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Kuerten S.,University of Cologne | Lehmann P.V.,Case Western Reserve University | Lehmann P.V.,Cellular Technology Ltd
Journal of Interferon and Cytokine Research | Year: 2011

Experimental autoimmune encephalomyelits (EAE) has been widely studied as a model for multiple sclerosis (MS). EAE also holds a special place in basic autoimmune research. It is induced by immunizing healthy, naïve mice with neuroantigen. Unlike in spontaneous autoimmune models, one can therefore clearly define the initiation time point, the inducing antigen, the circumstances of the immunization that elicit a pathogenic-or nonpathogenic-T cell response, and many other parameters that are required for the induction and perpetuation of autoimmune central nervous system pathology. In the following, we will provide an overview of our current understanding of the discrete steps that lead to the pathogenesis of EAE, and we will highlight several junctions at which the perpetuation or abortive course of the disease is defined. It has become abundantly clear that the induction of a pathogenic CD4 + T cell response is a necessary requirement for the induction of EAE. However, many downstream mechanisms need to be considered if we want to understand the pathomechanisms that define the variable outcomes of EAE, and by inference, of MS. © 2011, Mary Ann Liebert, Inc.

Hundgeburth L.C.,University of Cologne | Wunsch M.,University of Cologne | Rovituso D.,University of Cologne | Recks M.S.,University of Cologne | And 3 more authors.
Clinical Immunology | Year: 2013

So far, studies of the human autoimmune disease multiple sclerosis (MS) have largely been hampered by the absence of a pathogenic B cell component in its animal model, experimental autoimmune encephalomyelitis (EAE). To overcome this shortcoming, we have previously introduced the myelin basic protein (MBP)-proteolipid protein (PLP) MP4-induced EAE, which is B cell and autoantibody-dependent. Here we show that MP4-immunized wild-type C57BL/6 mice displayed a significantly lower disease incidence when their complement system was transiently depleted by a single injection of cobra venom factor (CVF) prior to immunization. Considering the underlying pathomechanism, our data suggest that the complement system is crucial for MP4-specific antibodies to trigger CNS pathology. Demyelinated lesions in the CNS were colocalized with complement depositions. In addition, B cell deficient JHT mice reconstituted with MP4-reactive serum showed significantly attenuated clinical and histological EAE after depletion of complement by CVF. The complement system was also critically involved in the generation of the MP4-specific T and B cell response: in MP4-immunized wild-type mice treated with CVF the MP4-specific cytokine and antibody response was significantly attenuated compared to untreated wild-type mice. Taken together, we propose two independent mechanisms by which the complement system can contribute to the pathology of autoimmune encephalomyelitis. Our data corroborate the role of complement in triggering antibody-dependent demyelination and antigen-specific T cell immunity and also provide first evidence that the complement system can modify the antigen-specific B cell response in EAE and possibly MS. © 2012 Elsevier Inc.

Lehmann P.V.,Cellular Technology Ltd | Rottlaender A.,University of Wurzburg | Kurten S.,University of Wurzburg
Pharmazie | Year: 2015

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. © 2015, Govi-Verlag Pharmazeutischer Verlag GmbH. All rights reserved.

Dittrich M.,University of Wurzburg | Lehmann P.V.,Cellular Technology Ltd
Methods in Molecular Biology | Year: 2012

Cytokine ELISPOT assays have emerged as a powerful tool for the detection of rare antigen-specific T cells in freshly isolated cell material, such as blood. While ELISPOT assays allow one to directly visualize and count extremely low frequencies of cytokine-secreting T cells among millions of nonsecreting bystander cells, the interpretation of ELISPOT data can become ambiguous when (a) spot numbers in antigen-containing wells are low, (b) spot counts in negative control wells are elevated, and particularly (c) when both of the above occur simultaneously. Thus, the primary task, even before statistics are employed, must be the optimization of the basic assay parameters and reagents such that the assay yields low background signal in the negative-control wells and the maximal number of antigen-induced spots in test wells, i.e., the signal-to-noise ratio is maximized. Furthermore, the use of proper spot-size gating parameters for data analysis is indispensable for screening out irrelevant background spots, and thus increasing the signal-to-noise ratio. The goal of most ELISPOT experiments is to identify positive T-cell responses as defined by a significantly elevated spot count in antigen-stimulated wells over the nonstimulated medium-control or negative-control antigen. In this chapter, we conclude that-with some limitations-the T-Test and related statistical methods which rely on the assumption of normal distribution are suitable for identifying positive ELISPOT results. © 2012 Springer Science+Business Media, LLC.

Kuerten S.,University of Cologne | Schickel A.,University of Cologne | Kerkloh C.,University of Cologne | Recks M.S.,University of Cologne | And 4 more authors.
Acta Neuropathologica | Year: 2012

While the role of T cells has been studied extensively in multiple sclerosis (MS), the pathogenic contribution of B cells has only recently attracted major attention, when it was shown that B cell aggregates can develop in the meninges of a subset of MS patients and were suggested to be correlates of late-stage and more aggressive disease in this patient population. However, whether these aggregates actually exist has subsequently been questioned and their functional significance has remained unclear. Here, we studied myelin basic protein (MBP)-proteolipid protein (PLP)-induced experimental autoimmune encephalomyelitis (EAE), which is one of the few animal models for MS that is dependent on B cells. We provide evidence that B cell aggregation is reflective of lymphoid neogenesis in the central nervous system (CNS) in MBP-PLP-elicited EAE. B cell aggregation was present already few days after disease onset. With disease progression CNS B cell aggregates increasingly displayed the phenotype of tertiary lymphoid organs (TLOs). Our results further imply that these TLOs were not merely epiphenomena of the disease, but functionally active, supporting intrathecal determinant spreading of the myelin-specific T cell response. Our data suggest that the CNS is not a passive "immune-privileged" target organ, but rather a compartment, in which highly active immune responses can perpetuate and amplify the autoimmune pathology and thereby autonomously contribute to disease progression. © 2012 Springer-Verlag.

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