follow-up assessment also included radiographic views of the lumbar spine in two planes in flexion and extension and standing. The follow-up interval for all patients was at least 1 year and 2 years for 14 patients. 26 patients were very satisfied with the operation, five patients were satisfied, and three patients were less satisfied. The clinical parameters recorded on the VAS, ODI and SF-36 improved from 7.4 to 2.8 (VAS), 48.0 to 13.1 (ODI) and 31.3 to 44.2 (SF-36, Physical Component Summary Score) from the time of the preoperative assessment to the 1-year follow-up. The range of motion at the segment with the implanted prosthesis was 10 degrees on average at L4/5 and 7 degrees on average at L5/S1 1 year postoperatively.     

von Willebrand factor in CHD and stroke: Relationships and therapeutic implications

Opinion statement Atherosclerotic cardiovascular disease (CVD), which includes coronary heart disease (CHD) and stroke, is now the most common cause of death in the middle aged and elderly in all parts of the world except subSaharan Africa. The direct cause of death is frequently an acute thrombotic arterial occlusion. Because atherosclerosis is a diffuse disease, patients with CHD also have a high risk of ischemic stroke. The hemostatic process is a needed defense mechanism to control hemorrhage after injury but at same time, if overactive, may have the potential to precipitate diseases such as myocardial infarction or stroke in the setting of atherosclerosis. In approximately 1% of all patients with ischemic stroke, and in up to 4% of young adults with stroke, the major precipitant of brain ischemia is a hematologic disorder or coagulopathy that predisposes to thrombosis. von Willebrand factor (vWF) plays an important role in platelet adhesion to subendothelial structures and in the intrinsic pathway of coagulation. It is regarded as an indirect measure of endothelial dysfunction. Deficiency of vWF in von Willebrand’s disease is well established. However, much less is known regarding the pathophysiologic implications of an elevated level of vWF, particularly in relation to CVD and cerebrovascular disease. The importance of vWF in the pathogenesis of this disease is poorly defined and information is limited and inconsistent. Elevated levels of vWF have been variably linked with risk of CHD; causal criteria are not fully met. Relationships with stroke risk are even less well established. Measurement of vWF adds little to risk prediction after considering the major risk factors—age, sex, smoking, raised blood cholesterol, and hypertension. vWF may have a greater role in predicting outcome in subjects with acute coronary syndromes (ACS), stroke, and perhaps atrial fibrillation. Investigation of the use of vWF level to guide treatment of ACS or stroke is ongoing; however, there is no compelling evidence to date.     

Role of axonal NaV1.6 sodium channels in action potential initiation of CA1 pyramidal neurons

In many neuron types, the axon initial segment (AIS) has the lowest threshold for action potential generation. Its active properties are determined by the targeted expression of specific voltage-gated channel subunits. We show that the Na⁺ channel Na_V1.6 displays a striking aggregation at the AIS of cortical neurons. To assess the functional role of this subunit, we used Scn8a^med mice that are deficient for Na_V1.6 subunits but still display prominent Na⁺ channel aggregation at the AIS. In CA1 pyramidal cells from Scn8a^med mice, we found a depolarizing shift in the voltage dependence of activation of the transient Na⁺ current (I_NaT), indicating that Na_V1.6 subunits activate at more negative voltages than other Na_V subunits. Additionally, persistent and resurgent Na⁺ currents were significantly reduced. Current-clamp recordings revealed a significant elevation of spike threshold in Scn8a^med mice as well as a shortening of the estimated delay between spike initiation at the AIS and its arrival at the soma. In combination with simulations using a realistic computer model of a CA1 pyramidal cell, our results imply that a hyperpolarized voltage dependence of activation of AIS Na_V1.6 channels is important both in determining spike threshold and localizing spike initiation to the AIS. In addition to altered spike initiation, Scn8a^med mice also showed a strongly reduced spike gain as expected with combined changes in persistent and resurgent currents and spike threshold. These results suggest that Na_V1.6 subunits at the AIS contribute significantly to its role as spike trigger zone and shape repetitive discharge properties of CA1 neurons.     

Eosinophil recruitment to nasal nerves after allergen challenge in allergic rhinitis

In allergen challenged animal models, eosinophils localize to airway nerves leading to vagally-mediated hyperreactivity. We hypothesized that in allergic rhinitis eosinophils recruited to nasal nerves resulted in neural hyperreactivity. Patients with persistent allergic rhinitis (n = 12), seasonal allergic rhinitis (n = 7) and controls (n = 10) were studied. Inferior nasal turbinate biopsies were obtained before, 8 and 48 h after allergen challenge. Eight hours after allergen challenge eosinophils localized to nerves in both rhinitis groups; this was sustained through 48 h. Bradykinin challenge, with secretion collection on the contralateral side, was performed to demonstrate nasal nerve reflexes. Twenty four hours after allergen challenge, bradykinin induced a significant increase in secretions, indicating nasal hyperreactivity. Histological studies showed that nasal nerves expressed both vascular cell adhesion molecule-1 (VCAM-1) and chemokine (C-C motif) ligand 26 (CCL-26). Hence, after allergen challenge eosinophils are recruited and retained at nerves and so may be a mechanism for neural hyperreactivity.     

The efficacy of intracranial PLG-based vaccines is dependent on direct implantation into brain tissue

We previously engineered a macroporous, polymer-based vaccine that initially produces GM-CSF gradients to recruit local dendritic cells and subsequently presents CpG oligonucleotides, and tumor lysate to cell infiltrates to induce immune cell activation and immunity against tumor cells in peripheral tumor models. Here, we demonstrate that this system eradicates established intracranial glioma following implantation into brain tissue, whereas implantation in resection cavities obviates vaccine efficacy. Rats bearing seven-day old, intracranial glioma tumors were treated with PLG vaccines implanted into the tumor bed, resulting in retention of contralateral forelimb function (day 17) that is compromised by tumor formation in control animals, and 90% long-term survival (> 100 days). Similar benefits were observed in animals receiving tumor resection plus vaccine implants into the adjacent parenchyma, but direct implantation of PLG vaccines into the resection cavity conferred no benefit. This dissociation of efficacy was likely related to GM-CSF distribution, as implantation of PLG vaccines within brain tissue produced significant GM-CSF gradients for prolonged periods, which was not detected after implantation in resection cavities. These studies demonstrate that PLG vaccine efficacy is correlated to GM-CSF gradient formation, which requires direct implantation into brain tissue, and justify further exploration of this approach for glioma treatment.