TY - JOUR
T1 - T cell-activation in neuromyelitis optica lesions plays a role in their formation
AU - Pohl, Maria
AU - Kawakami, Naoto
AU - Kitic, Maja
AU - Bauer, Jan
AU - Martins, Rui
AU - Fischer, Marie Therese
AU - Machado-Santos, Joana
AU - Mader, Simone
AU - Ellwart, Joachim W.
AU - Misu, Tatsuro
AU - Fujihara, Kazuo
AU - Wekerle, Hartmut
AU - Reindl, Markus
AU - Lassmann, Hans
AU - Bradl, Monika
N1 - Funding Information:
This work was supported by the European Union (grant numbers LSHM-CT-2005-018637 and PITN-GA-2012-316722), the Austrian Science Fund (FWF grant number P25240-B24 to MB and I916-B13 (International Programme, Eugène Devic European Network) to HL and MR), the PhD programme Cell Communication in Health and Disease (CCHD, cofunded by the Austrian Science Fund and the Medical University Vienna), and a research grant (number 2007104) of the Interdisciplinary Center for Research and Treatment (IFTZ) of Innsbruck Medical University. It was supported in parts by grants-in-aid for Scientific Research of the Ministry of Education, Culture, Sports, Science and Technology (19209032, 20390241, 22229008), and the Health and Labour Sciences Research Grant for Neuroimmunological Diseases of the Ministry of Health, Labor and Welfare of Japan.
Publisher Copyright:
© 2013 Pohl et al.; licensee BioMed Central Ltd.
PY - 2014/1/27
Y1 - 2014/1/27
N2 - Background: Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system (CNS), which is characterized by the presence of pathogenic serum autoantibodies against aquaporin 4 (AQP4) in the vast majority of patients. The contribution of T cells to the formation of astrocyte destructive lesions is currently unclear. However, active human NMO lesions contain CD4+ T-lymphocytes expressing the activation marker Ox40, and the expression is more profound compared to that seen in MS lesions of comparable activity. Therefore, we analyzed the role of T-cell activation within the CNS in the initiation of NMO lesions in an experimental model of co-transfer of different encephalitogenic T-cells and human AQP4 antibody containing NMO immunoglobulin (NMO IgG). We further studied the expression of the T-cell activation marker Ox40 in NMO and multiple sclerosis lesions in different stages of activity. Results: All encephalitogenic T-cell lines used in our experiments induced brain inflammation with a comparable extent of blood brain barrier damage, allowing human NMO IgG to penetrate into the brain and spinal cord tissue. However, astrocyte destructive NMO lesions were only seen with T-cells, which showed signs of activation in the lesions. T-cell activation was reflected by the expression of the activation marker Ox40 and pronounced production of γ-IFN, which was able to increase the production of complement proteins and of the Fc gamma III receptor (Fcgr3) and decreased production of complement inhibitory protein Factor H in microglia. Conclusions: Our data indicate that local activation of T-cells provide an inflammatory environment in the CNS, which allows AQP4 auto-antibodies to induce astrocyte destructive NMO-like lesions.
AB - Background: Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system (CNS), which is characterized by the presence of pathogenic serum autoantibodies against aquaporin 4 (AQP4) in the vast majority of patients. The contribution of T cells to the formation of astrocyte destructive lesions is currently unclear. However, active human NMO lesions contain CD4+ T-lymphocytes expressing the activation marker Ox40, and the expression is more profound compared to that seen in MS lesions of comparable activity. Therefore, we analyzed the role of T-cell activation within the CNS in the initiation of NMO lesions in an experimental model of co-transfer of different encephalitogenic T-cells and human AQP4 antibody containing NMO immunoglobulin (NMO IgG). We further studied the expression of the T-cell activation marker Ox40 in NMO and multiple sclerosis lesions in different stages of activity. Results: All encephalitogenic T-cell lines used in our experiments induced brain inflammation with a comparable extent of blood brain barrier damage, allowing human NMO IgG to penetrate into the brain and spinal cord tissue. However, astrocyte destructive NMO lesions were only seen with T-cells, which showed signs of activation in the lesions. T-cell activation was reflected by the expression of the activation marker Ox40 and pronounced production of γ-IFN, which was able to increase the production of complement proteins and of the Fc gamma III receptor (Fcgr3) and decreased production of complement inhibitory protein Factor H in microglia. Conclusions: Our data indicate that local activation of T-cells provide an inflammatory environment in the CNS, which allows AQP4 auto-antibodies to induce astrocyte destructive NMO-like lesions.
KW - Aquaporin 4
KW - IFN-γ
KW - Lesion
KW - Neuromyelitis optica
KW - T cell activation
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U2 - 10.1186/2051-5960-1-85
DO - 10.1186/2051-5960-1-85
M3 - Article
C2 - 24367907
AN - SCOPUS:85005777594
VL - 2
JO - Acta neuropathologica communications
JF - Acta neuropathologica communications
SN - 2051-5960
IS - 1
M1 - 85
ER -