Abstract
Several virus-induced models were used to study the underlying mechanisms of multiple sclerosis (MS). The infection of susceptible mice with Theiler’s murine encephalomyelitis virus (TMEV) establishes persistent viral infections and induces chronic inflammatory demyelinating disease. In this review, the innate and adaptive immune responses to TMEV are discussed to better understand the pathogenic mechanisms of viral infections. Professional (dendritic cells (DCs), macrophages, and B cells) and non-professional (microglia, astrocytes, and oligodendrocytes) antigenpresenting cells (APCs) are the major cell populations permissive to viral infection and involved in cytokine production. The levels of viral loads and cytokine production in the APCs correspond to the degrees of susceptibility of the mice to the TMEV-induced demyelinating diseases. TMEV infection leads to the activation of cytokine production via TLRs and MDA-5 coupled with NF-κB activation, which is required for TMEV replication. These activation signals further amplify the cytokine production and viral loads, promote the differentiation of pathogenic Th17 responses, and prevent cellular apoptosis, enabling viral persistence. Among the many chemokines and cytokines induced after viral infection, IFN α/β plays an essential role in the downstream expression of costimulatory molecules in APCs. The excessive levels of cytokine production after viral infection facilitate the pathogenesis of TMEV-induced demyelinating disease. In particular, IL-6 and IL-1β play critical roles in the development of pathogenic Th17 responses to viral antigens and autoantigens. These cytokines, together with TLR2, may preferentially generate deficient FoxP3+ CD25- regulatory cells converting to Th17. These cytokines also inhibit the apoptosis of TMEV-infected cells and cytolytic function of CD8+ T lymphocytes (CTLs) and prolong the survival of B cells reactive to viral and self-antigens, which preferentially stimulate Th17 responses.
Original language | English (US) |
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Article number | 5254 |
Journal | International journal of molecular sciences |
Volume | 22 |
Issue number | 10 |
DOIs | |
State | Published - May 2 2021 |
Funding
Funding: This work was supported by the United States Public Health Service Grants (RO1 NS28752 and RO1 NS33008) and a grant from the National Multiple Sclerosis Society (RG 4001-A6).
Keywords
- Demyelination
- FoxP3 CD4 T cells
- Inflammation
- Th cells
- Virus
ASJC Scopus subject areas
- Molecular Biology
- Spectroscopy
- Catalysis
- Inorganic Chemistry
- Computer Science Applications
- Physical and Theoretical Chemistry
- Organic Chemistry