Response-Letter zu „A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis“ (Ugur Sahin et al, Science 08 Jan 2021: Vol. 371, Issue 6525, pp. 145-153, DOI: 10.1126/science.aay3638)
- Fatme Seval Ismail, Neurologist, Department of Neurology, University Hospital Knappschaftskrankenhaus Bochum, Ruhr University Bochum, Germany
- Other Contributors:
- Sven G. Meuth, Neurologist, Department of Neurology, Heinrich-Heine University of Düsseldorf, Germany
- Nico Melzer, Neurologist, Department of Neurology, Heinrich-Heine University of Düsseldorf, Germany
(17 June 2021)
Future perspectives of mRNA vaccines in autoimmune CNS diseases
Fatme Seval Ismail1*, Sven G. Meuth2, Nico Melzer2
1Department of Neurology, University Hospital Knappschaftskrankenhaus Bochum, Ruhr University Bochum; In der Schornau 23-25, 44892 Bochum, Germany.
2Department of Neurology, Heinrich-Heine University of Düsseldorf; Moorenstraße 5, 40225 Düsseldorf, Germany.
*Corresponding author. Email: FatmeSeval.Ismail@kk-bochum.de
During the present coronavirus disease 2019 (COVID-19) pandemic, the first messenger RNA (mRNA)-based vaccines were approved in humans, supporting a new era in vaccinology (1, 2). mRNA vaccines are distinguished by high potency, cost efficiency, rapid development, safe administration, and the potential that virtually any (auto-)antigen can be encoded by mRNA (3).
Now, a recent study published in Science demonstrated that mRNA-based vaccines can also induce antigen-specific tolerance as a therapeutic approach for autoimmune diseases (4). Selective, nanoparticulate delivery of nucleoside-modified, auto-antigen-encoding mRNA (1-methylpseudouridine (m1Ψ) mRNA) into lymphoid tissue-resident CD11c+ antigen-presenting cells (APCs) led to induction and maintenance of peripheral tolerance in mouse models of multiple sclerosis (4). The presentation of auto-antigens in a non-inflammatory context reduced the effector T cells (Teff cell) and induced the development of regulatory T cell (Treg cell) populations as well as up-regulation of exhaustion markers such as CTLA-4 and PD-1 on antigen-specific CD4+ T cells. This led to therapeutically effective bystander immunosuppression mediated by Treg cells, but the immune response to completely unrelated antigens was not affected. In brief, expression of co-inhibitory receptors such as CTLA-4 and PD-1 on effector Treg cells contributed to suppression of disease-mediating TH1, TH17 and TH1/TH17 Teff cell populations. The authors pointed out that the m1Ψ mRNA approach enables personalization of vaccines such as in cancer and combination of different auto-antigens. In this context, m1Ψ mRNA vaccines might be applied in other autoimmune diseases of the central nervous system (CNS).
Autoimmune neurological diseases associated with pathogenic autoantibodies (Abs) i.e. adaptive immune responses against specific antigens are particularly interesting in this regard, e.g., autoimmune encephalitis, a group of inflammatory brain diseases associated with Abs against neuronal cell-surface proteins, ion channels, or receptors (5, 6). The N-methyl-D-aspartate receptor (NMDAR) encephalitis represents the most common form of autoimmune encephalitis, the type with Abs against the leucine-rich, glioma-inactivated 1 (LGI1) the second most common form (5). Other targets of Abs associated with autoimmune encephalitis are α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), γ-aminobutyric acid (GABA) type A or B receptor (GABAA/BR), contactin-associated protein-like 2 (CASPR2), dipeptidyl-peptidase-like protein 6 (DPPX), metabotropic glutamate receptor 5 (mGluR5), dopamine 2 receptor (D2R), Neurexin-3α. Two well-known triggers of autoimmune encephalitis are systemic tumors and viral encephalitis of the CNS such as Herpes simplex virus. Dalmau and colleagues proposed that antigens released by virus-induced neuronal cell destruction or apoptotic tumor cells are phagocytized and processed by APCs such as dendritic cells that migrate to regional lymph nodes and present the antigens to naive B cells in conjunction with CD4+ T cells (5, 6). Following this, the B cells differentiate into antibody-producing plasma cells. They can enter the brain and undergo restimulation, antigen-driven affinity maturation, and clonal expansion. In vitro studies with cultured neurons showed that Abs can affect neuronal function through different mechanisms: e.g., receptor cross-linking and internalization (NMDAR Abs), functional blocking of the target antigen (GABABR), and disruption of protein–protein interactions (LGI1 Abs), potentially altering the function of the voltage-gated potassium channels and decreasing the levels of AMPAR (5, 6). In a mouse model, the passive cerebroventricular transfer of Abs from the cerebrospinal fluid of affected patients led to NMDAR internalization and impairment of memory. The alterations gradually improved after stopping of the Ab infusion (5, 7, 8). Use of m1Ψ mRNA encoding neuronal antigens such as NMDAR, LGI1 or others mentioned above in a non-inflammatory context could be tested in animal models of autoimmune encephalitis as a new treatment perspective for this group of autoimmunity. Dendritic cells as APCs exposed to m1Ψ mRNA could induce antigen-specific T cell tolerance to prevent B cell activation and differentiation in Ab-producing plasma cells, supporting our theory that dendritic cells are involved as potential modulators in the immunopathogenesis of Ab-associated autoimmune encephalitis.
References and Notes:
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Author contributions: FSI was responsible for conception and planning. All authors were responsible for analysis and interpretation of the data. FSI drafted the manuscript. All authors edited and approved the final manuscript.
Competing interests: Authors declare that they have no competing interests.