Multiple sclerosis (MS), the most common inflammatory disease of the central nervous system (CNS), affects more than 2.5 million people worldwide. This autoimmune disease is characterized by perivascular inflammation in the CNS, demyelination of nerve fibers as well as axonal damage. The resulting interruption of motor and sensory impulses as they pass through demyelinated regions of the brain or spinal cord leads to visual disturbances, bowel and bladder incontinence, sensory and motor disturbances and lack of coordination. Myelin-specific CD4+ Th1 and Th17 cells are major orchestrators of the CNS inflammation. It is assumed that these cells along with CD8+ T cells are initially activated in peripheral lymphoid organs but must cross the normally relatively impermeable blood-brain barrier (BBB) to become reactivated and initiate inflammation. Many of these events were initially defined by studying the similar, even if imperfect, rodent model of MS, experimental allergic/autoimmune encephalomyelitis (EAE). Susceptible strains of mice develop many of the same neurological deficits and similar CNS histological features after immunization with myelin components. The MOG-induced C57BL/6 model mimics features of primary progressive (PP) disease that presents in ~ 10 % of MS patients. Arguably, the PLP-induced model in SJL mice is more relevant because it presents with a relapsing-remitting (RR) course experienced by ~85% of MS patients. There are significant advantages inherent in studying EAE in C57BL/6 mice including the availability of mice on the C57BL/6 background that contain targeted deletions in many immune system genes. Not surprisingly, the insight gained from these studies of PP-like disease in our laboratory and others has been invaluable. It has been clearly demonstrated that mast cells, an innate cell type that is widely distributed throughout the body, negatively modifies disease course. The primary site of mast cell action is the meninges, where they regulate BBB permeability and cellular accumulation in the CNS which is associated with neutrophil influx. There is also evidence that mast cells affect T cell reactivation in CNS-proximal sites such as the meninges and cervical lymph nodes. We have developed a mast cell deficient mouse on the SJL background that shows mast cell dependent severity of disease. This model will allow the investigation of mast cell actions during relapses that are associated with new waves of blood brain barrier permeability and inflammatory cell influx. We hypothesize that the co-localization of mast cells, T cells and neutrophils within the meninges in early disease results in cross-activation of cells and facilitates BBB breach associated with disease.
The specific aims of our study are:
Aim 1 : To determine the molecular requirements for MC-dependent PMN trafficking to the dura and CNS parenchyma during EAE.
Aim 2 : To examine PMN/MC/Tcell interactions and activation of resident and infiltrating cells in the meninges during EAE.

Public Health Relevance

Trafficking of immune cells across the blood brain barrier (BBB) is a critical step in the development of Multiple Sclerosis. Our studies use an animal model of this disease syndrome, EAE, and focus on how mast cells present in meningeal tissues, regulate this immune cell influx. We are testing the hypothesis that mast cells act by recruiting neutrophils into the meningeal tissues and through activation, arm them with the ability to directly increase permeability of this relatively impenetrable vasculature.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F01-F (20))
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Utz, Ursula
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Northwestern University at Chicago
Schools of Medicine
United States
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Walker-Caulfield, Margaret E; Hatfield, Julianne K; Brown, Melissa A (2015) Dynamic changes in meningeal inflammation correspond to clinical exacerbations in a murine model of relapsing-remitting multiple sclerosis. J Neuroimmunol 278:112-22
Hatfield, Julianne K; Brown, Melissa A (2015) Group 3 innate lymphoid cells accumulate and exhibit disease-induced activation in the meninges in EAE. Cell Immunol 297:69-79