Basic and Translational
The UCSF division of rheumatology maintains an active basic and translational research program that spans three sites (Parnassus, ZSFGH, VA).
Our faculty collaborate widely across the UCSF campuses to push forward an ambitious research agenda aimed at defining pathogenic mechanisms of rheumatic disease. Our work is integrated with the broader immunology community at UCSF, including:
Rheumatoid arthritis (RA) afflicts millions globally, causing significant joint deformity, pain, and functional disability. RA is without cure and its cause is unknown, but CD4 T cells—immune cells widely accepted to play a key role in RA pathogenesis—from patients with RA become activated by proteins through their T cell receptor (called “antigen-specific T cells”) and cause arthritis. Dr. Ashouri’s research uses a unique tool to identify and characterize these antigen-specific T cells in both a mouse model of RA and human RA. Elucidating the contribution of these pathogenic CD4 T cells to arthritis development in RA holds promise for the discovery of improved therapeutic targets.
Dr. Jon Levine’s research program focuses on understanding mechanisms underlying pain in rheumatic diseases. His current research includes studies of the impact of stress on pain, the transition from acute to chronic pain and gender differences in pain. The ultimate goal is to apply findings from these basic research studies to the important problem of pain management in rheumatic disease patients.
Dr. Matloubian co-directs the Molecular Medicine Consult Service and serves as the Science Coordinator of the PREMIER Center for Precision Medicine in Rheumatology. In these capacities, he is pushing forward translational studies of both common and rare diseases of immune dysregulation. He also has expertise and interest in understanding the trafficking of immune cells in the context of both infection and autoimmune disease.
Dr. Mary Nakamura’s research focuses on a relatively new field called osteoimmunology, which refers to the study of interactions between the skeletal and immune systems. Loss of bone or osteoporosis is a significant problem for patients due to aging, but the process is also accelerated by inflammatory and autoimmune diseases yet can also be worsened during therapy for these diseases. Dr. Nakamura’s research in the laboratory focuses on understanding mechanisms that regulate bone loss particularly due to autoimmune disease. In translational studies she is interested in determining factors that predispose rheumatoid arthritis patients to local and systemic bone loss and how bony erosion can be better assessed in patients. Dr. Nakamura also serves as the Associate Director of the PREMIER Center for Precision Medicine in Rheumatology.
Dr. Nayak is a physician-scientist dedicated to advancing the care and treatment of patients with rheumatologic conditions such as rheumatoid arthritis, lupus, psoriatic arthritis, and other autoimmune diseases. She uses her unique backgrounds in Biology, Computer Science, and Clinical Rheumatology to investigate the role of the human gut microbiome in the treatment of rheumatoid arthritis. She uses an innovative combination of patient specimens, microbiology, next generation sequencing, and gnotobiotic mouse models to better understand how our microbiome, which many consider our "second genome," influences health and disease.
Matija Peterlin, MD
The Peterlin laboratory uses molecular biology, immunology, virology and genetics to tackle intractable immunodeficiencies, be they the bare lymphocyte syndrome or AIDS. These approaches also find resonance in autoimmunity and cancer. In the process, these diseases and their pathogens educate us about human biology and evolution. Indeed, new paradigms in genomic stability, transcription, transport and intracellular traffic have been forthcoming from these studies. Our ultimate goals are to use this knowledge of basic molecular mechanisms to cure human diseases.
T cell receptor (TCR) recognition and signaling have long been recognized to play a critical role in the pathogenesis of a broad range of autoimmune diseases. However, how altered TCR signaling strength affects immune tolerance and promotes autoimmunity remains incompletely understood. Dr. Shen’s research seeks to understand how abnormal TCR signaling resulting from mutations from human patients with complex autoimmune syndrome may alter T cell antigen sensitivity, affect T helper cell fate, and impair immune tolerance. Studying human monogenic diseases with known genetic defects and autoimmune phenotypes provides us with a unique opportunity for advancing our knowledge of disease pathogenesis of more common polygenic autoimmune diseases. These studies may also have implications in preventing cancer immunotherapy related adverse events and identification of new therapeutic targets for autoimmune diseases.
Dr. Weiss’ laboratory studies investigate how the intracellular molecular machinery in lymphocytes – especially T cells - regulates normal and abnormal responses with an aim towards understanding what goes right during normal immune responses to infections and what goes wrong in autoimmune diseases. Understanding these molecular mechanisms provides valuable information towards developing drugs that target such intracellular machinery. Dr. Weiss’ laboratory has long focused on dissecting the fundamental molecular basis of T cell receptor signaling and defining how it normally functions to regulate T cell responses and maintain sensitivity to foreign antigens while at the same time preserving tolerance to ‘self’.
The Ye lab is interested in how the interaction between genetics and environment affect human variation at the level of molecular phenotypes. To study these interactions, the lab couples high-throughput sequencing approaches that measure cellular response under environmental challenges with population genetics where such measurements are collected and analyzed across large patient cohorts. The lab develops novel experimental approaches that enable the large-scale collection of functional genomic data en masse and computational approaches that translate the data into novel biological insights. This approach is used to initially study primary human immune cells in both healthy and diseased patients to understand host pathogen interactions and its role in autoimmunity. The Ye lab collaborates extensively within and outside of the rheumatology division and has applied single cell sequencing approaches to UCSF SLE cohort samples in order to obtain an unprecedented view of how gene expression is perturbed in patient with both active and quiescent SLE.
Julie Zikherman, MD
Dr. Julie Zikherman is interested in understanding why and how patients with autoimmune diseases such as systemic lupus erythematosus (SLE) develop autoantibodies. Her lab is focused on discovering novel molecular mechanisms that regulate how B cells (the cells that make antibodies) normally respond to both self- and foreign- antigens. Long term goals of this work are to manipulate B cell responses in the context of both autoimmune disease and vaccination to benefit human health. Dr. Zikherman also serves as the Associate Chief for Basic Research in the Rheumatology Division.