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The activation status of neuroantigen-specific T cells in the target organ determines the clinical outcome of autoimmune encephalomyelitis.

Kawakami N, Lassmann S, Li Z, Odoardi F, Ritter T, Ziemssen T, Klinkert WE, Ellwart JW, Bradl M, Krivacic K, Lassmann H, Ransohoff RM, Volk HD, Wekerle H, Linington C, Flügel A - J. Exp. Med. (2004)

Bottom Line: Irrespective of their pathogenicity, the migratory activity, gene expression patterns, and immigration of green fluorescent protein(+) T cells into the CNS were similar.However, exclusively highly pathogenic T cells were significantly reactivated within the CNS.Low-level reactivation of weakly pathogenic T cells was not due to anergy because these cells could be activated by specific antigen in situ as well as after isolation ex vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroimmunology, Max-Planck Institute for Neurobiology, 82152 Martinsried, Germany.

ABSTRACT
The clinical picture of experimental autoimmune encephalomyelitis (EAE) is critically dependent on the nature of the target autoantigen and the genetic background of the experimental animals. Potentially lethal EAE is mediated by myelin basic protein (MBP)-specific T cells in Lewis rats, whereas transfer of S100beta- or myelin oligodendrocyte glycoprotein (MOG)-specific T cells causes intense inflammatory response in the central nervous system (CNS) with minimal disease. However, in Dark Agouti rats, the pathogenicity of MOG-specific T cells resembles the one of MBP-specific T cells in the Lewis rat. Using retrovirally transduced green fluorescent T cells, we now report that differential disease activity reflects different levels of autoreactive effector T cell activation in their target tissue. Irrespective of their pathogenicity, the migratory activity, gene expression patterns, and immigration of green fluorescent protein(+) T cells into the CNS were similar. However, exclusively highly pathogenic T cells were significantly reactivated within the CNS. Without local effector T cell activation, production of monocyte chemoattractants was insufficient to initiate and propagate a full inflammatory response. Low-level reactivation of weakly pathogenic T cells was not due to anergy because these cells could be activated by specific antigen in situ as well as after isolation ex vivo.

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Quantitative chemokine mRNA expression in the CNS. The relative amount of mRNA transcripts for (A) MCP-1 and (B) MIP-1α was analyzed from spinal cord tissue of MBP-EAE (MBP), S100β-EAE (S100), and control animals (control) by dot blot hybridization at days 2 and 4 after transfer. Note the massive up-regulation of MCP-1 and MIP-1α mRNA in the CNS of TMBP cell–treated, but not in the TS100β cell–treated, animals. Amplification of β-tubulin and analysis on ethidium bromide–stained agarose gels demonstrated intact RNA in all samples (not depicted). The data were confirmed in a second set of independently prepared samples.
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fig7: Quantitative chemokine mRNA expression in the CNS. The relative amount of mRNA transcripts for (A) MCP-1 and (B) MIP-1α was analyzed from spinal cord tissue of MBP-EAE (MBP), S100β-EAE (S100), and control animals (control) by dot blot hybridization at days 2 and 4 after transfer. Note the massive up-regulation of MCP-1 and MIP-1α mRNA in the CNS of TMBP cell–treated, but not in the TS100β cell–treated, animals. Amplification of β-tubulin and analysis on ethidium bromide–stained agarose gels demonstrated intact RNA in all samples (not depicted). The data were confirmed in a second set of independently prepared samples.

Mentions: The neurological deficits in EAE seem to be caused by activated macrophages recruited to the CNS (19, 20). Indeed, CNS infiltrates induced by highly encephalitogenic TMBP-GFP and TDA-MOG-GFP cells contained large numbers of activated ED1+ macrophages, whereas these cells were rare in the CNS infiltrates induced by weakly pathogenic TS100β-GFP and TLE-MOG-GFP cells (Fig. 2 and Table II). Therefore, we compared the levels of macrophage-attracting CC chemokines MCP-1 and MIP-1α (21, 22) with both types of lesion. Quantification of MCP-1 and MIP-1α mRNA transcripts by RT-PCR in Lewis rats injected with either TMBP or TS100β cells revealed that, in animals injected with TMBP cells, MCP-1 and MIP-1α transcripts increased dramatically by day 4 coincident with the onset of clinical EAE (Fig. 7) . In contrast, in rats injected with S100β-specific T cells, there was no corresponding increase in the signals for MCP-1 and MIP-1α, which remained ∼10-fold lower than in animals with MBP-induced EAE (Fig. 7). Therefore, partial activation of T cells within the CNS can trigger the sustained recruitment of T cells into the lesions, but it is insufficient to activate MCP-1 and MIP-1α expression, which mediate the recruitment of macrophages into the CNS. Intrathecal injection of specific antigen induced a strong increase of MCP-1 and MIP-1α mRNA within the CNS (Fig. S2 A) followed by concomitant recruitment of ED1+ monocytes/macrophages into the CNS (Fig. S2 B) and aggravation of clinical disease (Fig. 6, A and B).


The activation status of neuroantigen-specific T cells in the target organ determines the clinical outcome of autoimmune encephalomyelitis.

Kawakami N, Lassmann S, Li Z, Odoardi F, Ritter T, Ziemssen T, Klinkert WE, Ellwart JW, Bradl M, Krivacic K, Lassmann H, Ransohoff RM, Volk HD, Wekerle H, Linington C, Flügel A - J. Exp. Med. (2004)

Quantitative chemokine mRNA expression in the CNS. The relative amount of mRNA transcripts for (A) MCP-1 and (B) MIP-1α was analyzed from spinal cord tissue of MBP-EAE (MBP), S100β-EAE (S100), and control animals (control) by dot blot hybridization at days 2 and 4 after transfer. Note the massive up-regulation of MCP-1 and MIP-1α mRNA in the CNS of TMBP cell–treated, but not in the TS100β cell–treated, animals. Amplification of β-tubulin and analysis on ethidium bromide–stained agarose gels demonstrated intact RNA in all samples (not depicted). The data were confirmed in a second set of independently prepared samples.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211765&req=5

fig7: Quantitative chemokine mRNA expression in the CNS. The relative amount of mRNA transcripts for (A) MCP-1 and (B) MIP-1α was analyzed from spinal cord tissue of MBP-EAE (MBP), S100β-EAE (S100), and control animals (control) by dot blot hybridization at days 2 and 4 after transfer. Note the massive up-regulation of MCP-1 and MIP-1α mRNA in the CNS of TMBP cell–treated, but not in the TS100β cell–treated, animals. Amplification of β-tubulin and analysis on ethidium bromide–stained agarose gels demonstrated intact RNA in all samples (not depicted). The data were confirmed in a second set of independently prepared samples.
Mentions: The neurological deficits in EAE seem to be caused by activated macrophages recruited to the CNS (19, 20). Indeed, CNS infiltrates induced by highly encephalitogenic TMBP-GFP and TDA-MOG-GFP cells contained large numbers of activated ED1+ macrophages, whereas these cells were rare in the CNS infiltrates induced by weakly pathogenic TS100β-GFP and TLE-MOG-GFP cells (Fig. 2 and Table II). Therefore, we compared the levels of macrophage-attracting CC chemokines MCP-1 and MIP-1α (21, 22) with both types of lesion. Quantification of MCP-1 and MIP-1α mRNA transcripts by RT-PCR in Lewis rats injected with either TMBP or TS100β cells revealed that, in animals injected with TMBP cells, MCP-1 and MIP-1α transcripts increased dramatically by day 4 coincident with the onset of clinical EAE (Fig. 7) . In contrast, in rats injected with S100β-specific T cells, there was no corresponding increase in the signals for MCP-1 and MIP-1α, which remained ∼10-fold lower than in animals with MBP-induced EAE (Fig. 7). Therefore, partial activation of T cells within the CNS can trigger the sustained recruitment of T cells into the lesions, but it is insufficient to activate MCP-1 and MIP-1α expression, which mediate the recruitment of macrophages into the CNS. Intrathecal injection of specific antigen induced a strong increase of MCP-1 and MIP-1α mRNA within the CNS (Fig. S2 A) followed by concomitant recruitment of ED1+ monocytes/macrophages into the CNS (Fig. S2 B) and aggravation of clinical disease (Fig. 6, A and B).

Bottom Line: Irrespective of their pathogenicity, the migratory activity, gene expression patterns, and immigration of green fluorescent protein(+) T cells into the CNS were similar.However, exclusively highly pathogenic T cells were significantly reactivated within the CNS.Low-level reactivation of weakly pathogenic T cells was not due to anergy because these cells could be activated by specific antigen in situ as well as after isolation ex vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroimmunology, Max-Planck Institute for Neurobiology, 82152 Martinsried, Germany.

ABSTRACT
The clinical picture of experimental autoimmune encephalomyelitis (EAE) is critically dependent on the nature of the target autoantigen and the genetic background of the experimental animals. Potentially lethal EAE is mediated by myelin basic protein (MBP)-specific T cells in Lewis rats, whereas transfer of S100beta- or myelin oligodendrocyte glycoprotein (MOG)-specific T cells causes intense inflammatory response in the central nervous system (CNS) with minimal disease. However, in Dark Agouti rats, the pathogenicity of MOG-specific T cells resembles the one of MBP-specific T cells in the Lewis rat. Using retrovirally transduced green fluorescent T cells, we now report that differential disease activity reflects different levels of autoreactive effector T cell activation in their target tissue. Irrespective of their pathogenicity, the migratory activity, gene expression patterns, and immigration of green fluorescent protein(+) T cells into the CNS were similar. However, exclusively highly pathogenic T cells were significantly reactivated within the CNS. Without local effector T cell activation, production of monocyte chemoattractants was insufficient to initiate and propagate a full inflammatory response. Low-level reactivation of weakly pathogenic T cells was not due to anergy because these cells could be activated by specific antigen in situ as well as after isolation ex vivo.

Show MeSH
Related in: MedlinePlus