Single Drop of Blood in Brain Can Trigger Immune Response Akin to Multiple Sclerosis

Disruption of the blood-brain barrier triggers a cascade of events that results in autoimmunity and brain damage characteristic of multiple sclerosis.

A new study from the Gladstone Institutes shows that a single drop of blood in the brain is sufficient to activate an autoimmune response akin to multiple sclerosis (MS). This is the first demonstration that introduction of blood in the healthy brain is sufficient to cause peripheral immune cells to enter the brain, which then go on to cause brain damage.

A break in the blood-brain barrier (BBB) allows blood proteins to leak into the brain and is a key characteristic of MS, a disabling autoimmune disease of the brain and spinal cord. However, it was unclear whether the BBB disruption caused the autoimmune response or resulted from it.

In the current study, published in Nature Communications, the scientists created a new animal model of disease to determine if BBB leakage can cause autoimmunity. They discovered that injecting just one drop of blood into the brain set off the brain’s immune response, kick-starting a chain reaction that resulted in inflammation and myelin damage. Myelin is the protective sheath that insulates nerve fibers in the brain, and it is the primary site of injury in MS. What’s more, the scientists were able to pinpoint a specific protein in the blood, the blood-clotting factor fibrinogen, as the trigger for the disease-causing process.

“These findings offer a completely new way of thinking about how the immune system attacks the brain–it puts the blood in the driver’s seat of the onset and progression of disease,” says senior author Katerina Akassoglou, PhD, a senior investigator at the Gladstone Institutes and professor of neurology at the University of California, San Francisco. “This opens up the possibility for new types of therapies that target blood coagulation factors, upstream of autoimmune processes.”

Fibrinogen activated the brain’s immune cells, called microglia, and caused them to send out signals summoning peripheral immune cells from other parts of the body to the brain. When these peripheral immune cells–macrophages and T cells–entered the brain, they attacked myelin.

“Our results provide the first evidence that blood promotes T cell responses against the brain,” says first author Jae Kyu Ryu, PhD, a staff research scientist at the Gladstone Institutes. “Not only did we confirm that the presence of blood in the brain recruits peripheral immune cells to the area, which is sufficient to cause myelin destruction, we also identified fibrinogen as the critical protein driving this process.”

To confirm their findings, the scientists deleted the fibrinogen receptor (complement receptor 3 or CD11b/CD18) on microglia, thereby preventing fibrinogen from activating the cells. Inhibiting this interaction blocked the autoimmune process, stopping the microglia from signaling to the peripheral immune cells and averting myelin damage and inflammation. The researchers are now attempting to block fibrinogen using biological and small-molecule approaches as potential new therapies to suppress autoimmunity directed against the brain, dampening inflammation caused by microglia and T cells.

Image of a myelinated axon.
Researchers discovered that injecting just one drop of blood into the brain set off the brain’s immune response, kick-starting a chain reaction that resulted in inflammation and myelin damage. Myelin is the protective sheath that insulates nerve fibers in the brain, and it is the primary site of injury in MS. Image is for illustrative purposes only. Credit: Roadnottaken.

“These findings question a long-held paradigm that myelin-specific T cells initiate inflammation in the brain through activation of microglia and brain macrophages,” says Scott Zamvil, MD, PhD, a professor of neurology at the University of California, San Francisco and co-author on the paper. “This study demonstrates that the original paradigm may also occur in reverse. Namely, initial activation of microglia and brain macrophages may activate T cells.”

The scientists say that having a model of blood-induced brain inflammation is a valuable tool, as it can be used to screen new drugs. These mechanisms may occur not only in autoimmune disorders, but also in other brain diseases that involve inflammation or a break in the BBB, including traumatic brain injury, stroke, Alzheimer’s disease, and other dementias.

About this neurology research

Scientists from the Medical University of Vienna and the University of Cincinnati College of Medicine also took part in the research.

Funding: Funding was provided by the National Institute of Neurological Disorders and Stroke; National Multiple Sclerosis Society; American Heart Association; National Heart, Blood, and Lung Institute; Pediatric Scientist Development Program; and the Howard Hughes Medical Institute Medical Research Fellowship. Additional funding sources include the University of California San Francisco-Gladstone Institute of Virology and Immunology Center for AIDS Research; the Mouse Pathology Core of the UCSF Helen Diller Family Comprehensive Cancer Center; the Guthy Jackson Charitable Foundation; and the Maisin Foundation.

Source: Dana Smith – Gladstone Institute
Image Credit: The image is credited to Roadnottaken and is licensed CC BY-SA 3.0
Original Research: Full open access research for “Blood coagulation protein fibrinogen promotes autoimmunity and demyelination via chemokine release and antigen presentation” by Jae Kyu Ryu, Mark A. Petersen, Sara G. Murray, Kim M. Baeten, Anke Meyer-Franke, Justin P. Chan, Eirini Vagena, Catherine Bedard, Michael R. Machado, Pamela E. Rios Coronado, Thomas Prod’homme, Israel F. Charo, Hans Lassmann, Jay L. Degen, Scott S. Zamvil and Katerina Akassoglou in Nature Communications. Published online September 10 2015 doi:10.1038/ncomms9164


Abstract

Blood coagulation protein fibrinogen promotes autoimmunity and demyelination via chemokine release and antigen presentation

Autoimmunity and macrophage recruitment into the central nervous system (CNS) are critical determinants of neuroinflammatory diseases. However, the mechanisms that drive immunological responses targeted to the CNS remain largely unknown. Here we show that fibrinogen, a central blood coagulation protein deposited in the CNS after blood–brain barrier disruption, induces encephalitogenic adaptive immune responses and peripheral macrophage recruitment into the CNS leading to demyelination. Fibrinogen stimulates a unique transcriptional signature in CD11b+ antigen-presenting cells inducing the recruitment and local CNS activation of myelin antigen-specific Th1 cells. Fibrinogen depletion reduces Th1 cells in the multiple sclerosis model, experimental autoimmune encephalomyelitis. Major histocompatibility complex (MHC) II-dependent antigen presentation, CXCL10- and CCL2-mediated recruitment of T cells and macrophages, respectively, are required for fibrinogen-induced encephalomyelitis. Inhibition of the fibrinogen receptor CD11b/CD18 protects from all immune and neuropathologic effects. Our results show that the final product of the coagulation cascade is a key determinant of CNS autoimmunity.

“Blood coagulation protein fibrinogen promotes autoimmunity and demyelination via chemokine release and antigen presentation” by Jae Kyu Ryu, Mark A. Petersen, Sara G. Murray, Kim M. Baeten, Anke Meyer-Franke, Justin P. Chan, Eirini Vagena, Catherine Bedard, Michael R. Machado, Pamela E. Rios Coronado, Thomas Prod’homme, Israel F. Charo, Hans Lassmann, Jay L. Degen, Scott S. Zamvil and Katerina Akassoglou in Nature Communications. Published online September 10 2015 doi:10.1038/ncomms9164

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