Regional CNS responses to IFN-γ determine lesion localization patterns during EAE pathogenesis

Lees, Jason R.; Golumbek, Paul T.; Sim, Julia; Dorsey, Denise A.; Russell, John H.

doi:10.1084/jem.20080155

Cited by 152 publications

(162 citation statements)

References 49 publications

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“…Although this may be the case for the spinal cord as a unit, it does not always hold true for the CNS because, as shown in mice with PLPinduced EAE, there is early (preclinical) blood-brain barrier breakdown, particularly in the cerebellum (29). Similar observations obtained with histochemical and MR imaging techniques have been reported (3,30,31). The regional differences in the sensitivity of brain areas to upregulation of inflammatory molecules earlier or more rapidly (after encephalitogenic T cells producing a variety of proinflammatory molecules have passed through these areas) influence the susceptibility of different brain regions to neuroinflammation.…”

Section: Discussionsupporting

confidence: 71%

Central Nervous System Expression and PET Imaging of the Translocator Protein in Relapsing–Remitting Experimental Autoimmune Encephalomyelitis

et al. 2013

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Glial neuroinflammation is associated with the development and progression of multiple sclerosis. PET imaging offers a unique opportunity to evaluate neuroinflammatory processes longitudinally in a noninvasive and clinically translational manner. 18 F-PBR111 is a newly developed PET radiopharmaceutical with high affinity and selectivity for the translocator protein (TSPO), expressed on activated glia. This study aimed to investigate neuroinflammation at different phases of relapsing-remitting (RR) experimental autoimmune encephalomyelitis (EAE) in the brains of SJL/J mice by postmortem histologic analysis and in vivo by PET imaging with 18 F-PBR111. Methods: RR EAE was induced by immunization with PLP 139-151 peptide in complete Freund's adjuvant. Naive female SJL/J mice and mice immunized with saline-complete Freund's adjuvant were used as controls. The biodistribution of 18 F-PBR111 was measured in 13 areas of the central nervous system and compared with PET imaging results during different phases of RR EAE. The extents of TSPO expression and glial activation were assessed with immunohistochemistry, immunofluorescence, and a real-time polymerase chain reaction. Results: There was significant TSPO expression in all of the central nervous system areas studied at the peak of the first clinical episode and, importantly, at the preclinical stage. In contrast, only a few TSPO-positive cells were observed at the second episode. At the third episode, there was again an increase in TSPO expression. TSPO expression was associated with microglial cells or macrophages without obvious astrocyte labeling. The dynamics of 18 F-PBR111 uptake in the brain, as measured by in vivo PET imaging and biodistribution, followed the pattern of TSPO expression during RR EAE. Conclusion: PET imaging with the TSPO ligand 18 F-PBR111 clearly reflected the dynamics of microglial activation in the SJL/J mouse model of RR EAE. The results are the first to highlight the discrepancy between the clinical symptoms of EAE and TSPO expression in the brain, as measured by PET imaging at the peaks of various EAE episodes. The results suggest a significant role for PET imaging investigations of neuroinflammation in multiple sclerosis and allow for in vivo follow-up of antiinflammatory treatment strategies.

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Section: Discussionsupporting

confidence: 71%

Central Nervous System Expression and PET Imaging of the Translocator Protein in Relapsing–Remitting Experimental Autoimmune Encephalomyelitis

et al. 2013

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“…It is important to note that EAE is severe and often fatal in GKO mice (25,26,40). Nearly two thirds of the placebo-treated GKO mice developed an atypical axial-rotary disease phenotype that has been attributed to cerebellar and brainstem inflammation (41,42). In- Table I).…”

Section: 25-(oh) 2 D 3 Prevented Fatal Progressive Eae In Gko Micementioning

confidence: 99%

TheIfngGene Is Essential forVdrGene Expression and Vitamin D3-Mediated Reduction of the Pathogenic T Cell Burden in the Central Nervous System in Experimental Autoimmune Encephalomyelitis, a Multiple Sclerosis Model

Spanier

Nashold

Olson

et al. 2012

The Journal of Immunology

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Compelling evidence suggests that vitamin D3 insufficiency may contribute causally to multiple sclerosis (MS) risk. Experimental autoimmune encephalomyelitis (EAE) research firmly supports this hypothesis. Vitamin D3 supports 1,25-dihydroxyvitamin D3 (1,25-[OH]2D3) synthesis in the CNS, initiating biological processes that reduce pathogenic CD4+ T cell longevity. MS is prevalent in Sardinia despite high ambient UV irradiation, challenging the vitamin D–MS hypothesis. Sardinian MS patients frequently carry a low Ifng expresser allele, suggesting that inadequate IFN-γ may undermine vitamin D3-mediated inhibition of demyelinating disease. Testing this hypothesis, we found vitamin D3 failed to inhibit EAE in female Ifng knockout (GKO) mice, unlike wild-type mice. The two strains did not differ in Cyp27b1 and Cyp24a1 gene expression, implying equivalent vitamin D3 metabolism in the CNS. The 1,25-(OH)2D3 inhibited EAE in both strains, but 2-fold more 1,25-(OH)2D3 was needed in GKO mice, causing hypercalcemic toxicity. Unexpectedly, GKO mice had very low Vdr gene expression in the CNS. Injecting IFN-γ intracranially into adult mice did not increase Vdr gene expression. Correlating with low Vdr expression, GKO mice had more numerous pathogenic Th1 and Th17 cells in the CNS, and 1,25-(OH)2D3 reduced these cells in GKO and wild-type mice without altering Foxp3+ regulatory T cells. Thus, the Ifng gene was needed for CNS Vdr gene expression and vitamin D3-dependent mechanisms that inhibit EAE. Individuals with inadequate Ifng expression may have increased MS risk despite high ambient UV irradiation because of low Vdr gene expression and a high encephalitogenic T cell burden in the CNS.

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“…Results from many laboratories point to critical roles for both cytokines (1, 2), although neither is absolutely required for EAE (3,4), and indeed, Ifng 2/2 mice develop more severe disease (5,6). Individual T cells in EAE and MS can produce both cytokines (7), and current thinking suggests that the balance between IL-17 and IFN-g determines the outcome of disease (8,9). It is therefore necessary to better understand how these cytokines are controlled.…”

mentioning

confidence: 99%

Inflammation in the Central Nervous System and Th17 Responses Are Inhibited by IFN-γ–Induced IL-18 Binding Protein

Millward

Løbner

Wheeler

et al. 2010

The Journal of Immunology

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Regional CNS responses to IFN-γ determine lesion localization patterns during EAE pathogenesis

Cited by 152 publications

References 49 publications

Central Nervous System Expression and PET Imaging of the Translocator Protein in Relapsing–Remitting Experimental Autoimmune Encephalomyelitis

Central Nervous System Expression and PET Imaging of the Translocator Protein in Relapsing–Remitting Experimental Autoimmune Encephalomyelitis

TheIfngGene Is Essential forVdrGene Expression and Vitamin D3-Mediated Reduction of the Pathogenic T Cell Burden in the Central Nervous System in Experimental Autoimmune Encephalomyelitis, a Multiple Sclerosis Model

Inflammation in the Central Nervous System and Th17 Responses Are Inhibited by IFN-γ–Induced IL-18 Binding Protein

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