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.
b cell antigen presentation
Our understanding of the basic pathogenic mechanisms of MS has been radically changed by the emergence of novel immune-based treatments that have specifically targeted B cells. Because there is strong clinical and experimental evidence that B cells contribute to MS via their role as antigen presenting cells, we have used our conditional MHCII mouse system to explore the extent to which B cells can independently drive CD4 T cell auto-reactivity in vivo. In our initial studies, we have found that antigen presentation by B cells alone is not sufficient to support adoptive transfer EAE unless B cells also express receptors specific for cognate antigen. Currently, we are exploring the mechanisms by which B cells drive CD4 T cell auto-reactivity during EAE and the features of B cells that promote efficient antigen presentation during neuroinflammation. Moreover, we seek to define the timing and location for which B cells capture CNS antigens during various stages of neuroinflammation.
trpv4 in eae and ms
Myelin is targeted in MS by both innate and adaptive immune cells. We have observed a role for a vanilloid-type member of the Transient Receptor Potential (TRP) channel family, TRPV4 in EAE. In collaboration with Hongzhen Hu from the Center for the Study of Itch, we have observed in preliminary studies the expression of TRPV4 by immune cells. We are presently testing the requirement for innate immune cell expression of TRPV4 during neuro-inflammation using in vivo genetic manipulation of TRPV4. Additionally, we are pursuing studies using human specimens to explore whether TRPV4 is involved in the development of inflammatory demyelinating MS plaques.
clock-ms
CLOCK-MS is a multi-site, phase IV clinical trial (sponsored by EMD Serono) designed to understand the mechanism of action of Cladribine (Mavenclad®) tablets by exploring the effect on CNS biomarkers relevant in the relapsing forms of MS. The study is designed to generate hypotheses regarding the impact and relevance of Cladribine tablet activity in the CNS by assessing the cerebrospinal fluid (CSF) levels of lymphocyte subsets, other immune cells, neuronal injury markers, and soluble immunological markers in study participants with relapsing forms of MS before and during treatment with Cladribine, and the association of these CSF markers with corresponding blood markers and with clinical outcomes. ClinicalTrials.gov Identifier: NCT03963375
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.
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.