Studies on Immune Frenemies in the Brain Reveal Private Source in Local Bone Marrow

Immune cells can be our brain’s best friend and worst enemy. They protect the brain from infection and heal injury, but they can also instigate autoimmunity and inflammation.

Two back-to-back studies from scientists at the Washington University School of Medicine St. Louis, published in the journal Science, demonstrate that immune cells that survey the protective coverings of the brain and spinal cord (meninges), earlier believed to solely derive from the circulating blood, have another unexpected and previously unknown source closer to home.

The findings, published in the articles, “Heterogeneity of meningeal B cells reveals a lymphopoietic niche at the CNS borders” and “Skull and vertebral bone marrow are myeloid cell reservoirs for the meninges and CNS parenchyma” may result in new therapeutic approaches to help maintain immune privilege in neurological and neurodegenerative diseases and call for a reconsideration of current understandings on CNS-immune infiltration in health and disease.

Through a battery of analytical approaches including single-cell transcriptomics, flow cytometry, confocal and electron microscopy, bone marrow chimeras, and parabiosis experiments, the authors of the complementary studies show that an unexpected source of innate (monocytes and neutrophils) and adaptive (B lymphocytes) meningeal immune cells is the bone marrow in the skull and vertebrae.

The team that focuses on the innate immune cells is led by co-first authors Andrea Cugurra, a graduate student, Tornike Mamuladze, MD, a visiting researcher, and Justin Rustenhoven, PhD, a postdoctoral researcher in the lab of Jonathan Kipnis, PhD, BJC Investigator, Alan A. and Edith L. Wolff Distinguished Professor of Pathology and Immunology, while the team that focuses on the adaptive immune cells is led by co-first authors and postdoctoral researchers Simone Brioschi, PhD, and Wei-Le Wang, PhD, and graduate student Vincent Peng, from the lab of Marco Colonna, MD, Robert Rock Belliveau Professor of Pathology and Immunology.

These local immune cells, the researchers show, travel from the bone marrow in the skull and vertebrae to the meningeal layers through special vessels and provide the brain and spinal cord with a steady supply of immune cells educated in recognizing antigens of the central nervous system.

“B cells in the bone marrow of the skull come into contact with the central nervous system and are educated by the central nervous system,” says Colonna. “That would not happen if they were released into the blood. Because they are directly in contact with the brain, they learn to be tolerant of brain proteins.”

On the other hand, a distinct subset of mature B cells in the meninges of aging mice, the Colonna group shows, are derived from the circulating bloodstream. These cells are more likely to wrongly recognize harmless central nervous system proteins as foreign and produce antibodies against them.

The scientists, through gene expression analyses, show that the immune cells that infiltrate the CNS from the local bone marrow niches upon injury or inflammation, are transcriptionally different from their blood-borne cousins.

“Understanding where these cells come from and how they behave is a critical part of understanding the basic mechanisms of neuro-immune interactions, so we can design new therapeutic approaches for neurological conditions associated with inflammation,” says Kipnis. “The location of these cells in the skull makes them relatively accessible and opens up the possibility of designing therapies to alter the behavior of these cells and treat neuro-immune conditions.”