Antje Kroner

Publications of Antje Kroner

• Evidence for VAV2 and ZNF433 as susceptibility genes for multiple sclerosis.

  Authors: Sandra Nischwitz, Sabine Cepok, Antje Kroner, Christiane Wolf, Matthias Knop, Felix Müller-Sarnowski, Hildegard Pfister, Darina Roeske, Peter Rieckmann, Bernhard Hemmer, Marcus Ising, Manfred Uhr, Thomas Bettecken, Florian Holsboer, Bertram Müller-Myhsok, Frank Weber

  Journal of neuroimmunology. 10/2010; 227(1-2):162-6.

  In a genome wide association study consisting of 592 German multiple sclerosis (MS) patients and 825 controls we were able to replicate the association of the HLA region with MS independently ofIn a genome wide association study consisting of 592 German multiple sclerosis (MS) patients and 825 controls we were able to replicate the association of the HLA region with MS independently of previous case control studies. No SNPs outside the HLA region reached a genome wide level of significance. Nevertheless, we found suggestive evidence for an association of MS with variants in two new genes, the VAV2 gene and the gene for ZNF433.

• Lack of evidence for a pathogenic role of T-lymphocytes in an animal model for Charcot-Marie-Tooth disease 1A.

  Authors: Bianca Kohl, Janos Groh, Carsten Wessig, Heinz Wiendl, Antje Kroner, Rudolf Martini

  Neurobiology of disease. 04/2010; 38(1):78-84.

  We have previously shown that in two distinct models for inherited neuropathies of the Charcot-Marie-Tooth (CMT) type, T-lymphocytes are critically involved in demyelination. In the present study, weWe have previously shown that in two distinct models for inherited neuropathies of the Charcot-Marie-Tooth (CMT) type, T-lymphocytes are critically involved in demyelination. In the present study, we tested whether T-lymphocytes have a similar pathogenetic impact in another CMT model, i.e., in mice overexpressing the peripheral myelin protein (PMP)-22, representing the most prevalent form CMT1A. By cross breeding the myelin mutant mice with mutants lacking mature T- and B-lymphocytes (RAG-1-deficient mice), the pathological alterations were not changed in comparison to PMP22 mutants with a normal immune system. Reciprocal enhancement of lymphocyte activation, by inactivation of the lymphocytic co-inhibitor programmed death-1, also did not alter pathological changes, as opposed to models with approved lymphocytic involvement. These findings strongly suggest that lymphocytes are not pathogenetically relevant in this model for CMT1A. We suggest that - in contrast to myelin phagocytosing macrophages - T-lymphocytes are not a promising target for treatment of CMT1A.

• Ectopic T-cell specificity and absence of perforin and granzyme B alleviate neural damage in oligodendrocyte mutant mice.

  Authors: Antje Kroner, Chi Wang Ip, Johannes Thalhammer, Klaus-Armin Nave, Rudolf Martini

  The American journal of pathology. 02/2010; 176(2):549-55.

  In transgenic mice overexpressing the major myelin protein of the central nervous system, proteolipid protein, CD8+ T-lymphocytes mediate the primarily genetically caused myelin and axon damage. InIn transgenic mice overexpressing the major myelin protein of the central nervous system, proteolipid protein, CD8+ T-lymphocytes mediate the primarily genetically caused myelin and axon damage. In the present study, we investigated the cellular and molecular mechanisms underlying this immune-related neural injury. At first, we investigated whether T-cell receptors (TCRs) are involved in these processes. For this purpose, we transferred bone marrow from mutants carrying TCRs with an ectopic specificity to ovalbumin into myelin mutant mice that also lacked normal intrinsic T-cells. T-lymphocytes with ovalbumin-specific TCRs entered the mutant central nervous system to a similar extent as T-lymphocytes from wild-type mice. However, as revealed by histology, electron microscopy and axon- and myelin-related immunocytochemistry, these T-cells did not cause neural damage in the myelin mutants, reflecting the need for specific antigen recognition by cytotoxic CD8+ T-cells. By chimerization with bone marrow from perforin- or granzyme B (Gzmb)-deficient mice, we demonstrated that absence of these cytotoxic molecules resulted in reduced neural damage in myelin mutant mice. Our study strongly suggests that pathogenetically relevant immune reactions in proteolipid protein-overexpressing mice are TCR-dependent and mediated by the classical components of CD8+ T-cell cytotoxicity, perforin, and Gzmb. These findings have high relevance with regard to our understanding of the pathogenesis of disorders primarily caused by genetically mediated oligodendropathy.

• Accelerated Course of Experimental Autoimmune Encephalomyelitis in PD-1-Deficient Central Nervous System Myelin Mutants.

  Authors: Antje Kroner, Nicholas Schwab, Chi Wang Ip, Sonja Ortler, Kerstin Göbel, Klaus-Armin Nave, Mathias Mäurer, Rudolf Martini, Heinz Wiendl

  The American journal of pathology. 06/2009;

  It is assumed that the onset and course of autoimmune inflammatory central nervous system (CNS) disorders (eg, multiple sclerosis) are influenced by factors that afflict immune regulation as well asIt is assumed that the onset and course of autoimmune inflammatory central nervous system (CNS) disorders (eg, multiple sclerosis) are influenced by factors that afflict immune regulation as well as CNS vulnerability. We challenged this concept experimentally by investigating how genetic alterations that affect myelin (primary oligodendrocyte damage in PLPtg mice) and/or T-cell regulation (deficiency of PD-1) influence both the onset and course of an experimental autoimmune CNS inflammatory disease [MOG35-55-induced experimental autoimmune encephalomyelitis (EAE)]. We observed that double pathology was associated with a significantly earlier onset of disease, a slight increase in the neurological score, an increase in the number of infiltrating cells, and enhanced axonal degeneration compared with wild-type mice and the respective, single mutant controls. Double-mutant PLPtg/PD-1(-/-) mice showed an increased production of interferon-gamma by CNS immune cells at the peak of disease. Neither PD-1 deficiency nor oligodendropathy led to detectable spread of antigenic MHC class I- or class II-restricted epitopes during EAE. However, absence of PD-1 clearly increased the propensity of T lymphocytes to expand, and the number of clonal expansions reliably reflected the severity of the EAE disease course. Our data show that the interplay between immune dysregulation and myelinopathy results in a stable exacerbation of actively induced autoimmune CNS inflammation, suggesting that the combination of several pathological issues contributes significantly to disease susceptibility or relapses in human disease.

• PD-1 regulates neural damage in oligodendroglia-induced inflammation.

  Authors: Antje Kroner, Nicholas Schwab, Chi Wang Ip, Christoph Leder, Klaus-Armin Nave, Mathias Mäurer, Heinz Wiendl, Rudolf Martini

  PLoS ONE. 02/2009; 4(2):e4405.

  We investigated the impact of immune regulatory mechanisms involved in the modulation of the recently presented, CD8+ lymphocyte mediated immune response in a mouse model of oligodendropathy-inducedWe investigated the impact of immune regulatory mechanisms involved in the modulation of the recently presented, CD8+ lymphocyte mediated immune response in a mouse model of oligodendropathy-induced inflammation (PLPtg-mutants). The focus was on the role of the co-inhibitory molecule PD-1, a CD28-related receptor expressed on activated T- and B-lymphocytes associated with immune homeostasis and autoimmunity. PLPtg/PD-1-deficient double mutants and the corresponding bone marrow chimeras were generated and analysed using immunohistochemistry, light- and electron microscopy, with particular emphasis on immune-cell number and neural damage. In addition, the immune cells in both the CNS and the peripheral immune system were investigated by IFN-gamma elispot assays and spectratype analysis. We found that mice with combined pathology exhibited significantly increased numbers of CD4+ and CD8+ T-lymphocytes in the CNS. Lack of PD-1 substantially aggravated the pathological phenotype of the PLPtg mutants compared to genuine PLPtg mutants, whereas the PD-1 deletion alone did not cause alterations in the CNS. CNS T-lymphocytes in PLPtg/PD-1-/- double mutants exhibited massive clonal expansions. Furthermore, PD-1 deficiency was associated with a significantly higher propensity of CNS but not peripheral CD8+ T-cells to secrete proinflammatory cytokines. PD-1 could be identified as a crucial player of tissue homeostasis and immune-mediated damage in a model of oligodendropathy-induced inflammation. Alterations of this regulatory pathway lead to overt neuroinflammation of high pathogenetic impact. Our finding may have implications for understanding the mechanisms leading to the high clinical variability of polygenic or even monogenic disorders of the nervous system.

• Analysis of the Stathmin rs182455 Single Nucleotide Promoter Polymorphism in Patients with Multiple Sclerosis.

  Authors: Mathias Buttmann, Eva Nowak, Antje Kroner, Bernhard Hemmer, Klaus-Peter Lesch, Peter Rieckmann

  Journal of neurogenetics. 12/2008;

  Stathmin, a steroid-responsive regulatory protein of oligodendrocyte migration and survival, is highly expressed in active brain lesions of patients with multiple sclerosis (MS) and probably involvedStathmin, a steroid-responsive regulatory protein of oligodendrocyte migration and survival, is highly expressed in active brain lesions of patients with multiple sclerosis (MS) and probably involved in myelin degeneration and repair. Here, we analyzed a single nucleotide polymorphism (rs182455) within the stathmin promoter that is close to a putative steroid-responsive element and has a high minor allelic frequency, in 647 clinically well characterized MS patients and 519 healthy controls. Allelic frequencies were comparable between MS patients and healthy controls. Furthermore, disease course (relapsing-remitting versus secondary progressive versus primary progressive), age of onset or progression index did not convincingly differ between genotypes. We conclude that despite potential importance of stathmin in the pathogenesis of MS, the rs182455 polymorphism does not influence MS susceptibility or clinical disease course.

• B7-H1 restricts neuroantigen-specific T cell responses and confines inflammatory CNS damage: implications for the lesion pathogenesis of multiple sclerosis.

  Authors: Sonja Ortler, Christoph Leder, Michel Mittelbronn, Alla L Zozulya, Percy A Knolle, Lieping Chen, Antje Kroner, Heinz Wiendl

  European journal of immunology. 07/2008; 38(6):1734-44.

  The co-inhibitory B7-homologue 1 (B7-H1/PD-L1) influences adaptive immune responses and has been proposed to contribute to the mechanisms maintaining peripheral tolerance and limiting inflammatoryThe co-inhibitory B7-homologue 1 (B7-H1/PD-L1) influences adaptive immune responses and has been proposed to contribute to the mechanisms maintaining peripheral tolerance and limiting inflammatory damage in parenchymal organs. To understand the B7-H1/PD1 pathway in CNS inflammation, we analyzed adaptive immune responses in myelin oligodendrocyte glycoprotein (MOG)(35-55)-induced EAE and assessed the expression of B7-H1 in human CNS tissue. B7-H1(-/-) mice exhibited an accelerated disease onset and significantly exacerbated EAE severity, although absence of B7-H1 had no influence on MOG antibody production. Peripheral MOG-specific IFN-gamma/IL-17 T cell responses occurred earlier and enhanced in B7-H1(-/-) mice, but ceased more rapidly. In the CNS, however, significantly higher numbers of activated neuroantigen-specific T cells persisted during all stages of EAE. Experiments showing a direct inhibitory role of APC-derived B7-H1 on the activation of MOG-specific effector cells support the assumption that parenchymal B7-H1 is pivotal for delineating T cell fate in the target organ. Compatible with this concept, our data investigating human brain tissue specimens show a strong up-regulation of B7-H1 in lesions of multiple sclerosis. Our findings demonstrate the critical importance of B7-H1 as an immune-inhibitory molecule capable of down-regulating T cell responses thus contributing to the confinement of immunopathological damage.

• Origin of CD11b+ macrophage-like cells in the CNS of PLP-overexpressing mice: Low influx of haematogenous macrophages and unchanged blood-brain-barrier in the optic nerve.

  Authors: Chi Wang Ip, Bianca Kohl, Christoph Kleinschnitz, Bernhard Reuss, Klaus-Armin Nave, Antje Kroner, Rudolf Martini

  Molecular and cellular neurosciences. 06/2008;

  We have recently reported that overexpression of proteolipid protein in oligodendrocytes leads to a pathologically relevant increase of both CD8+ T-lymphocytes and CD11b+ cells in the CNS. We nowWe have recently reported that overexpression of proteolipid protein in oligodendrocytes leads to a pathologically relevant increase of both CD8+ T-lymphocytes and CD11b+ cells in the CNS. We now focussed on the origin of the CD11b+ cells in the optic nerve, a well established structure for the analysis of the mutant, using bone marrow chimeric mice. Although there is an age-related increase in CD11b+ cells in the myelinated part of the optic nerve of the mutants, the percentage of infiltrating cells was not increased, but enhanced proliferation was detectable. In the non-myelinated optic nerve head, the rate of infiltrating CD11b+ cells and albumin extravasation was high in both genotypes. However, albumin extravasation was also high in the rostral myelinated part, where CD11b+ cell influx was low. Our study demonstrates an intrinsic origin of CD11b+ cells in the presence of an unchanged blood-brain-barrier in a CNS myelin mutant.

• mtDNA nt13708A variant increases the risk of multiple sclerosis.

  Authors: Xinhua Yu, Dirk Koczan, Anna-Maija Sulonen, Denis A Akkad, Antje Kroner, Manuel Comabella, Gianna Costa, Daniela Corongiu, Robert Goertsches, Montserrat Camina-Tato, Hans-Juergen Thiesen, Harald I Nyland, Sverre J Mørk, Xavier Montalban, Peter Rieckmann, Maria G Marrosu, Kjell-Morten Myhr, Joerg T Epplen, Janna Saarela, Saleh M Ibrahim

  PLoS ONE. 01/2008; 3(2):e1530.

  BACKGROUND: Mitochondrial DNA (mtDNA) polymorphism is a possible factor contributing to the maternal parent-of-origin effect in multiple sclerosis (MS) susceptibility. METHODS AND FINDINGS: In orderBACKGROUND: Mitochondrial DNA (mtDNA) polymorphism is a possible factor contributing to the maternal parent-of-origin effect in multiple sclerosis (MS) susceptibility. METHODS AND FINDINGS: In order to investigate the role of mtDNA variations in MS, we investigated six European MS case-control cohorts comprising >5,000 individuals. Three well matched cohorts were genotyped with seven common, potentially functional mtDNA single nucleotide polymorphisms (SNPs). A SNP, nt13708 G/A, was significantly associated with MS susceptibility in all three cohorts. The nt13708A allele was associated with an increased risk of MS (OR = 1.71, 95% CI 1.28-2.26, P = 0.0002). Subsequent sequencing of the mtDNA of 50 individuals revealed that the nt13708 itself, rather than SNPs linked to it, was responsible for the association. However, the association of nt13708 G/A with MS was not significant in MS cohorts which were not well case-control matched, indicating that the significance of association was affected by the population structure of controls. CONCLUSIONS: Taken together, our finding identified the nt13708A variant as a susceptibility allele to MS, which could contribute to defining the role of the mitochondrial genome in MS pathogenesis.

• Visualization of degenerating axons in a dysmyelinating mouse mutant with axonal loss.

  Authors: Birgit Ey, Igor Kobsar, Heinrich Blazyca, Antje Kroner, Rudolf Martini

  Molecular and cellular neurosciences. 06/2007; 35(1):153-60.

  Mice homozygously deficient for the myelin component P0 show loss of axons in peripheral nerves. In order to investigate the morphological characteristics of degenerating axons, we crossbred theMice homozygously deficient for the myelin component P0 show loss of axons in peripheral nerves. In order to investigate the morphological characteristics of degenerating axons, we crossbred the myelin mutants with a transgenic mouse line expressing yellow fluorescent protein (YFP) in a small proportion of neurons. Peripheral nerves of the double mutants were prepared into small fiber bundles and investigated by fluorescence microscopy. We could identify the tips of degenerating axon as bulb-like structures. Additionally, by electron microscopy, these structures were characterized as axoplasmic extensions containing numerous membraneous compartments. By immunoelectron microscopy, the degenerating end bulbs were in contact with ensheathing Schwann cells that contained YFP-immunoreactivity possibly reflecting phagocytosis of axon material by these cells. Immunohistochemistry using antibodies against macrophages revealed that YFP-positive bulbs, but also other axonal swellings, were often associated with macrophages supporting our previous findings that myelin-related axonal loss is partially mediated by these cells.

• The genetic influence of the nonclassical MHC molecule HLA-G on multiple sclerosis.

  Authors: Antje Kroner, Alexander Grimm, Kirsten Johannssen, Mathias Mäurer, Heinz Wiendl

  Human immunology. 06/2007; 68(5):422-5.

  Human leukocyte antigen (HLA)-G is a nonclassical major histocompatibility complex (MHC) molecule located at MHC complex at chromosome 6 and chiefly attributed immunoregulatory and tolerogenicHuman leukocyte antigen (HLA)-G is a nonclassical major histocompatibility complex (MHC) molecule located at MHC complex at chromosome 6 and chiefly attributed immunoregulatory and tolerogenic functions. HLA-G is upregulated at sites of inflammation in multiple sclerosis (MS) and assumed to counterbalance immune responses. Different functionally relevant genetic variants of HLA-G have been described and shown to be statistically associated with human diseases such as fetal loss or sarcoidosis. We investigated the influence of three different variations in the HLA-G gene for disease susceptibility and course of MS (n = 698): (1) The -725 C/G exchange in the HLA-G promoter region, (2) HLA-G*0105N, a deletion that results in an irregular stopcodon in exon 3, and (3) a 14 bp insertion / deletion in the untranslated exon 8. None of these variations significantly influenced the susceptibility to multiple sclerosis. No association was seen with the age of onset of disease, disease severity or disease course. Although HLA-G is assumed to play an important role in the immunoregulatory processes of MS, our results do not support a role of genetic factors influencing disease susceptibility of the disease course.

• Sialoadhesin deficiency ameliorates myelin degeneration and axonopathic changes in the CNS of PLP overexpressing mice.

  Authors: Chi Wang Ip, Antje Kroner, Paul R Crocker, Klaus-Armin Nave, Rudolf Martini

  Neurobiology of disease. 02/2007; 25(1):105-11.

  PLP overexpressing mice display demyelination and axonopathic changes, accompanied by an elevation of CD8+ T-lymphocytes and CD11b+ macrophages in the CNS. By crossbreeding these mutants withPLP overexpressing mice display demyelination and axonopathic changes, accompanied by an elevation of CD8+ T-lymphocytes and CD11b+ macrophages in the CNS. By crossbreeding these mutants with RAG-1-deficient mice lacking mature lymphocytes, we could recently demonstrate a pathogenetic impact of the CD8+ cells. In the present study, we investigated the pathogenetic impact of CD11b+ macrophages by crossbreeding the myelin mutants with knockout mice deficient for the macrophage-restricted adhesion molecule sialoadhesin (Sn). In the wild-type mice, Sn is barely detectable on CD11b+ cells, whereas in the myelin mutants, almost all CD11b+ cells express Sn. In the double mutants, upregulation of CD8+ T-cells and CD11b+ macrophages is reduced and pathological alterations are ameliorated. These data indicate that in a primarily genetically caused myelin disorder of the CNS macrophages expressing Sn partially mediate pathogenesis. These findings may have substantial impact on treatment strategies for leukodystrophic disorders and some forms of multiple sclerosis.

• Frequency analysis of HLA-B7-restricted Epstein-Barr virus-specific cytotoxic T lymphocytes in patients with multiple sclerosis and healthy controls.

  Authors: Felix Gronen, Klemens Ruprecht, Benedikt Weissbrich, Erdwine Klinker, Antje Kroner, Harald H Hofstetter, Peter Rieckmann

  Journal of neuroimmunology. 12/2006; 180(1-2):185-92.

  The Epstein-Barr virus (EBV) has been implicated in the pathogenesis of multiple sclerosis (MS), however, the mechanisms by which EBV may be involved in MS are unknown. We here have investigated theThe Epstein-Barr virus (EBV) has been implicated in the pathogenesis of multiple sclerosis (MS), however, the mechanisms by which EBV may be involved in MS are unknown. We here have investigated the frequency of EBV-specific cytotoxic T lymphocytes (CTL) in human leukocyte antigen (HLA)-B7(+) patients with MS and healthy controls using enzyme-linked immunospot assays and seven previously characterized HLA-B7-restricted immunogenic EBV peptides. Overall, there were no significant differences in the frequency of EBV-specific CTL between both groups. These data do not support the hypothesis that EBV could play a role in MS by inducing quantitatively altered EBV-specific CTL responses. Other pathogenic mechanisms for EBV in MS remain to be elucidated.

• Immune cells contribute to myelin degeneration and axonopathic changes in mice overexpressing proteolipid protein in oligodendrocytes.

  Authors: Chi Wang Ip, Antje Kroner, Martin Bendszus, Christoph Leder, Igor Kobsar, Stefan Fischer, Heinz Wiendl, Klaus-Armin Nave, Rudolf Martini

  The Journal of neuroscience : the official journal of the Society for Neuroscience. 09/2006; 26(31):8206-16.

  Overexpression of the major myelin protein of the CNS, proteolipid protein (PLP), leads to late-onset degeneration of myelin and pathological changes in axons. Based on the observation that in whiteOverexpression of the major myelin protein of the CNS, proteolipid protein (PLP), leads to late-onset degeneration of myelin and pathological changes in axons. Based on the observation that in white matter tracts of these mutants both CD8+ T-lymphocytes and CD11b+ macrophage-like cells are numerically elevated, we tested the hypothesis that these cells are pathologically involved in the primarily genetically caused neuropathy. Using flow cytometry of mutant brains, CD8+ cells could be identified as activated effector cells, and confocal microscopy revealed a close association of the T-cells with MHC-I+ (major histocompatibility complex class I positive) oligodendrocytes. Crossbreeding the myelin mutants with mice deficient in the recombination activating gene-1 (RAG-1) lacking mature T- and B-lymphocytes led to a reduction of the number of CD11b+ cells and to a substantial alleviation of pathological changes. In accordance with these findings, magnetic resonance imaging revealed less ventricular enlargement in the double mutants, partially because of more preserved corpora callosa. To investigate the role of CD8+ versus CD4+ T-lymphocytes, we reconstituted the myelin-RAG-1 double mutants with bone marrow from either CD8-negative (CD4+) or CD4-negative (CD8+) mice. The severe ventricular enlargement was only found when the double mutants were reconstituted with bone marrow from CD8+ mice, suggesting that the CD8+ lymphocytes play a critical role in the immune-related component of myelin degeneration in the mutants. These findings provide strong evidence that a primary glial damage can cause secondary immune reactions of pathological significance as it has been suggested for some forms of multiple sclerosis and other leukodystrophies.

• The role of leukemia-derived B7-H1 (PD-L1) in tumor-T-cell interactions in humans.

  Authors: Helmut Rainer Salih, Sabine Wintterle, Matthias Krusch, Antje Kroner, Yu-Hwa Huang, Lieping Chen, Heinz Wiendl

  Experimental hematology. 08/2006; 34(7):888-94.

  OBJECTIVE: Expression of the B7 homolog B7-H1 (PD1-Ligand) has been proposed to enable tumor cells to evade immune surveillance. Recently, B7-H1 on murine leukemia cells was reported to mediateOBJECTIVE: Expression of the B7 homolog B7-H1 (PD1-Ligand) has been proposed to enable tumor cells to evade immune surveillance. Recently, B7-H1 on murine leukemia cells was reported to mediate resistance to cytolytic T-cell destruction. We here investigate the expression and function of the B7 homolog B7-H1 in human leukemia. PATIENTS AND METHODS: Leukemia cells from 30 patients and 9 human leukemia cell lines were investigated for B7-H1 expression by flow cytometry. Functional relevance of B7-H1 for tumor-immune interactions was assessed by coculture experiments using purified, alloreactive CD4 and CD8 T cells in the presence of a neutralizing anti-B7-H1 antibody. RESULTS: Significant B7-H1 expression levels on leukemia cells were detected in 17 of 30 patients and in eight of nine cell lines. In contrast to various other tumor entities and the data reported from a murine leukemia system, no significant inhibitory effect of leukemia-derived B7-H1 on CD4 and CD8 cytokine production (IFN-gamma, IL-2), proliferation or expression of T-cell activation markers (ICOS, CD69) was observed. Furthermore, in the presence of neutralizing B7-H1 antibody (mAb 5H1) occurred no significant changes in T cell IFN-gamma or IL-2 production or proliferation. CONCLUSIONS: Our data demonstrate that leukemia-derived B7-H1 seems to have no direct influence on T-cell activation, proliferation, and cytokine production in humans. Further experiments are warranted to delineate factors and characterize yet-unidentified B7-H1 receptor(s) that determine inhibitory and stimulatory functions of B7-H1 in human leukemia.

• Attenuated demyelination in the absence of the macrophage-restricted adhesion molecule sialoadhesin (Siglec-1) in mice heterozygously deficient in P0.

  Authors: Igor Kobsar, Cornelia Oetke, Antje Kroner, Carsten Wessig, Paul Crocker, Rudolf Martini

  Molecular and cellular neurosciences. 05/2006; 31(4):685-91.

  Mouse mutants heterozygously deficient for the myelin component P0 mimic some forms of inherited neuropathies in humans. We have previously shown that both T lymphocytes and macrophages contribute toMouse mutants heterozygously deficient for the myelin component P0 mimic some forms of inherited neuropathies in humans. We have previously shown that both T lymphocytes and macrophages contribute to the demyelinating neuropathy. Both cell types appear to influence each other mutually, i.e., impaired T lymphocyte development in RAG-1-deficient P0 mutants leads to decreased macrophage numbers and retarded macrophage activation causes reduced T lymphocyte numbers in the peripheral nerves of P0(+/-) mice. In the present study, we investigated the possible role of the macrophage-restricted sialic acid-binding Ig-like lectin sialoadhesin (Sn, Siglec-1) in the pathogenesis of inherited demyelination in P0(+/-) mice. We found that most peripheral nerve macrophages express Sn in the mutants. Myelin mutants devoid of Sn show reduced numbers of CD8+ T lymphocytes and macrophages in peripheral nerves and less severe demyelination, resulting in improved nerve conduction properties. Our findings are potentially important in the development of future treatment strategies for inherited demyelinating neuropathies.

• A member of the transforming growth factor-beta receptor family from Echinococcus multilocularis is activated by human bone morphogenetic protein 2.

  Authors: Ricardo Zavala-Góngora, Antje Kroner, Peter Bernthaler, Petra Knaus, Klaus Brehm

  Molecular and biochemical parasitology. 05/2006; 146(2):265-71.

• Role of immune cells in animal models for inherited peripheral neuropathies.

  Authors: Chi Wang Ip, Antje Kroner, Stefan Fischer, Martin Berghoff, Igor Kobsar, Mathias Mäurer, Rudolf Martini

  Neuromolecular medicine. 02/2006; 8(1-2):175-90.

  Mice expressing half of the normal dose of protein zero (P0+/- mice) or completely deficient gap-junction protein connexin 32 -/- mice mimic demyelinating forms of inherited neuropathies, such asMice expressing half of the normal dose of protein zero (P0+/- mice) or completely deficient gap-junction protein connexin 32 -/- mice mimic demyelinating forms of inherited neuropathies, such as Charcot-Marie-Tooth (CMT) neuropathies type 1B and CMT type 1X, respectively. In both models, an almost normal myelin formation is observed during the first months of life, followed by a slowly progressing demyelinating neuropathy. In both models, there is a substantial increase of CD8+ T-lymphocytes and macrophages within the demyelinating nerves. Recently, this has also been observed in mice mildly overexpressing human peripheral myelin protein 22 kD mimicking the most common form of CMT, CMT type 1A. In all demyelinating models, the macrophages show close contacts with intact myelin sheaths or demyelinated axons, suggesting an active role of these cells in myelin degeneration. Additionally, fibroblast-like cells contact macrophages, suggesting a functional role of fibroblast-like cells in macrophage activation. By cross-breeding P0+/- and gap-junction protein connexin 32-/- mice with immunodeficient recombination activating gene-1-deficient mutants, a substantial alleviation of the demyelinating phenotype was observed. Similarly, cross-breeding of P0+/- mice with mutants with a defect in macrophage activation led to an alleviated phenotype as well. These findings demonstrate that the immune system is involved in the pathogenesis of demyelinating neuropathies. In contrast, in P0-/- mice, which display a compromised myelin compaction and axonal loss from onset, immune cells appear to have a neuroprotective effect because cross-breeding with recombination activating gene-1 mutants leads to an aggravation of axonopathic changes. In the present review, we discuss the influence of the immune system on inherited de- and dysmyelination regarding disease mechanisms and possible clinical implications.

• Association of a common polymorphism in the promoter of UCP2 with susceptibility to multiple sclerosis.

  Authors: Susanne Vogler, René Goedde, Bianca Miterski, Ralf Gold, Antje Kroner, Dirk Koczan, Uwe Klaus Zettl, Peter Rieckmann, Joerg T Epplen, Saleh M Ibrahim

  Journal of molecular medicine (Berlin, Germany). 11/2005; 83(10):806-11.

  Uncoupling protein 2 (UCP2) is a member of the mitochondrial proton transport family that uncouples proton entry to the mitochondria from ATP synthesis. UCP2 expression levels have been linked toUncoupling protein 2 (UCP2) is a member of the mitochondrial proton transport family that uncouples proton entry to the mitochondria from ATP synthesis. UCP2 expression levels have been linked to predisposition to diabetes and obesity. In addition, UCP2 prevents neuronal death and injury. Here we show that the common -866G/A promoter polymorphism is associated with susceptibility to multiple sclerosis (MS) in the German population. We analysed altogether 1,097 MS patients and 462 control subjects from two cohorts and found that the common G allele is associated with disease susceptibility (p = 0.0015). The UCP2 -866G allele is correlated with lower levels of UCP2 expression as shown here in vitro and in vivo. Thus, UCP2 promoter polymorphism may contribute to MS susceptibility by regulating the level of UCP2 protein in the central nervous and/or the immune systems.

• A PD-1 polymorphism is associated with disease progression in multiple sclerosis.

  Authors: Antje Kroner, Matthias Mehling, Bernhard Hemmer, Peter Rieckmann, Klaus V Toyka, Mathias Mäurer, Heinz Wiendl

  Annals of neurology. 08/2005; 58(1):50-7.

  T cells are considered to play a pivotal role in orchestrating the self-reactive immune responses in multiple sclerosis (MS). Programmed death 1 (PD-1) is a member of the B7/CD28 superfamily ofT cells are considered to play a pivotal role in orchestrating the self-reactive immune responses in multiple sclerosis (MS). Programmed death 1 (PD-1) is a member of the B7/CD28 superfamily of costimulatory molecules exerting inhibitory functions on T cells. Recently, an intronic 7146G/A polymorphism within the PD-1 gene was described and suggested to be associated with autoimmunity. We investigated whether this genetic polymorphism is a genetic modifier for risk and progression of MS. Blood samples from 939 German MS patients (mean age, 39 years; range, 13-71; 566 patients [60%] with relapsing-remitting MS, 279 (30%) with secondary, and 94 (10%) with primary progressive MS) and 272 healthy white controls were tested. Genotyping was performed by polymerase chain reaction and restriction enzyme digestion; results were confirmed by automatic sequencing. A significant association of the mutated allele with a progressive disease course was detected (44% 7146G vs 56% 7146A, chi(2) p = 0.002). Consequences of the PD-1 mutation for T-cell function were assessed ex vivo in some patients using microsphere-stimulated peripheral blood lymphocytes and purified CD4 cells. Importantly, PD-1-mediated inhibition of T-cell cytokine secretion (interferon-gamma) is impaired in patients carrying the PD-1 polymorphism. In conclusion, our data suggest that PD-1 polymorphism is a genetic modifier of the progression of MS, possibly through inducing a partial defect in PD-1-mediated inhibition of T-cell activation.