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Bone marrow has an unrecognized role in multiple sclerosis

Apr 5, 2023 | Neuroscience

Multiple sclerosis (MS), as one of the most important neurological diseases, is characterized by multiple areas of inflammation and demyelination in the white matter of the brain and spinal cord. The clinician manifestations are protean, determined by the various locations and extent of the demyelinating foci. Demyelinating lesions of the central nervous system (CNS), MS plaques, are characterized by infiltration of mononuclear cells, the proliferation of macrophages, and loss of oligodendrocytes, myelin-producing cells. In this article, Chinese authors investigated the unrecognized role that bone marrow, as the primary site of hematopoiesis, has in multiple sclerosis.

In relapsing-remitting MS, infiltrating immune cells are considered to be primed in the periphery and reactivated in the CNS by local antigen-presenting cells. Macrophage-type cells are considered the most important antigen-presenting cells in the inflammatory lesions of MS, as well as true effectors of the clinical and pathological expression of the disease. The massive infiltration of leukocytes into the CNS suggests their rapid consumption from limited peripheral reserves and the dynamic production and supply from the bone marrow. Upon entry into the CNS, autoreactive T cells induce a cascade of cytokines and chemokines, which recruit hematogenic myeloid cells, neutrophils, and monocytes.

Chemokines are small proteins that attract different cytokines, cells, and substances to specific sites. Depending on the number of amino acids between the first two cysteine residues, the chemokines are classified into four subfamilies, CXC, CC, CX3C, and XC. The majority of inflammatory cells can express the CCL5 chemokine which has the highest affinity for the receptor CCR5. T-cells and monocytes are the most common cell types that express CCL5. Chemokine CXCL12, i.e. stromal cells- derived factor-1, is a key factor derived from bone marrow stromal cells. This chemokine binds to its cognate receptor CXCR4 and attracts the target cells to the bone marrow.

About the study

The research team utilized a single-cell analysis of bone marrow biopsy samples from treatment-naive MS patients and found that autoreactive T cells migrate into the bone marrow via the CXCL12- CXCR4 axis. Using a mouse model for MS, experimental autoimmune encephalomyelitis, the authors confirmed in vivo that the CXCL12-CXCR4 axis is necessary for autoreactive T cells to migrate into the bone marrow.

Researchers then quantified the factors derived from the bone marrow-residing T cells to understand how autoreactive T cells induce bone marrow myelopoiesis. They found that among 113 cytokines measured, the cytokine CCL5, also called RANTES, was highly expressed by CD4+ T cells. These results show that T lymphocytes residing in the bone marrow are a major source of CCL5.

According to the authors, autoreactive T-cells augment myelopoiesis (but not lymphopoiesis) of hematopoietic stem and progenitor cells involving the CCL5-CCR5 axis. Consequently, myelopoiesis increases bone marrow myeloid cells which can invade the CNS and accelerate inflammation and demyelination. Although the current understanding of the role of autoreactive T lymphocytes in MS pathogenesis is focused on their expansion into lymphoid organs and penetration into the CNS, this study revealed that bone marrow, as the primary site of hematopoiesis, has an unrecognized role in MS, promoting intimate interactions between autoreactive T cells and hematopoietic cells.

Conclusion

The results of this article showed that bone marrow, as the primary site of hematopoiesis, has an unrecognized role in multiple sclerosis. The authors concluded that these findings that highlight the role of myelopoiesis in the development of autoimmune encephalomyelitis might provide a therapeutic opportunity for MS. Restricting the migration of autoreactive T lymphocytes into the bone marrow can suppress harmful myelopoiesis in MS.

The article was published in Cell.

Journal Reference

Shi K, et al. Bone marrow hematopoiesis drives multiple sclerosis progression. Cell 2022; 185, 2234–2247. (Open Access)  https://doi.org/10.1016/j.cell.2022.05.020

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