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Determining Immune System Suppression versus CNS Protection for Pharmacological Interventions in Autoimmune Demyelination
Published on: September 12, 2016
Self-reactive CD4(+) T cells activated during viral-induced demyelination do not prevent clinical recovery
Carine Savarin1, Cornelia C Bergmann2, Melanie Gaignage3,4
1Department of Neurosciences NC-30, Lerner Research Institute, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH, 44195, USA. savaric@ccf.org.
Background:
Microbial infections have been implicated in initiating and enhancing severity of autoimmune diseases including the demyelinating disease multiple sclerosis (MS). Nevertheless, the incidence of both acute and persisting viral infections without evidence of autoimmune sequelae suggests that this process is well controlled. The conditions promoting or stemming self-reactive (SR) T cells following viral-induced tissue damage thus need to be better defined. Using a non-fatal viral mouse model of encephalomyelitis associated with demyelination and disability, yet ultimate clinical improvement, this study set out to monitor uptake and presentation of endogenous myelin antigens, as well as induction and fate of SR T cells.
Methods:
Activation and central nervous system (CNS) recruitment of myelin-specific CD4 T cells was analyzed by flow cytometry during encephalomyelitis induced by a glia tropic murine coronavirus. Potential antigen-presenting cells (APC) ingesting myelin were characterized by flow cytometry and their ability to activate SR T cells tested by co-culture with carboxyfluorescein succinimidyl ester (CFSE)-labeled myelin-specific CD4 T cells. Endogenous SR T cell kinetics was analyzed within both cervical lymph nodes and CNS by Enzyme-Linked ImmunoSpot (ELISPOT) following viral infection.
Results:
The data demonstrate the presence of APC capable of activating SR T cells in both draining lymph nodes and the CNS temporally correlating with overt demyelination. While both the CNS-infiltrating myeloid population and microglia ingested myelin, only CNS-infiltrating APC were capable of presenting endogenous myelin antigen to SR T cells ex vivo. Finally, SR T cell activation from the endogenous T cell repertoire was most notable when infectious virus was controlled and paralleled myelin damage. Although SR T cell accumulation peaked in the persistently infected CNS during maximal demyelination, they were not preferentially retained. Their gradual decline, despite ongoing demyelination, suggested minimal re-stimulation and pathogenic function in vivo consistent with the lack of autoimmune symptoms.
Conclusions:
The results demonstrate the potential for CNS tissue destruction to induce and recruit SR T cells to the injury site and support a host suppressive mechanism limiting development of autoimmunity.
Insights
Viral infections can trigger autoimmune responses, but this study shows the body controls self-reactive T cells after viral-induced tissue damage. This suggests a natural mechanism prevents autoimmunity following central nervous system injury.
Area of Science:
- Neuroimmunology
- Viral Pathogenesis
- Autoimmunity
Background:
- Microbial infections are linked to autoimmune diseases like multiple sclerosis (MS).
- However, viral infections often occur without autoimmune consequences, indicating effective host control.
- Understanding factors influencing self-reactive (SR) T cell responses post-viral injury is crucial.
Purpose of the Study:
- To investigate the uptake and presentation of endogenous myelin antigens.
- To monitor the induction and fate of self-reactive (SR) T cells following viral-induced demyelination.
- To define conditions that promote or suppress SR T cell activation after viral tissue damage.
Main Methods:
- A non-fatal viral encephalomyelitis mouse model was used.
- Flow cytometry analyzed myelin-specific CD4 T cell activation and CNS recruitment.
- Antigen-presenting cells (APCs) ingesting myelin were identified, and their SR T cell activation capacity was tested via co-culture.
- Enzyme-Linked ImmunoSpot (ELISPOT) assays tracked endogenous SR T cell kinetics in lymph nodes and CNS.
Main Results:
- APCs capable of activating SR T cells were found in draining lymph nodes and the CNS during demyelination.
- Both myeloid cells and microglia ingested myelin, but only CNS-infiltrating APCs presented myelin antigen ex vivo.
- SR T cell activation was most prominent when viral infection was controlled and correlated with myelin damage.
- SR T cells declined in the CNS despite ongoing demyelination, suggesting limited re-stimulation and pathogenic function.
Conclusions:
- Central nervous system (CNS) tissue damage can induce and recruit SR T cells.
- Host-based suppressive mechanisms appear to limit the development of autoimmunity following viral injury.
- These findings highlight the body's capacity to manage autoimmune responses after CNS damage.
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