Inflammatory and infectious causes of encephalitis affect 20,000 people a year in the US. More than 50% of patients have inflammatory disorders requiring prolonged treatment with expensive and dangerous biological or immunosuppressive agents. The most common identifiable causes of these syndromes are paraneoplastic, post-infectious or associated with other underlying autoimmune diseases; however, the majority of patients are still classified as idiopathic. In the last 1-2 decades many of these syndromes have been shown to be associated with anti-neural autoantibodies that either cause the pathophysiology or serve as critical biomarkers. The most widely cited examples of these are anti-Hu antibodies, which are highly correlated with an underlying cancer, and anti-NMDA receptor antibodies, which cause psychosis, seizures and memory disturbances. Over the past 5 years, a unique interdisciplinary team of neurologists and basic scientists at UCSF was formed to develop and deploy an integrated approach to rapidly identify anti-neural antibodies associated with encephalitis, with the explicit intent to discover and validate clinically actionable biomarkers in addition to uncovering the fundamental mechanisms of disease pathogenesis underlying these syndromes. The centerpiece of these efforts is a patient cohort being collected at UCSF called the NID (Neuroinflammatory Disease) cohort, consisting of patients with suspected infectious or inflammatory encephalitis. This cohort is now >1,200 patients referred by clinicians at UCSF and from other centers around the world. Already, this cohort has yielded a new paraneoplastic autoimmune syndrome with important implications for men with seminoma. More importantly, we have reason to believe this to be just the tip of the iceberg. Our preliminary data indicates that at least 20% of these patients have associated high titer antibodies in their CSF reactive to neural antigens in mouse brain. Here, we propose to pursue the hypothesis that a plurality of undiscovered autoimmune targets underlie a significant fraction of idiopathic encephalitis cases. Using our unique clinical and molecular approach and our world class patient collection, we will investigate this hypothesis through the following specific aims:
Aim 1 : To stratify and characterize the UCSF 1,200 patient NID cohort for the presence of anti-neural antibodies in CSF.
Aim 2 : High-throughput phage display screen to identify and validate auto antigens.
Aim 3 : Produce recombinant human antibodies from patients with autoantibody syndromes and develop animal models to test autoantibody pathogenicity.
Autoimmune encephalitis is an increasingly recognized cause of neuroinflammatory diseases that present with a wide range of signs and symptoms ranging from ataxia to psychosis. This project leverages an innovative and high-throughput pipeline for identifying and regenerating autoantibodies from a cerebrospinal fluid biobank collected from a large and diverse cohort of patients with idiopathic encephalitis which will lead to improved diagnostics for autoimmune encephalitis, better understanding of its pathogenesis and insights into neural mechanisms that underly complex brain functions ranging from coordination to maintenance of mood and personality.
