Bernd C. Kieseier

The role of macrophages in immune-mediated damage to the peripheral nervous system

Macrophage-mediated segmental demyelination is the pathological hallmark of autoimmune demyelinating polyneuropathies, including the demyelinating form of Guillain-Barré syndrome and chronic inflammatory demyelinating polyneuropathy. Macrophages serve a multitude of functions throughout the entire pathogenetic process of autoimmune neuropathy. Resident endoneurial macrophages are likely to act as local antigen-presenting cells by their capability to express major histocompatibility complex antigens and costimulatory B7-molecules, and may thus be critical in triggering the autoimmune process. Hematogenous infiltrating macrophages then find their way into the peripheral nerve together with T-cells by the concerted action of adhesion molecules, matrix metalloproteases and chemotactic signals. Within the nerve, macrophages regulate inflammation by secreting several pro-inflammatory cytokines including IL-1, IL-6, IL-12 and TNF-alpha. Autoantibodies are likely to guide macrophages towards their myelin or primarily axonal targets, which then attack in a complement-dependent and receptor-mediated manner. In addition, non-specific tissue damage occurs through the secretion of toxic mediators and cytokines. Later, macrophages contribute to the termination of inflammation by promoting T-cell apoptosis and expressing anti-inflammatory cytokines including TGF-beta1 and IL-10. During recovery, they are tightly involved in allowing Schwann cell proliferation, remyelination and axonal regeneration to proceed. Macrophages, thus, play dual roles in autoimmune neuropathy, being detrimental in attacking nervous tissue but also salutary, when aiding in the termination of the inflammatory process and the promotion of recovery.

Effector pathways in immune mediated central nervous system demyelination.

Multiple sclerosis is generally regarded to be a primarily T-cell driven disease. Recent evidence has refocused interest on antibodies. Adhesion molecules, matrix metalloproteinases, chemokines and cytokines, and nitric oxide and oxygen metabolites all participate in the amplification and effector stages of the disease.

Schwann cell-specific regulation of IL-1 and IL-1Ra during EAN: Possible relevance for immune regulation at paranodal regions

We reported Schwann cell (SC)-specific autoregulation of IL-1 in vitro [J. Neuroimmunol. 74 (1997a)]. Whether SC resume this autoregulatory potential in vivo and what significance it may have for processes leading to inflammation and demyelination of the peripheral nerve remain obscure. Therefore, we examine SC-specific autoregulation of IL-1alpha, IL-1beta and their natural antagonist IL-1 receptor antagonist (IL-1Ra) during experimental autoimmune neuritis (EAN), a model for the human Guillain-Barre syndrome. Autoregulation of IL-1 by SC was analyzed in both, actively induced and adoptively transferred, EAN. Sciatic nerves were sampled before the onset of clinical signs, 2 to 11 days post immunization (dpi), with P2 peptide, and during clinically manifest disease, 11 to 15 dpi. In adoptively transferred EAN, sciatic nerves were analyzed at preclinical stage, 2 to 4 days post P2 peptide-specific cell transfer (dpt) and during clinical manifested phase, 5 to 10 dpt. In both models, IL-1alpha and IL-1beta were expressed by SC, during preclinical EAN. IL-1Ra was not detectable in SC at preclinical stage. Further development and progression to clinically manifest disease was accompanied by SC-specific expression of IL-1Ra. Although present in other cells in the nerve, IL-1alpha and IL-1beta were hardly detectable in SC during clinical EAN. IL-1Ra immunoreactivity highly co-localized with myelin associated glycoprotein (MAG), one of the markers for paranodal regions, sites essential for proper impulse transmission. Paranodes are also primary sites where activated macrophages make contact with SC, prior to infiltration.SC-specific autoregulation of IL-1 and IL-1Ra is suggestive of its relevance for immune regulation at paranodes during EAN.

Matrix Metalloproteinases Exhibit Different Expression Patterns in Inflammatory Demyelinating Diseases of the Central and Peripheral Nervous System

Inflammatory demyelinating diseases of the nervous system, such as multiple sclerosis (MS) or the Guillain-Barré syndrome (GBS), represent common neurologic disorders. The understanding of the pathogenesis implicated in these conditions is incomplete. It is commonly accepted that these diseases are immune mediated. An emerging body of evidence suggests that matrix metalloproteinases (MMPs) may be of paramount importance in mediating inflammatory demyelinating diseases of the central (CNS) and peripheral nervous system (PNS). Primarily, this evidence is based on studies in animal models, such as experimental autoimmune encephalomyelitis (EAE), an animal model for inflammatory demyelination of the CNS, and experimental autoimmune neuritis (EAN), a model for inflammatory demyelination of the PNS. We investigated the temporospatial expression pattern of various MMPs in both experimental models in an attempt to elucidate the role of these proteases in the pathogenesis of these disabling diseases.

Neuromuskuläre Erkrankungen bei Intensivpatienten

Neuromuskulare Erkrankungen sind Storungen, die das periphere Nervensystem, die neuromuskulare Endplatte und/oder die quergestreifte Muskulatur betreffen. Sie konnen sowohl Ursache als auch Folge einer intensivmedizinischen Behandlung sein.

Chemokines in the Inflamed Peripheral Nervous System

Publisher Summary Chemokines are involved in the composition of cellular infiltrates in immune-mediated demyelinating disorders of the peripheral nervous system (PNS). A consistent chemokine receptor expression pattern was immunohistochemically detected in inflammatory demyelinating neuropathies. The distribution of the two chemokines, IP-10 and RANTES, mirrored the distribution of equivalent receptors within the inflamed peripheral nervous system. Results from studies in experimental autoimmune neuritis, describing various maximum chemokine expression levels to be coincident with peak of clinical disease, suggest that these chemokines exert an amplifying rather than initiating role in generating PNS inflammation. Moreover, chemokines might also be involved in modulating the immune response during the course of the disease. It appears that RANTES, and potentially other chemokines, might exhibit beneficial effects by promoting axonal regeneration after axonal degeneration caused by severe demyelination. Therefore, it can be assumed that the PNS might have its own chemokine ligand–receptor network whose function could extend well beyond the regulation of leukocyte trafficking in immunoinflammatory disease. Further research is needed to understand the biological implications of this observation. Increased knowledge of the expression and specific function of individual chemokines and their receptors will hopefully help to design inhibitors that could be administered at critical checkpoints in the evolution of immune-mediated demyelination of the PNS.

Matrix-Metalloproteinasen Mögliche Ansatzpunkte neuer Therapien bei entzündlich demyelinisierenden Erkrankungen des Nervensystems

ZusammenfassungEntzündlich demyelinisierende Erkrankungen des Nervensystems, wie beispielsweise die multiple Sklerose oder das Guillain-Barré-Syndrom, stellen schwer behindernde Krankheitsbilder dar, denen der Neurologe häufig begegnet und deren Behandlungsmöglichkeiten bis heute unzureichend sind. Die zugrundeliegenden Pathomechanismen sind nur zum Teil geklärt, es mehren sich jedoch Hinweise, daß Enzyme aus der Gruppe der Matrix-Metalloproteinasen einen wichtigen Beitrag zur Entstehung dieser Erkrankungen zu liefern scheinen. Sowohl tierexperimentelle Ergebnisse als auch Befunde aus anderen medizinischen Bereichen deuten darauf hin, daß die gezielte Hemmung dieser Proteasen einen vielversprechenden therapeutischen Ansatz darstellt. In der folgenden Übersicht soll die Rolle der Matrix-Metalloproteinasen bei entzündlich demyelinisierenden Erkrankungen des zentralen als auch peripheren Nervensystems dargestellt, sowie der therapeutische Einsatz synthetischer Inhibitoren bei diesen Erkrankungen diskutiert werden.SummaryInflammatory demyelinating diseases of the nervous system, such as multiple sclerosis or the Guillain-Barré syndrome represent severely disabling disorders, often seen by the neurologist, with still only limited means for therapeutical intervention. The underlying pathomechanisms remain in large part elu-sive, however mounting evidence suggests that enzymes of the family of matrix metalloproteinases are of relevance in the pathogenesis of these disorders. Experimental in vivo data as well as results from other medical fields emphasize that the selective inhibition of these proteases could be a promising therapeutical approach. The following review summarizes the role of matrix metalloproteinases in inflammatory demyelinating diseases of the central as well as peripheral nervous system and discusses the therapeutical application of synthetic inhibitors in these disorders.