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A 75-year-old woman with unremarkable medical history, consulted for a 5-month history of involuntary shaking of left upper limb. Clinical examination revealed polyminimyoclonus of the upper limbs with cogwheel-like rigidity, hyperreflexia, bradykinesia, inconstant spastic-like rigidity in the lower limbs and a stiff and cautious gait. These symptoms, together with the memory impairment found on neuropsychological assessment yielded suspicion for a subacute encephalopathy probably due to a non-conventional infectious agent. There was no 14-3-3 protein found in the cerebrospinal fluid and no periodic sharp wave complexes on EEG. These findings made the diagnosis of Creutzfeldt-Jakob disease (CJD) rather unlikely according to the current WHO diagnostic criteria. However, typical isolated cortical hyperintensity of right temporal, parietal and occipital lobes on MRI suggested a probable CJD and prompted cerebral biopsy which confirmed the diagnosis. This article emphasises the need to update the current WHO criteria by including radiological findings.

Bacterial and viral infections have long been implicated in pathogenesis and progression of multiple sclerosis (MS). Incidence and severity of its animal model experimental autoimmune encephalomyelitis (EAE) can be enhanced by concomitant administration of pertussis toxin (PTx), the major virulence factor of Bordetella pertussis. Its adjuvant effect at the time of immunization with myelin antigen is attributed to an unspecific activation and facilitated migration of immune cells across the blood brain barrier into the central nervous system (CNS). In order to evaluate whether recurring exposure to bacterial antigen may have a differential effect on development of CNS autoimmunity, we repetitively administered PTx prior to immunization. Mice weekly injected with PTx were largely protected from subsequent EAE induction which was reflected by a decreased proliferation and pro-inflammatory differentiation of myelin-reactive T cells. Splenocytes isolated from EAE-resistant mice predominantly produced IL-10 upon re-stimulation with PTx, while non-specific immune responses were unchanged. Longitudinal analyses revealed that repetitive exposure of mice to PTx gradually elevated serum levels for TGF-β and IL-10 which was associated with an expansion of peripheral CD4(+)CD25(+)FoxP3(+) regulatory T cells (Treg). Increased frequency of Treg persisted upon immunization and thereafter. Collectively, these data suggest a scenario in which repetitive PTx treatment protects mice from development of CNS autoimmune disease through upregulation of regulatory cytokines and expansion of CD4(+)CD25(+)FoxP3(+) Treg. Besides its therapeutic implication, this finding suggests that encounter of the immune system with microbial products may not only be part of CNS autoimmune disease pathogenesis but also of its regulation.

Immune-mediated diseases of the CNS, such as multiple sclerosis and its animal model, experimental autoimmune encephalitis (EAE), are characterized by the activation of antigen-presenting cells and the infiltration of autoreactive lymphocytes within the CNS, leading to demyelination, axonal damage, and neurological deficits. Hepatocyte growth factor (HGF) is a pleiotropic factor known for both neuronal and oligodendrocytic protective properties. Here, we assess the effect of a selective overexpression of HGF by neurons in the CNS of C57BL/6 mice carrying an HGF transgene (HGF-Tg mice). EAE induced either by immunization with myelin oligodendrocyte glycoprotein peptide or by adoptive transfer of T cells was inhibited in HGF-Tg mice. Notably, the level of inflammatory cells infiltrating the CNS decreased, except for CD25(+)Foxp3(+) regulatory T (T(reg)) cells, which increased. A strong T-helper cell type 2 cytokine bias was observed: IFN-gamma and IL-12p70 decreased in the spinal cord of HGF-Tg mice, whereas IL-4 and IL-10 increased. Antigen-specific response assays showed that HGF is a potent immunomodulatory factor that inhibits dendritic cell (DC) function along with differentiation of IL-10-producing T(reg) cells, a decrease in IL-17-producing T cells, and down-regulation of surface markers of T-cell activation. These effects were reversed fully when DC were pretreated with anti-cMet (HGF receptor) antibodies. Our results suggest that, by combining both potentially neuroprotective and immunomodulatory effects, HGF is a promising candidate for the development of new treatments for immune-mediated demyelinating diseases associated with neurodegeneration such as multiple sclerosis.

Mechanisms of action as well as cellular targets of glatiramer acetate (GA) in multiple sclerosis (MS) are still not entirely understood. IL-1beta is present in CNS-infiltrating macrophages and microglial cells and is an important mediator of inflammation in experimental autoimmune encephalitis (EAE), the MS animal model. A natural inhibitor of IL-1beta, the secreted form of IL-1 receptor antagonist (sIL-1Ra) improves EAE disease course. In this study we examined the effects of GA on the IL-1 system. In vivo, GA treatment enhanced sIL-1Ra blood levels in both EAE mice and patients with MS, whereas IL-1beta levels remained undetectable. In vitro, GA per se induced the transcription and production of sIL-1Ra in isolated human monocytes. Furthermore, in T cell contact-activated monocytes, a mechanism relevant to chronic inflammation, GA strongly diminished the expression of IL-1beta and enhanced that of sIL-1Ra. This contrasts with the effect of GA in monocytes activated upon acute inflammatory conditions. Indeed, in LPS-activated monocytes, IL-1beta and sIL-1Ra production were increased in the presence of GA. These results demonstrate that, in chronic inflammatory conditions, GA enhances circulating sIL-1Ra levels and directly affects monocytes by triggering a bias toward a less inflammatory profile, increasing sIL-1Ra while diminishing IL-1beta production. This study sheds light on a mechanism that is likely to participate in the therapeutic effects of GA in MS.

A patient with chronic inflammatory demyelinating polyneuropathy (CIDP) presented with an isolated unilateral adduction deficit and ptosis. Investigations were negative until the onset of limb weakness and fatigue 2 years later. At that time, electroneuromyography, cerebrospinal fluid examination, and magnetic resonance imaging confirmed the diagnosis of CIDP. Thus, ophthalmic signs can precede extremity and bulbar signs with a long latency in CIDP.

Multiple sclerosis (MS) has been associated with an imbalance in the T helper type 1 (Th1) and Th2 subsets. We investigated, at the single-cell level, the synthesis of pro-inflammatory cytokines by CD4 and CD8 T cells from MS patients. We report the relationship between priming of CD4 and CD8 T cells for interleukin-2 (IL-2), interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) and disease evolution in MS patients, clinically subdivided into relapsing-remitting MS (RRMS) in remission, RRMS in relapse, or chronic progressive MS (CPMS). Moreover, we report the in vivo influence of co-polymer 1 (COP) treatment on the pattern of cytokine producers in RRMS patients. We show that the frequency of CD4 T cells primed for TNF-alpha synthesis increased in all stages of MS, including RRMS remitting, and was normalized to control values in COP-treated patients (43.2 +/- 11.8% in treated patients versus 47 +/- 7.3% in RRMS remitting versus 40.3 +/- 8% in controls). In addition, a significant decrease in the frequency of CD4 T cells primed for IL-2 was found in COP-treated patients as compared to the other groups of patients, reaching values below that of controls (59.1 +/- 9.9% in treated patients versus 70 +/- 11.6% in RRMS remitting versus 67.1 +/- 7.4% in controls). Unexpectedly, COP-treated patients also showed a significantly decreased priming for IFN-gamma at the CD4 T-cell level (9.1 +/- 3.4% in treated patients versus 18.8 +/- 0.6.4% in RRMS remitting versus 15.4 +/- 4.7% in controls), but not at the CD8 T-cell level. This bystander suppression on the inflammatory cells should be considered in the monitoring of MS patients submitted to COP treatment, in order to evaluate better its clinical efficacy.

1. The hypothesis that a transcortical loop can be activated by electrical stimulation of low-threshold muscle afferents was tested. The effect of these afferents on the excitability of motoneurones was measured with the monosynaptic spinal reflex (H-reflex).2. Four monkeys were trained to maintain a constant tonic activity in the soleus muscle so that the amplitude of evoked H-reflexes was constant. The intensity of conditioning stimuli was just subthreshold for direct or reflex electromyographic responses. The intensity of the test stimuli was adjusted to evoke an H-reflex of maximal amplitude. The amplitude of the H-reflex was recorded for different intervals between conditioning and test stimuli (10-1000 msec).3. The excitability curve obtained showed three components: (1) an early excitatory process, F1, at intervals of 10-20 msec, (2) a late excitatory process, F2, at intervals of 40-80 msec and (3) a short latency depression of about 400 msec duration, on which F1 and F2 were superimposed.4. F2 was selectively abolished during cooling of the contralateral motor cortex, after an irreversible lesion of the motor cortex, and after pyramidotomy; however, F1 and the inhibition remained unchanged.5. The conduction time from the tibial nerve to the somatosensory cortex (SI), the cortical delay between SI and motor cortex, and the conduction time from motor cortex to the soleus muscle were measured in an anaesthetized animal. The sum of these values as an estimate of the transcortical loop time was 5 msec shorter than the latency of F2.6. It is concluded that a transcortical loop can be activated by electrical stimulation of low-threshold muscle afferents and, by analogy, also by mechanical perturbations applied during a motor task.