Hans Hartung

Activation of macrophages by substance P: Induction of oxidative burst and thromboxane release

Substance P (SP), a putative neuropeptide transmitter, was examined for its effects on macrophages. Guinea-pig peritoneal macrophages were purified by adherence, challenged with SP and incubated for up to 18 h. Culture supernatants were collected to determine the release of O-2, H2O2 and TXB2. SP dose-dependently evoked O-2 and H2O2 production by C. parvum-activated macrophages and liberation of TXB2 from albumin-elicited macrophages. Generation of these proinflammatory macrophage products by SP may be relevant in the context of neuroinflammatory disease.

Alexithymia and impaired facial affect recognition in multiple sclerosis

Despite the high relevance of emotion processing for social functioning, the study of the impairment of facial affect in multiple sclerosis (MS) has received little attention. Previous research reported evidence for emotion processing deficits but the nature and extent are not fully explained. Thirty-five MS patients underwent dedicated neuropsychological assessment of emotion processing using two facial affect recognition tasks and self-report measures of alexithymia. For comparison, healthy participants served as controls. Relative to healthy controls, MS patients were impaired in facial affect recognition on four of the six Ekman basic emotions, except happiness and disgust. The MS patients were more alexithymic than the healthy controls. These data provide evidence for deficits in the recognition of emotional face expressions and emotional introspection.

Multiple paraneoplastic syndromes in a patient with antibodies to neuronal nucleoproteins (anti-Hu)

We report the clinical and autopsy studies of a patient with an unusual combination of multiple paraneoplastic neurological syndromes in association with antibodies to a 35–40 kDa neuronal nucleoprotein (anti-Hu). Neurological disease preceded the detection of a small cell carcinoma of the lung. The patient had combined sensory and motor neuronopathy or neuropathy, cerebellar degeneration, brain-stem and limbic encephalitis, and clinical evidence of the Lambert-Eaton myasthenic syndrome and gastrointestinal pseudo-obstruction of paraneoplastic origin.

Dimethyl fumarate in relapsing–remitting multiple sclerosis: rationale, mechanisms of action, pharmacokinetics, efficacy and safety

Dimethyl fumarate (DMF), a fumaric acid ester, is a new orally available disease-modifying agent that was recently approved by the US FDA and the EMA for the management of relapsing forms of multiple sclerosis (MS). Fumaric acid has been used for the management of psoriasis, for more than 50 years. Because of the known anti-inflammatory properties of fumaric acid ester, DMF was brought into clinical development in MS. More recently, neuroprotective and myelin-protective mechanism actions have been proposed, making it a possible candidate for MS treatment. Two Phase III clinical trials (DEFINE, CONFIRM) have evaluated the safety and efficacy of DMF in patients with relapsing–remitting MS. Being an orally available agent with a favorable safety profile, it has become one of the most commonly prescribed disease-modifying agents in the USA and Europe.

Dual roles of the adenosine A2a receptor in autoimmune neuroinflammation

BackgroundConditions of inflammatory tissue distress are associated with high extracellular levels of adenosine, due to increased adenosine triphosphate (ATP) degradation upon cellular stress or the release of extracellular ATP upon cell death, which can be degraded to adenosine by membrane-bound ecto-enzymes like CD39 and CD73. Adenosine is recognised to mediate anti-inflammatory effects via the adenosine A2a receptor (A2aR), as shown in experimental models of arthritis. Here, using pharmacological interventions and genetic inactivation, we investigated the roles of A2aR in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS).MethodsWe used two independent mouse EAE variants, i.e. active immunization in C57BL/6 with myelin oligodendrocyte glycoprotein (MOG)35-55 or transfer-EAE by proteolipid protein (PLP)139-155-stimulated T lymphocytes and EAE in mice treated with A2aR-agonist CGS21680 at different stages of disease course and in mice lacking A2aR (A2aR−/−) compared to direct wild-type littermates. In EAE, we analysed myelin-specific proliferation and cytokine synthesis ex vivo, as well as inflammation and demyelination by immunohistochemistry. In vitro, we investigated the effect of A2aR on migration of CD4+ T cells, macrophages and microglia, as well as the impact of A2aR on phagocytosis of macrophages and microglia. Statistical tests were Mann-Whitney U and Student’s t test.ResultsWe found an upregulation of A2aR in the central nervous system (CNS) in EAE, predominantly detected on T cells and macrophages/microglia within the inflamed tissue. Preventive EAE treatment with A2aR-specific agonist inhibited myelin-specific T cell proliferation ex vivo and ameliorated disease, while application of the same agonist after disease onset exacerbated non-remitting EAE progression and resulted in more severe tissue destruction. Accordingly, A2aR-deficient mice showed accelerated and exacerbated disease manifestation with increased frequencies of IFN-γ-, IL-17- and GM-CSF-producing CD4+ T helper cells and higher numbers of inflammatory lesions in the early stage. However, EAE quickly ameliorated and myelin debris accumulation was lower in A2aR−/− mice. In vitro, activation of A2aR inhibited phagocytosis of myelin by macrophages and primary microglia as well as migration of CD4+ T cells, macrophages and primary microglia.ConclusionsA2aR activation exerts a complex pattern in chronic autoimmune neurodegeneration: while providing anti-inflammatory effects on T cells and thus protection at early stages, A2aR seems to play a detrimental role during later stages of disease and may thus contribute to sustained tissue damage within the inflamed CNS.

Molecular mechanism underlying the impact of vitamin D on disease activity of MS

Some previous studies suggest modest to strong effects of 25‐hydroxyvitamin D (25(OH)D) on multiple sclerosis (MS) activity. The objective of this study was to explore the mechanistic rationale that may explain potential clinical effects of 25(OH)D.

A patient with a benign course of neuromyelitis optica (Devic's syndrome) over 12 years: MRI follow up and histological findings.

Sirs: Neuromyelitis optica (NMO) was originally defined as a monophasic disease with simultaneously appearing unilateral or bilateral optic neuritis and severe transverse myelitis causing blindness and paraplegia. Disease onset with either optic neuritis or myelitis suggested that NMO may represent a variant of multiple sclerosis although diagnostic and immunological features with respect to MRI [4] and CSF analysis [2, 8, 12] as well as autoantibody reactivity [7] differ between the two conditions [3, 6]. Recent evidence suggests a broader spectrum of the clinical course in NMO. Accordingly, published diagnostic criteria include recurrent or monophasic optic neuritis and myelitis and absence of disease activity outside the optic nerve and spinal cord [10, 11]. The female patient reported here developed unilateral optic neuritis at the age of 24 years. Six years later she was admitted to a foreign hospital with a marked paraparesis and a complete loss of bladder function. MRI of the spinal cord revealed a marked swelling with gadolinium enhancement on T1 (Fig. 1A). CSF examination showed no abnormalities, i. e. no elevation of intrathecal IgG synthesis and no oligoclonal bands. She was put on steroids which resulted only in very poor recovery over the next few weeks. A second MRI four weeks later showed persistent swelling of the spinal cord suggestive of a low grade tumour. Therefore, spinal cord biopsy was undertaken which, however, revealed the histopathological findings of a subacute myelitis (Fig. 2). The patient recovered nearly completely from her myelitis during the following months. In the following years unilateral optic neuritis appeared repeatedly for 6 times affecting both eyes. So far visual acuity of the right eye was always completely restored. She was then readmitted to our department after a seventh episode of optic neuritis, in this case of the left eye. On neurological examination she had brisk tendon reflexes and a positive right sided Babinski sign. MRI showed atrophy of the cervical spinal cord (Fig. 1B) while the cerebral scan continued to be normal. The patient reported here fulfilled the diagnostic criteria (recurrent optic neuritis, an episode of transverse myelitis and absence of disease activity outside the spinal cord and optic nerves) and supportive criteria (cerebral MRI without signs of demyelination and abnormalities on spinal cord MRI extending over more than 3 vertebral segments) [10, 11]. Recently, more advanced MR techniques including magnetization transfer imaging provided further evidence that NMO is a clinicopathological entity distinct from multiple sclerosis [5, 9]. The patient’s history is unusual because her index events – the initial myelitis and first episode of optic neuritis – were separated by 6 LETTER TO THE EDITORS

Effect of prior treatment status and reasons for discontinuation on the efficacy and safety of fingolimod vs. interferon β-1a intramuscular: Subgroup analyses of the Trial Assessing Injectable Interferon vs. Fingolimod Oral in Relapsing–Remitting Multiple Sclerosis (TRANSFORMS)

BACKGROUND Fingolimod demonstrated superior efficacy compared with interferon β-1a intramuscular in relapsing multiple sclerosis. The impact of treatment history on fingolimod efficacy is unknown. OBJECTIVES This post-hoc analysis of phase 3 TRANSFORMS data compared the efficacy and safety of fingolimod and interferon β-1a intramuscular among patient subgroups defined by prior treatment history. METHODS Annualized relapse rate and safety of once-daily oral fingolimod 0.5mg, 1.25mg, or once-weekly interferon β-1a 30μg intramuscular for 12 months were analyzed in 1292 patients with relapsing multiple sclerosis according to prior disease-modifying therapy, reason for prior disease-modifying therapy discontinuation (adverse events or unsatisfactory therapeutic effect), and prior disease-modifying therapy duration. RESULTS Compared with interferon β-1a intramuscular, fingolimod 0.5mg significantly reduced annualized relapse rate in patients who were treatment naive, received prior interferon-β treatment, discontinued prior disease-modifying therapy for unsatisfactory therapeutic effect, or had prior disease-modifying therapy duration of ≥1 year (P≤0.05, all comparisons). Similar trends were observed in patients with prior glatiramer acetate treatment. Significant reductions were also seen with fingolimod 1.25mg for treatment-naive and prior interferon-β-treated patients. CONCLUSIONS This analysis demonstrates superiority of fingolimod over interferon β-1a intramuscular regardless of prior (interferon-β) treatment and prior treatment efficacy and duration. ClinicalTrials.gov identifier: NCT00340834.

Rituximab induces clinical stabilization in a patient with fulminant multiple sclerosis not responding to natalizumab Evidence for disease heterogeneity

JO N 2 95 6 II trial in relapsing-remitting MS (RRMS) [6–9]. At present, the duration of the treatment effect, its effect on progression of disability, and types of adverse events associated with this drug that may occur remain elusive [10]. We report an 18-year old righthanded Caucasian male who was diagnosed with RRMS in 2001 at the age of 12 years by a neurologist in private practice. At that time, the patient experienced 3–4 relapses per year, and treatment was initiated with interferon-beta 1a (Rebif®) s.c. tiw, initially 22 μg followed by 44 μg for two years. Due to lack of clinical efficacy immunosuppression with mitoxantrone was initiated in 2003, with a dose of 12 mg/m2 i.v. every 12 weeks. A total of 4 infusions were applied without any effect on relapse rate. His neurologist then changed therapy to interferon-beta 1a (Avonex®) 30 μg i.m. once weekly in 2004 without any tangible effect. In 2006, the patient first presented to our out-patient clinic with a severe relapse, characterized primarily by cerebellar ataxia. At this time, the Expanded Disability Status Scale (EDSS) score was 5.0. Two courses of intravenous methylprednisolone (IVMP) did not result in any clinical benefit. Consequently, six courses of plasma exchange (PE) were initiated resulting in a clinical improvement to an EDSS of 2.5. Treatment with interferon-beta 1a was terminated, and therapy with natalizumab 300 mg i.v. q month was initiated. The patient received a total of 6 infusions. Unfortunately, two clinical relapses occurred during this time, the second one characterized by a large brainstem lesion and a worsening to an EDSS of 7.0. The patient did not respond to IVMP. Again, clinical improvement was seen after six courses of PE, and his clinical status improved to an EDSS of 5.0. Because natalizumab treatment did Verena I. Leussink Helmar C. Lehmann Gerd Meyer zu Horste Hans-Peter Hartung Olaf Stuve Bernd C. Kieseier

Alteration of T cell cytokine production in PLPp-139-151-induced EAE in SJL mice by an immunostimulatory CpG Oligonucleotide

Experimental autoimmune encephalomyelitis (EAE) is - in certain aspects - regarded as an animal model of the human CNS autoimmune disease multiple sclerosis (MS). While in EAE CNS-autoantigen-specific immunity is induced in a defined way, the initial processes leading to CNS autoimmunity in humans are so far unknown. Despite essential restrictions, which exist regarding the interpretation of EAE data towards MS, EAE might be a useful model to study certain basic aspects of CNS autoimmunity. Studies in MS have demonstrated that established autoimmune pathology can be critically influenced by environmental factors, in particular viral and bacterial infections. To investigate this interaction, EAE as an instrument to study CNS autoimmunity under defined conditions appears to be a suitable experimental tool. For this reason, we here investigated the influence of the Toll-like-receptor (TLR) ligand CpG oligonucleotide (CpG) on already established CNS autoimmunity in murine proteolipid protein (PLP)-induced EAE in SJL mice. CpG were found to co-stimulate PLPp-specific IFN-γ production in the peripheral immune system and in the CNS. However, CpG induced Interleukin (IL)-17 production in the inflamed CNS both alone and in combination with additional PLPp stimulation. These findings might indicate a mechanism by which systemic infections and the microbial stimuli associated with them may influence already existing CNS autoimmune pathology.