Spontaneous and Induced CD8 T Cell Lesions in the Central Nervous System of HLA-DR15-Positive Multiple Sclerosis Patient-Derived Humanized Mice

Belangrijkste concepten

Humanized mice engrafted with peripheral blood mononuclear cells from HLA-DR15-positive multiple sclerosis patients develop spontaneous and induced inflammatory lesions in the brain and spinal cord, predominantly composed of CD8 T cells.

Samenvatting

The study describes the development of a humanized mouse model using peripheral blood mononuclear cells (PBMCs) from multiple sclerosis (MS) patients and healthy individuals to investigate the immunopathology of MS in the central nervous system (CNS).

Key findings:

• B2m-NOG mice engrafted with PBMCs from HLA-DR15-positive MS patients, but not HLA-DR13-positive MS patients or HLA-DR15-positive healthy individuals, developed spontaneous infiltration of CD8+ T cells in the brain and spinal cord.
• Immunization of the humanized mice with myelin peptides further increased CD4+ T cell infiltration, leading to mixed CD4+/CD8+ T cell lesions in the brain and spinal cord of HLA-DR15-positive MS mice.
• The inflammatory lesions were associated with local activation of microglia and astrocytes but lacked infiltration of human or mouse monocytes and did not result in clinical symptoms or demyelination.
• The model highlights the importance of the HLA-DR15 genotype in driving spontaneous and induced CD8+ T cell-mediated CNS inflammation in a patient-specific manner.

Statistieken

Mice engrafted with PBMCs from HLA-DR15-positive MS patients showed higher numbers of parenchymal CD3+ T cell lesions in the spinal cord grey matter compared to HLA-DR15-positive healthy individuals.
Immunized HLA-DR15-positive MS mice developed large confluent lesions in the brain white matter, including the corpus callosum, containing both CD4+ and CD8+ T cells.

Citaten

"Mice engrafted with PBMCs from HLA-DR15-positive MS patients uniquely developed spontaneous T cell lesions in spinal cord grey matter and brain parenchyma."
"Immunization with myelin peptides increased CD4+ T cell infiltration, leading to mixed CD4+/CD8+ T cell lesions in the brain and spinal cord of HLA-DR15-positive MS mice."

Belangrijkste Inzichten Gedestilleerd Uit

Spontaneous human CD8 T cell and EAE-inducible human CD4/CD8 T cell lesions in the brain and spinal cord of HLA-DRB1*15-positive multiple sclerosis PBMC humanized mice

by Papazian,I.,... om www.biorxiv.org 06-07-2023

https://www.biorxiv.org/content/10.1101/2023.06.07.543414v3

Diepere vragen

How do the spontaneous and induced inflammatory lesions in the humanized mouse model compare to the lesion pathology observed in MS patients?

In the humanized mouse model, both spontaneous and induced inflammatory lesions in the brain and spinal cord showed similarities to the lesion pathology observed in MS patients. The model exhibited features such as infiltration of human CD8+ T cells in the CNS borders and parenchyma, which is a hallmark of MS pathology. Additionally, the presence of mixed hCD4/hCD8 T cell lesions in the brain and spinal cord of the humanized mice after immunization with myelin peptides mirrors the immune cell composition seen in MS lesions. The localization and severity of the lesions varied between different patient donors, reflecting the heterogeneity of MS pathology observed in patients.

What are the potential mechanisms by which the HLA-DR15 genotype contributes to the development of CD8+ T cell-mediated CNS inflammation in MS?

The HLA-DR15 genotype is strongly associated with MS and has been linked to an increased risk of developing the disease. One potential mechanism by which the HLA-DR15 genotype contributes to CD8+ T cell-mediated CNS inflammation in MS is through its role in antigen presentation. HLA-DR15 molecules are involved in presenting antigens to CD4+ T cells, which can then activate CD8+ T cells. This process may lead to the activation and infiltration of CD8+ T cells into the CNS, contributing to the inflammatory response seen in MS lesions. Additionally, the HLA-DR15 genotype has been associated with T cell autoproliferation, which could further exacerbate the immune response in the CNS and contribute to the development of inflammation and lesions.

Can this humanized mouse model be further developed to incorporate human myeloid cells and recapitulate the full spectrum of MS immunopathology, including demyelination and clinical symptoms?

The humanized mouse model described in the study has shown promise in replicating certain aspects of MS immunopathology, such as T cell infiltration and inflammation in the CNS. To further develop the model and recapitulate the full spectrum of MS immunopathology, including demyelination and clinical symptoms, incorporating human myeloid cells is crucial. Human monocytes play a significant role in the pathogenesis of MS, and their absence in the current model limits the ability to fully replicate the disease process. By modifying the model to allow for the engraftment of human myeloid cells, such as monocytes, and enhancing lymph node organization, researchers may be able to better mimic the complex immune responses and demyelination observed in MS patients. Additionally, optimizing the model to induce clinical symptoms of EAE, such as motor deficits, would be essential for studying the full spectrum of MS pathology and evaluating potential therapeutic interventions.