The Tissue-Specific Self-Pathogen Is the Protective Self-Antigen: The Case of Uveitis

Mizrahi, Tal; Hauben, Ehud; Schwartz, Michal

doi:10.4049/jimmunol.169.10.5971

Cited by 67 publications

(48 citation statements)

References 40 publications

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“…Hence, the potential ability of T cells to modulate a neuroprotective response via glutamate is consistent with previously published observations suggesting that recognition between the neuroprotective T cells and Ag is required before initiation of the neuroprotective immune response (64).…”

Section: Discussionsupporting

confidence: 90%

Neuroprotective Immunity: T Cell-Derived Glutamate Endows Astrocytes with a Neuroprotective Phenotype

Garg

Banerjee

Kipnis

2008

The Journal of Immunology

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A well-controlled T cell response to CNS injury may result in increased neuronal survival. However, the precise mechanism of T cell-induced neuroprotection is unknown. In this study, we report the unexpected finding that during culture of T cells, high levels of glutamate accumulate, which are efficiently cleared if T cells are cocultured with astrocytes. The T cell-derived glutamate elicits in turn, the release of neuroprotective thiols (cysteine, glutathione, and cysteinyl-glycine) and lactate from astrocytes. Media obtained from astrocytes conditioned in the presence of T cells reduce neuronal apoptosis induced by oxidative stress in primary neuronal cultures from 48 ± 14 to 9 ± 4% (p < 0.001). Inhibition of glutamate-dependent signaling during astrocyte-T cell cocultivation by a glutamate uptake inhibitor, l-aspartic acid β-hydroxamate, abolishes this neuroprotective effect. The ability of astrocytes to clear extracellular glutamate is impaired under conditions of oxidative stress. We demonstrate that T cells, via secreted cytokines, restore glutamate clearance capacity of astrocytes under oxidative conditions. Furthermore, under normoxic conditions, glutamate-buffering capacity of astrocytes is increased upon cocultivation with T cells. It is known that, following CNS injury, astrocytes can respond with beneficial or destructive effects on neurons. However, the context and signaling mechanisms for this dual astrocytic response are unknown. Our results implicate T cells as potential determinants of the context that elicits a protective role for astrocytes in the damaged CNS.

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Section: Discussionsupporting

confidence: 90%

Neuroprotective Immunity: T Cell-Derived Glutamate Endows Astrocytes with a Neuroprotective Phenotype

Garg

Banerjee

Kipnis

2008

The Journal of Immunology

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“…Relative to normal rodents, those deprived of mature T cells lose significantly more neurons after a CNS insult (13,15). Experimental evidence suggests that, under stress, the CNS signals to the immune system, evoking an adaptive immune response that is directed against abundant antigens residing at the site of the lesion (15,16,31,32). Individuals differ in their ability to spontaneously evoke such an immune response (13).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, T helper 1 cells directed against immunodominant proteins were shown to be capable of inducing autoimmune disease, as well as neuroprotection (34). Disease-free protection was achieved by inducing an immune response against cryptic epitopes residing within the same potentially pathogenic immune-abundant protein, or by using an altered pathogenic peptide to eliminate the potential pathogenicity of the peptide (17,32).…”

Section: Discussionmentioning

confidence: 99%

Therapeutic vaccine for acute and chronic motor neuron diseases: Implications for amyotrophic lateral sclerosis

Angelov

Waibel

Guntinas‐Lichius

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

178

104

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Therapeutic vaccination with Copaxone (glatiramer acetate, Cop-1) protects motor neurons against acute and chronic degenerative conditions. In acute degeneration after facial nerve axotomy, the number of surviving motor neurons was almost two times higher in Cop-1-vaccinated mice than in nonvaccinated mice, or in mice injected with PBS emulsified in complete Freund's adjuvant (P < 0.05). In mice that express the mutant human gene Cu͞Zn superoxide dismutase G93A (SOD1), and therefore simulate the chronic human motor neuron disease amyotrophic lateral sclerosis, Cop-1 vaccination prolonged life span compared to untreated matched controls, from 211 ؎ 7 days (n ‫؍‬ 15) to 263 ؎ 8 days (n ‫؍‬ 14; P < 0.0001). Our studies show that vaccination significantly improved motor activity. In line with the experimentally based concept of protective autoimmunity, these findings suggest that Cop-1 vaccination boosts the local immune response needed to combat destructive self-compounds associated with motor neuron death. Its differential action in CNS autoimmune diseases and neurodegenerative disorders, depending on the regimen used, allows its use as a therapy for either condition. Daily administration of Cop-1 is an approved treatment for multiple sclerosis. The protocol for non-autoimmune neurodegenerative diseases such as amyotrophic lateral sclerosis, remains to be established by future studies.

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“…11 Furthermore, immune neuroprotection is antigen-specific, and aimed at antigens expressed at the site of insult. 6,12,13 In addition to the role of CNSspecific T cells in CNS repair, our group has found that adaptive immune cells are key players in CNS maintenance under nonpathological conditions, especially in hippocampal plasticity. 9,14 We showed that autoreactive T cells are needed to support hippocampal-dependent learning and memory tasks, as well as for the regulation of adult hippocampal neurogenesis and neurotrophic factor production, 14 possibly by regulating microglial phenotype.…”

Section: Introductionmentioning

confidence: 99%

Behavioral immunization: immunity to self-antigens contributes to psychological stress resilience

Lewitus

Schwartz

2008

Mol Psychiatry

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The psychobiological mechanisms that contribute to the development of stress resilience are not fully elucidated. One potential approach for enhancing resilience is the exposure to mild challenges. According to this approach, a mildly stressful episode may immunize the individual, thereby strengthening resistance to subsequent stressors. This phenomenon is often viewed as a form of behavioral immunization. Although, the term 'behavioral immunization' was borrowed from the field of immunology, the involvement of the adaptive immune system in stress resilience was never investigated. However, based on accumulated new data, we suggest that the immunological memory does have a significant role in developing coping responses to stress. Although, immune deficiency results in an impaired ability to cope with stress, boosting immunological memory can increase stress resilience. Therefore, we propose that defense against mental challenge, similarly to defense against intruders, involves an immunological mechanism, which establishes stress resilience to a later challenge. Here, we review the involvement of the adaptive immune system in coping mechanisms in response to psychological stress, and discuss the connection between cognitive memory and immunological memory in establishing ability to efficiently cope with stressful episodes.

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The Tissue-Specific Self-Pathogen Is the Protective Self-Antigen: The Case of Uveitis

Cited by 67 publications

References 40 publications

Neuroprotective Immunity: T Cell-Derived Glutamate Endows Astrocytes with a Neuroprotective Phenotype

Neuroprotective Immunity: T Cell-Derived Glutamate Endows Astrocytes with a Neuroprotective Phenotype

Therapeutic vaccine for acute and chronic motor neuron diseases: Implications for amyotrophic lateral sclerosis

Behavioral immunization: immunity to self-antigens contributes to psychological stress resilience

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