Genetics, Immunology, and Therapeutics of Demyelinating Diseases
The Genomics of Multiple Sclerosis (MS)
My laboratory has a longstanding interest in the genetic basis of MS. This work involves collaborations with colleagues at UCSF (Jorge Oksenberg and Sergio Baranzini), as well as through a large global consortium founded in 2003. Accomplishments include identification of DRB1 as the primary MS signal in the HLA region on chromosome 6; fine mapping other secondary loci in HLA, including identifying a protective gene in the class I region; identification of the first non-HLA risk genes for MS; building maps of essentially all common variants numbering more than 200 that influence risk; elucidating functional consequences of causative variants; application of admixture analyses to identify MS risk genes in non-Caucasian populations; and using whole genome sequencing and epigenetic studies to understand missing heritability. These results revealed that the genetic landscape of MS risk is dominated by genes and pathways with roles in both the adaptive and innate immune system. Current work is focused on understanding functional consequences of MS variants on B cells and defining genotype-phenotype relationships in patients.
Immune Mechanisms in MS
My laboratory developed an animal model that, for the first time, recapitulated the essential pathology of MS, and demonstrated that autoantibodies directed against myelin oligodendrocyte glycoprotein (MOG), a quantitatively minor myelin protein, were a major factor in producing MS-like lesions. These characteristic lesions could be adoptively transferred by pathogenic T cells only when accompanied by co-transfer of autoantibodies. We next went on to identify myelin reactive autoantibodies in contact with disintegrating myelin membranes within lesions in humans with MS. Subsequently, the work revealed that a highly focused B cell response is present in MS; these B cells produce oligoclonal immunoglobulins characteristic of the disease, are activated on both sides of the blood-brain barrier, and dynamically traffic between the periphery and CNS. These data challenged previous assumptions on the pathogenesis of MS, and indicated clearly that autoimmune T cells, previously thought to be the sole trigger of MS, synergize with pathogenic B cells. Understanding the repertoire of pathogenic B cells and antibodies, and functional effects of disease-associated B cells on neurodegeneration represents a focus of current work.
Based on this work implicating B cells in MS, clinical trials were undertaken with the CD20+ B-cell-depleting drugs rituximab (Genentech and Roche), ocrelizumab (Roche), and the phase 3 trial of ofatumumab (Novartis). In March 2017 ocrelizumab received FDA approval for treatment of relapsing forms of MS, as well primary progressive MS, a previously untreatable form of the disease, followed by approvals in the European Union and elsewhere around the globe. Rituximab is now the most commonly used treatment for MS in many parts of Europe, ocrelizumab has now been approved for use in more than 70 countries and >200,000 individuals with MS are now receiving this therapy, and ofatumumab received FDA approval in August 2020. The clinical trials programs are now focused on developing more effective B cell-based therapeutics by targeting treatment-resistant B cells in the CNS that mediate progressive MS.
Academic community service and committee membership:
Director, UCSF Weill Institute for Neurosciences; Member, UCSF Institute for Human Genetics; Member, UCSF Biomedical Sciences Program