RESEARCH

The main goal of our research is to define the regulation of adaptive immune responses during inflammation within the central nervous system (CNS). The Wu lab has several areas of ongoing investigation into the pathogenesis of multiple sclerosis (MS) and related diseases. We are exploring characteristics of monocytes, microglia, and B cells from patients to better understand cell-intrinsic abnormalities underpinning neuroimmunologic dysregulation in human diseases. In addition, we are modeling cellular and molecular immune contributions to neuro-inflammation by utilizing various experimental autoimmune encephalomyelitis (EAE) systems. Finally, we are actively engaged in several clinical trials to identify new highly efficacious disease-modifying therapies and mechanisms of action for currently approved MS therapies.

antibody production in mogad and mS

MOG Antibody Disease (MOGAD) is a relatively new entity involving inflammation of the brain and spinal cord. Antibody production is abnormal in both MS and MOGAD, but identification of the antibody target in MOGAD allows for accurate diagnoses and treatments thereof. We are currently studying the prevalence of serum anti-MOG antibodies in CNS inflammatory demyelinating diseases with the hypothesis that anti-MOG antibodies are present in some patients who carry a diagnosis of MS. We are performing Cell-Based Assays (CBAs) on a repository of samples to determine the diagnostic sensitivity and specificity of anti-MOG antibodies for MOGAD.

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Ectopic lymphoid tissue in ms

Due to chronic inflammation in MS, ectopic lymphoid tissues (ELTs), which are similar to immune organs such as lymph nodes, are formed in the covering layer of the brain and spinal cord known as meninges. ELTs are organized aggregates or clusters of immune cells that include a specific type of lymphocyte called a B cell. ELTs contribute to neuroinflammation by acting as local reservoirs of various immune cells and are associated with worse clinical outcomes in MS. There is a lack of information on B cell traits that contribute to the formation of ELT in MS. Greater clarity on the formation and maintenance of ELT would contribute to the development of successful therapies in MS. To address this, we utilize a mouse model that exhibit key features of ELT formation in the spinal meninges. This research focuses on exploring the extent, diversity, phenotype, and metabolic requirements of B cells in the spinal meninges during neuroinflammation. antigen presentation in meningeal ectopic lymphoid tissue development.

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Cerebrospinal fluid cells in health and multiple sclerosis

The cerebrospinal fluid (CSF) occupies the subarachnoid space and overlies the entirety of the central nervous system. For nearly a century, clinicians and researchers have recognized that neurologic disease reshapes the quantity and quality of the cells that reside in the CSF. With the advent of single cell sequencing, we and others have performed detailed transcriptional profiling of the cells within the CSF. These studies have unveiled unique cell subsets restricted to the CSF compared to other fluids and distinct cell profiles in multiple sclerosis compared to other neurologic diseases. We continue to recruit research subjects for these studies to uncover how the cells of the CSF might change in neurologic diseases like multiple sclerosis.

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Bruton's tyrosine kinase signaling in B cells and microglia

Bruton's tyrosine kinase (BTK) is a key signaling protein expressed in B cells and microglia that is being explored as a novel therapeutic target for the treatment of MS. Using several conditional knockout models, we are attempting to characterize how BTK signaling regulates various features of B cells and microglia that drive pathogenesis of MS and its mouse model EAE. 

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CAR T CELL DESIGN Optimization

Chimeric antigen receptor (CAR) T cell therapy has advanced from a promising experimental approach to a clinically validated cancer treatment, particularly for several B cell malignancies. Current CAR designs are most effective when they target high-density surface antigens, like CD19 or BCMA, where strong antigen recognition can drive robust T cell activation and tumor killing. Despite these successes, a major frontier in CAR engineering is overcoming key limitations related to low-affinity antigen recognition. This is especially relevant to multiple sclerosis (MS) and MOGAD (MOG antibody-associated disease), where disease-associated targets can involve weaker, transient, or low-affinity interactions rather than strong, high-avidity binding. In these settings, CAR strategies may need to be tuned to detect or respond to subtle antigen signatures including designs that emulate weak TCR-like interactions.

Our current optimization efforts focus on engineering the transmembrane region to improve CAR function and signaling to enhance performance against challenging targets where recognition is inherently limited.

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CD4 T cellS in MOGAD

MOG antibody disease (MOGAD) is a rare autoimmune disorder characterized by a robust autoantibody response against myelin oligodendrocyte glycoprotein (MOG), a protein expressed in the myelin sheath and restricted to the central nervous system (CNS). There are currently no FDA-approved treatments for MOGAD. Notably, B cell-depleting approaches, which were initially expected to be highly effective given the prominent anti-MOG antibody response, have shown highly variable clinical efficacy in this patient population.

To develop effective and targeted therapies, we seek a deeper understanding of the immune mechanisms that are unique to MOGAD. Although anti-MOG antibodies in peripheral blood are a hallmark feature, numerous studies suggest that anti-MOG antibodies alone are not sufficient to initiate and propagate disease. CD4 T cells are thought to play a substantial role in MOGAD pathogenesis due to their presence in lesions and because the anti-MOG antibodies are predominantly CD4 T cell-dependent IgG1. However, the exact contribution of CD4 T cells and the MOG epitopes they recognize have not yet been fully determined.

Our goal is to characterize the molecular phenotypes and MOG-specificity of CD4 T cells in MOGAD, clarifying their role in disease and informing the development of more precise therapeutic strategies.

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