T-cells in Bone Marrow Work to Drive Inflammatory MS Attacks

Unusual growth in an immune cell class called myeloid cells is evident in the bone marrow of people with multiple sclerosis (MS), and these cells likely contribute to the inflammation that drives the disease, according to a new study.

Experiments in mice suggest that myelin-reactive T-cells can migrate to the bone marrow to promote the growth of myeloid cells. Researchers suggested that disrupting these processes could be a therapeutic approach for MS.

The study, “Bone marrow hematopoiesis drives multiple sclerosis progression,” was published in Cell.

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In MS, immune cells launch an inflammatory attack that damages parts of the central nervous system. A number of different types of immune cells participate in this attack, but the specific mechanisms that control their behavior in MS remain incompletely understood.

A team led by scientists in China conducted a series of experiments aiming to explore how the bone marrow is affected in MS. The bone marrow is the body’s major site for hematopoiesis or the generation of new blood cells, including most immune cells.

The scientists first analyzed bone marrow samples from seven people with MS and seven others without the disease as controls. Results showed that, compared with controls, MS patients had substantially greater growth of a class of immune cells called myeloid cells.

They then conducted experiments in mice with experimental autoimmune encephalitis (EAE), a mouse disease commonly used to model MS. In line with previous results, mouse data showed a substantial increase in the growth of inflammatory myeloid cells such as neutrophils and monocytes.

In further experiments, fluorescent markers were used to track the movement of myeloid cells generated in the bone marrow of EAE mice. These cells were seen to enter the central nervous system (CNS, the brain and spinal cord), where they presumably could contribute to disease-driving inflammation.

“These results demonstrate that newly generated neutrophils and … monocytes can be mobilized from bone marrow and penetrate the CNS tissue, suggesting that these cells may contribute to neuroinflammation during EAE development,” the researchers wrote.

Because the bone marrow is the major seat of immune cell development, a number of mechanisms exist by which bone marrow can change its activity in response to inflammatory signals from elsewhere in the body. The researchers hypothesized that abnormal myeloid cell growth in the bone marrow of MS patients might be prompted by inflammatory T-cells that migrate from the CNS.

To test this idea, the scientists performed additional tracking experiments using T-cells that primed to attack myelin, the fatty substance around nerve fibers that is targeted in MS immune attacks. Results demonstrated that myelin-reactive T-cells migrated to the bone marrow of mice with EAE.

Lowering levels of a T-cell receptor protein called CXCR4, which binds to a signaling molecule called CXCL12 to help control T-cell movement, reduced this migration to the bone marrow.

“These results suggest a pivotal role of the CXCL12-CXCR4 axis in the recruitment of myelin-reactive T cells into bone marrow in EAE,” the researchers wrote.

Further investigation demonstrated that, after the T-cells migrated to the bone marrow, they promoted the growth of myeloid cells, a process called myelopoiesis.

“Our findings unveil the bone marrow as a previously unrecognized site which fosters the intimate interactions between autoreactive [self-attacking] T cells and hematopoietic [blood progenitor] cells,” the team wrote.

Specifically, the researchers determined that the T-cells produced a signaling protein called CCL5, which binds to a receptor protein called CCR5 in stem cells to promote myelopoiesis. Blocking this signaling axis lowered myeloid cell growth in the bone marrow and reduced CNS inflammation in mice with EAE.

“We performed a comprehensive investigation by coupling experiments in EAE mice to reveal the bone marrow as a preferential homing site for autoreactive T cells, which in turn augment myelopoiesis involving the CCL5-CCR5 axis,” the researchers concluded. “Importantly, disruption of the CCL5-CCR5 axis suppressed bone marrow myelopoiesis, neuroinflammation, and neurological deficits.”

Study findings “assign a detrimental role to bone marrow myelopoiesis during EAE development, and perhaps during MS initiation and progression,” they added, noting that “myelopoiesis and its contribution to EAE development may open a therapeutic opportunity to treat MS.”