Persistent intrathecal immunoglobulin (Ig) synthesis is a key feature in the CSF of the majority of MS patients (Thompson et al., 1979) and contributes to diagnostic decision making. In fact, two distinct CSF parameters are important in the context of MS: the oligoclonal bands (OCB) and the Measles/Rubella/[Herpes] Zoster (MRZ) reaction. The OCB represent a distinct pattern of Ig in the CSF which cannot be found in the peripheral blood. They have a high sensitivity, being detectable in around 90% of MS patients. However, their presence is not restricted to MS, as they can be found transiently in many inflammatory CNS conditions as the expression of a humoral host response. For instance, Herpes simplex virus (HSV)-specific Ig can be detected in the CSF of patients suffering from HSV encephalitis, with the majority of antibodies directed against the pathogen (Vandvik et al., 1982). By contrast, OCB in MS have failed to display a predominant specificity inter- and intraindividually, as they are directed not only against many different pathogen-associated antigens but also against CNS structural epitopes. When compared to the corresponding ratio in blood, the MRZ-reaction describes an elevated ratio of intrathecally synthesized antibodies specific for MRZ (about 2% of all intrathecal IgG) versus all intrathecally synthesized IgG. It therefore has a higher specificity for MS than OCB, making it an attractive complement to the highly sensitive OCB (Reiber et al., 1998). Although intrathecal antibodies are present in the human disease and also in some of the animal models, passive transfer studies and antibody depletion strategies failed to prove a clear-cut disease initiating or perpetuating effect (Antel and Bar-Or, 2006). In the animal model, some studies have shown a slightly exacerbating effect of MOG-specific antibodies on demy-elination and clinical score in already established EAE (Urich et al., 2006). Thus, in the context of T cell-mediated disease [or in the presence of a high number of autoreactive T cells (Bettelli et al., 2006a; Krishnamoorthy et al., 2006)], the disease can be modified by autoantibodies against myelin and other neural components, while systemic presence of these antibodies without T cell help has not proved to be pathogenic. Thus, intrathecal polyvalent antibody production in MS might in fact be an epiphenome-non rather than a disease promoting mechanism, and this can be utilized as diagnostic tool to discriminate MS from other CNS inflammatory conditions. This would also explain the broad array of specificities, which may reflect the individual patient's medical history of infections and CNS damage rather than an autoimmune response against an MS-relevant antigen. This concept of "bystander humoral response'' has been supported by findings in basic research in B cell and plasma cell development. Radbruch and coworkers showed that migrating plasma blasts are capable of entering inflamed tissue by CXCR4- and CXCR3-mediated chemotaxis (which are also crucial factors for T cell migration to the CNS) irrespective of their antigen specificity. If they succeed in occupying a survival niche, which is defined by the availability of surviving factors, such as CXCL12 and other IL-6-induced B cell relevant factors, plasma-blasts can develop into immobile, long-lived plasma cells, secreting large amounts of the antibodies (Radbruch et al., 2006). Long-lived plasma cells are only present in the target organ during inflammation, disappearing after resolution of inflammation due to apoptosis, and the elimination of survival niches. This basic mechanism makes sense if there is an infectious attack against the CNS, as for instance in neuroborreliosis, in which bacteria attack the CNS, and the enrichment of peripherally generated plasma blasts leads to an enrichment of specific plasma blasts in the diseased target organ, and to a forceful antigen-specific local humoral response (Li et al., 2006; Reiber and Peter, 2001). On the whole, this seems to be similar for MS in which chronically activated B cells, having undergone germinal center maturation, and plasma blasts are selectively enriched in the target tissue (Cepok et al., 2005; Corcione et al., 2004). In MS, however, there is no specific humoral immune response against a pathogen and thus no generation of specific plasma blasts in the bone marrow or spleen, which leads to an unselective attraction of traveling plasma blasts to the diseased target organ. This concept correlates well with low-level presence of B cells in chronic autoimmunity in the CNS (Esiri, 1977; Magliozzi et al., 2004). These findings lead us to hypothesize that intrathecal antibody synthesis in classic MS reflects a nonspecific recruitment of antibody-secreting cells into the CNS by inflammatory cues released in the process of T cell-mediated autoimmune inflammation. In situ, the provision of survival factors for plasma cells leads to long-term antibody production in the CNS. Indeed, myeloablative therapy in MS followed by successful autologous hematopoietic stem cell transplantation left OCB presence in the CSF unchanged, most likely resulting from the resistance of long-lived plasma cells to irradiation, cytostatics, and depletion by an anti-CD20 antibody (Rituximab, see below; Saiz et al., 2001).
A genuine autoimmune humoral response, as in the (NZB x NZW) F1 murine model for systemic lupus erythematodes (SLE), presents with stable and persistent autoantibodies in the serum as a hallmark of its pathology. These serum autoantibodies presumably derive from long-lived plasma cells in the bone marrow and are characteristically present already before onset of the disease (Hoyer et al., 2004). This is not the case for classic MS (Antel and Bar-Or, 2006), but some of these traits can be found in another type of chronic neuroinflammation called neuromyelitis optica (NMO, also Devic's syndrome), a demyelinating CNS disease with distinct clinical, therapeutic, and histopathologic features compared to MS. CNS infiltrates in NMO are marked by extensive eosinophil infiltration, complement activation, and necrotizing demyelination with prominent vascular hyalinization (Lucchinetti et al., 2002). Recent serological studies have identified a serum autoantibody called NMO-IgG, which binds to the abluminal face of CNS microvessels in different areas of the spinal cord and brain of murine CNS tissue, and which can be detected in the serum of most NMO patients while they are absent in healthy controls, MS, and other diseases (Lennon et al., 2004). This autoantibody presumably recognizes the aquaporin-4 water channel, which is highly expressed in astrocytic end feet along CNS microvasulature (Lennon et al., 2005). These findings make aquaporin-4 a likely suspect as an autoantigen which might be involved in initiating humoral autoimmune CNS disease. Another piece of evidence supporting this hypothesis is supplied by a first open trial in which patients were treated with the CD20-depleting antibody Rituximab. Results from this trial have been promising for this otherwise rapidly progressive disease, with six out of eight patients staying relapse-free over an observation period of one year (Cree et al., 2005). However, while serological studies, histopathologic results, and success of specific treatments are all crucial, it has yet to be proven that passive transferal of the antibody or serum from diseased animals is sufficient to induce the disease in healthy animals.
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