The autoimmune pathogenesis of multiple sclerosis.

One of the major goals of biomedical research is to reveal the pathomechanisms that lead to a disease on a level on which diagnostic criteria and causal therapies can be designed. The understanding and treatment of multiple sclerosis (MS) is still far from this goal, but exciting developments are on the way. MS is thought to be an autoimmune disease that is mediated by brain tissue-reactive lymphocytes, T cells and B cells, but so far these lymphocytes could not be reliably detected. This article highlights recent developments that permit the detection of autoreactive B cells in MS, the implications of this finding for early diagnosis of the disease, monitoring its activity, and eventually for gaining insight into the specific immune pathology that drives MS.

Blockade of tumour necrosis factor-α in experimental autoimmune encephalomyelitis reveals differential effects on the antigen-specific immune response and central nervous system histopathology.

In various autoimmune diseases, anti-tumour necrosis factor (TNF)-α treatment has been shown to reduce both clinical disease severity and T helper type 1 (Th1)1/Th17 responses. In experimental autoimmune encephalomyelitis (EAE), however, the role of TNF-α has remained unclear. Here, C57BL/6 mice were immunized with myelin oligodendrocyte glycoprotein (MOG) peptide 35-55 and treated with anti-TNF-α, control antibody or vehicle. The clinical disease course, incidence and severity were assessed. On day 20 after immunization the antigen-specific Th1/Th17 response was evaluated by enzyme-linked immunospot (ELISPOT) in spleen and central nervous system (CNS). Also, the extent of spinal cord histopathology was analysed on semi- and ultrathin sections. Our results demonstrate that anti-TNF-α treatment reduced the incidence and delayed the onset of EAE, but had no effect on disease severity once EAE had been established. Whereas anti-TNF-α treatment induced an increase in splenic Th1/Th17 responses, there was no effect on the number of antigen-specific Th1/Th17 cells in the spinal cord. Accordingly, the degree of CNS histopathology was comparable in control and anti-TNF-α-treated mice. In conclusion, while the anti-TNF-α treatment had neither immunosuppressive effects on the Th1/Th17 response in the CNS nor histoprotective properties in EAE, it enhanced the myelin-specific T cell response in the immune periphery.

[Axonal damage and its significance for the concept of neurodegeneration in multiple sclerosis]. / Die Bedeutung axonaler Pathologie für das Konzept der Neurodegeneration bei der Multiplen Sklerose.

In spite of tremendous scientific effort, the mechanisms underlying multiple sclerosis (MS) still remain to be elucidated. The prevalent pathogenetic concept adheres to the assumption of a strict hierarchical sequence of the triad inflammation, demyelination and axonal damage. However, recent studies have provided evidence that axonal pathology can occur independently of inflammation and demyelination. The present article critically re-evaluates the traditional paradigm of MS pathology. Potential cellular, humoral and metabolic mechanisms of axonal pathology are delineated and the development of isolated axonal damage is assessed. A better understanding of the pathological processes underlying MS is likely to result in an improvement of current therapeutic strategies. These should not only target the inflammatory, but also the neurodegenerative component of the disease.

[The significance of a B cell-dependent immunopathology in multiple sclerosis]. / Die Relevanz einer B-Zell-abhängigen Immunpathologie für die Multiple Sklerose.

In spite of keen clinical and neuroscientific interest, the aetiology and immunopathology of multiple sclerosis (MS) remain to be elucidated. The present work seeks to give insight into the important, but thus far underestimated contribution of B cells to the disease. Emphasis will be placed on the role of B cells as producers of autoantibodies and as antigen presenting cells. In addition, the development of ectopic B cell follicles in the CNS and their potential correlation with the course of the disease and MS severity will be discussed. Finally, regulatory functions of a B cell-dependent immunopathology should be mentioned. A better understanding of the complex pathomechanisms of MS will allow for therapeutic options that are causative. Potential targets of a B cell-oriented therapy will be delineated in the following review. We hereby aim at triggering a critical re-evaluation of traditional paradigms assigned to MS, appreciating the importance of B cells in the disease.

[The dural arteriovenous fistula - an unimposing morphological correlate with imposing consequences]. / Die Durafistel - ein unscheinbares morphologisches Korrelat mit grossen Konsequenzen.

Dural arteriovenous fistulas (DAVFs) are abnormal arteriovenous shunts located within the dura mater representing approximately 10 - 15 % of all arteriovenous shunts in the central nervous system. The aetiology of spontaneous DAVFs remains to be elucidated. The symptoms associated with DAVFs can be highly variable and dependent upon the direction of the blood flow, the amount of arteriovenous shunting and the specific location of the fistula. Considering the diversity of clinical presentation in the setting of unremarkable imaging results, diagnosing a DAVF can be difficult. To avoid permanent neurological deficits due to DAVFs, it is important to consider the possibility of a DAVF whenever one encounters unclear neurological symptoms and to initiate appropriate diagnostic procedures including intraarterial DSA and MRI/MRA. The current DAVF classification accounts for the disparity of clinical symptoms, therapeutic/interventional implications as well as vital complications depending on each particular fistula subtype. While type I DAVFs drain anterogradely into a cerebral sinus and mainly cause functional deficits, the risk for severe intracerebral bleeding increases when DAVFs drain retrogradely (type II), or into cortical (types III and IV), perimedullar or radiculo-medullar veins (type V), respectively. In particular in the case of type IIb to V DAVFs, the appropriate treatment option is a complete fistula occlusion by transvenous embolization, transarterial glue or particulate embolization or surgery. In the following we systematically explain the differential anatomy underlying DAVFs and discuss possible symptoms and necessary diagnostic and therapeutic means. In that, we are seeking to increase attention for this rare, but clinically relevant neurological disease.

Manual stimulation of forearm muscles does not improve recovery of motor function after injury to a mixed peripheral nerve.

Transection and re-anastomosis of the purely motor facial nerve leads to poor functional recovery. However, we have recently shown in rat that manual stimulation (MS) of denervated vibrissal muscles reduces the number of polyinnervated motor endplates and promotes full recovery of whisking. Here, we examined whether MS of denervated rat forearm muscles would also improve recovery following transection and suture of the mixed (sensory and motor) median nerve (median-median anastomosis, MMA). Following MMA of the right median nerve, animals received no postoperative treatment, daily MS of the forearm muscles or handling only. An almost identical level of functional recovery, measured by the force of grip in grams, was reached in all animals by the sixth postoperative week and maintained till 3 months following surgery regardless of the postoperative treatment. Also, we found no differences among the groups in the degree of axonal sprouting, the extent of motor endplate polyinnervation and in the soma size of regenerated motoneurons. Taken together, we show that while MS is beneficial following motor nerve injury, combined strategies will be required for functional recovery following mixed nerve injury.