Research

Autoimmune diseases of the nervous system — multiple sclerosis, autoimmune encephalitis, and many rarer disorders — affect millions of people and remain among the most difficult conditions in clinical neurology to predict, diagnose precisely, and treat. In neurology, we often have to tell our patients an uncomfortable truth: that we still lack a fundamental understanding of the diseases they live with, and that even our best treatments are blunt instruments. Most current therapies work by broadly suppressing the immune system. These treatments help many of our patients, but they are imprecise, carry real risks, and rarely address the specific process that initiated the disease. Our lab focuses on enhancing disease understanding to achieve precise, disease-focused therapies.

The central scientific problem we study is deceptively simple to state: in autoimmune disease, what is the immune system actually reacting to? Autoimmunity arises when immune cells turn against molecules in the body's own tissues — "self antigens." T cells, in particular, are major drivers of tissue damage across autoimmune disease, yet for most conditions the specific molecular targets that T cells recognize remain unknown. Conversely, for B cells, the discovery of autoantibody targets has transformed clinical practice; the identification of NMDA receptor antibodies, for instance, revealed an entire category of treatable autoimmune encephalitis. T cell antigen discovery has lagged far behind, held back by the inherent difficulty of measuring how T cells recognize their targets. Closing that gap would connect immune activity to the molecular logic of disease — opening the door to better diagnostics, risk prediction, and therapies precise enough to disable the disease-driving cells while leaving protective immunity intact.

Our research builds on a powerful recent advance: single-cell-resolved sequencing of the immune repertoire directly from sites of autoimmune inflammation. When T cells encounter their target, they proliferate into clonal populations defined by a shared T cell receptor sequence, and these expanded clonotypes accumulate in inflamed tissue and cerebrospinal fluid. Identifying them gives a direct, patient-specific window onto the immune cells most likely to be driving disease — a list of the precise receptors whose targets we most want to know. We are capitalizing on this opportunity by developing precision tools that reconstitute these patient-derived immune receptors in the laboratory and study their function using synthetic biology approaches that we developed, allowing us to systematically connect a T cell receptor to the antigen it recognizes.

This work sits at the interface of synthetic biology, immunology, and neurobiology. We engineer cell-based systems that sense the molecular interactions occurring at close range between immune cells — as within the immunological synapse — and we use them to ask, at scale, what activates and guides the T cells involved in autoimmune disease. The aim is both to discover the antigenic targets of disease in individual patients and to build a more general understanding of how self-directed T cell responses begin, mature, and spread.

Our approach is intentionally broad. Rather than focusing on a single disease, we deploy a common discovery strategy across conditions, leveraging multiple cross-departmental collaborations at UCSF. As a recent example, in collaboration with colleagues at UCSF we applied this strategy to ROHHAD syndrome, a rare and devastating pediatric neuroimmunologic disorder, and found that the B cells and T cells expanded within the brain converge on a shared antigenic target — a rare and clarifying glimpse into the antigen biology of an autoimmune attack on the nervous system.

Ultimately, our goal is to map the antigens driving autoimmune disease to enable more precise disease-targeted therapies. By identifying what the immune system is reacting to in autoimmune neurologic disease, we hope to provide the molecular foundation for diagnostics, prognostic tools, and a future generation of antigen-specific therapies, and to be able to improve our patient’s lives.