Research Projects: Shi Lab
Inflammatory and immune responses in the central nervous system (CNS) can shape the clinical presentation and outcome of many brain diseases, including stroke, trauma, Alzheimer’s disease, Parkinson’s disease, epilepsy, encephalomyelitis, and multiple sclerosis (MS). Our laboratory group has a vital interest in understanding the role of innate immunity and inflammation in neurological disorders.
The confocal image in the left panel above shows activated microglia (denoted by the increased size of the cell body and the thickening of proximal processes) with the suppressive effect of NK cells
absent in situ. Compared to mice with intact NK cells, the level of reactive oxygen species (a key indicator of inflammation) is significantly higher in mice lacking NK cells (left panel). The right panel shows PE-positive natural killer cells and green fluoresence-positive microglia in brain sections from an EAE model.In a NIH/NIAID-funded project funded by the National Institutes of Health and the National Institute of Allergy and Infectious Diseases directed at researching MS in humans, as exemplified in experimental models of autoimmune encephalomyelitis, we are studying the effect of a key component of the innate immune system, natural killer cells. Natural killer (NK) cells orchestrate inflammatory responses and determine the magnitude of local inflammation. Using a combination of cellular and genetic tools, we were able to demonstrate that NK cells reside near microglia during brain inflammation (see right). Interactions between these immune system cells and specialized brain cells significantly affect the function of myelin-reactive helper T cells and their ability to destroy tissues, as shown using bioluminescence imaging and high-field 7T MRI. Our active work on these topics includes the following:
- Assessing and linking the molecular features of NK cells as they home in on the inflamed brain to pathologic effects
- Using 2-photon microscopy to follow the migratory patterns of NK cells and their interactions with brain cells
Our work extends to other neurological diseases associated with inflammatory pathology. We have established a model of middle cerebral artery (MCA) occlusion and stroke in mice and have applied models of Alzheimer’s disease in transgenic mice altered genetically to represent the disease in humans. Our goal is to understand how the manipulation of innate immune responses in the brain affects the pathologic consequences and clinical outcomes of these conditions.
We are collaborating with neurobiologists and neurosurgeons at Barrow to study the anti-inflammatory property of neurotransmitters and artificial peptide-induced macrophage/microglia in glioblastomas. We also are collaborating with neural stem cell biologists at the Waisman Center at the University of Wisconsin. We expect this collaboration to yield a definition of homeostasis of differentiated glial and neuronal cells in the inflamed brain compared to the noninflamed brain.
In myasthenia gravis, autoantibodies produced by B cells interfere with neuromuscular transmission and lead to muscle weakness and fatigue. This “autoimmune” disease can be treated by general suppression of the immune system and other therapies. However, a treatment that would specifically target only the disease-causing actions of the immune system while sparing its more far-reaching functions is highly desirable.
We began our work toward this goal by demonstrating that NK cells promote autoreactive B cells, likely via the action of helper T cells. Using experimental autoimmune myasthenia gravis (EAMG) induced in C57BL/6 mice, we are investigating whether NK cells can act directly on autoreactive B cells in vivo, and, if so, what biological consequences follow for disease expression. Since 2001, the Muscular Dystrophy Association has awarded the Neuroimmunology Laboratory at the Barrow more than $1.1 million to fund studies directed toward defining the roles of regulatory T cells and Th17 cells in the initiation and maintenance of antiacetylcholine receptor antibody production. We continue to investigate the behavior of regulatory B cells in patients with myasthenia gravis and EAMG mice during rituxan therapy.
Neuromyelitis optica, possibly a B cell disease like myasthenia, occurs with more frequency in Chinese and Japanese population. Working with neurologists in China, we are characterizing clinical and immunological features of Chinese patients with neuromyelitis optica while attempting to contrast the features of their disease with those in Caucasian populations. The objectives of these projects are twofold:
We expect to define responsiveness to several disease-modifying drugs
We hope to establish principles of management for Asian patients with NMO
Our laboratory programs focus on innate immunity related to NK cells in a range of neurological disorders and to target inflammation as a primary (multiple sclerosis) or secondary (stroke, Alzheimer’s) cause of disease. We also concentrate on discovering innate immune elements that can modulate B cells in B-cell dominant neurological diseases (myasthenia gravis and neuromyelitis optica). The hypotheses underlying our research have always been derived from our patients. The research conducted in the neuroimmunology laboratory has always emphasized the parallel inclusion of patients and relevant animal models. Our previous work, along with that of the present and future is, has been, and will continue to be dedicated to improving the clinical practice of neurology and medicine.