Rheumatoid arthritis (RA) is a chronic, destructive autoimmune disease that targets joints and other organs. CD4 T cells are known to play a key role in the pathogenesis of RA. Yet, how arthritis-causing T cells contribute to disease is not understood since it is difficult to differentiate T cells that have been activated by the inflammatory milieu in the arthritic joint from those activated through their TCR by auto- antigens. Identification of antigen-activated T cells in RA would allow us to investigate arthritogenic clones and elucidate early events in disease pathogenesis. We have pioneered a strategy and model to identify and study antigen-specific T cell responses in arthritis. In this study we aim to 1. To identify antigen-activated T cells from human RA synovium, 2. To identify the TCR and BCR specificity and transcriptome of antigen-activated lymphocytes from RA synovium, and 3. Phenotype immune and non-immune cells present in RA joints. Completion of this pilot study will provide new mechanistic insights of how arthritis-causing lymphocytes and dysregulated inflammatory pathways contribute to destructive RA and holds promise for improved therapeutic targets. 

Funded by the Bakar ImmunoX Initiative 

Our project will perform a first in-depth immunoprofiling of the healthy, diseased, and resilient human brain across lifespan. While the brain was historically considered immune privileged, neuroimmune interactions are 

increasingly appreciated as key regulators of brain health, aging, and disease. Neuroimmunology is thus a critical research frontier. Our CoProject has two Aims that will generate a unique paired perivascular and parenchymal brain immune cell atlas across life from a total of 144 white and grey matter cortical tissues from 72 healthy, diseased, and cognitively resilient cases. We aim to 1. Reveal the molecular and neuroimmunological basis of human brain aging across the lifespan and 2. Discover a neuroimmune signature of pathologic and resilient brain aging. Results from this study will generate a first understanding of neuroimmune interactions in the diseased and resilient brain—and thereby discover a neuroimmune signature of cognition. We will reveal disease- 

associated perturbations in immune cell numbers and states, interactions with brain cell types, and thus promising new therapeutic targets. With spatial transcriptomics, we will understand where immune cells are located relative to pathology (eg immune cells near amyloid plaques) and interacting cell types (eg vulnerable neuronal subtypes). Finally, we will attain a global view of neuroimmune contributions to pathologic aging—and understand the molecular nature of cognitive resilience—is it preservation of a young molecular state or a third state? 

Funded by the Bakar ImmunoX Initiative 

Our study is focused on epigenetic states within immune populations. We seek to test the hypothesis that tumor-associated cells of the mononuclear phagocyte system (MPS) lineage uniquely form super-enhancers (SEs) as they enter the tumor, which favor their tumor-promoting identity. To test this hypothesis, we will access and piggyback an existing pipeline 

to study 20 healthy lung (or lymph nodes), cancer tissue, and blood samples from the same cancer patient, process them in parallel through CoLabs (Disease to Biology, Genomics, and Data Science).  By identifying epigenetic marks in this number of patients, we will be able to determine: 1. Whether there are classes of patients whose macrophages or (MPS populations) share patterns of epigenetic marking (e.g., depicting SEs) and 2. How patients classes defined in this way relate to other features such as outcome and tumor immune composition (e.g. frequency of particular immune cells) and 3. Whether the epigenetic states within tumors are the same (i.e., predictable) or are different from immune populations studied in the same patients but from different sites. 

Funded by the Bakar ImmunoX Initiative 

Many fibrosing skin diseases are characterized by inflammation and fibrosis of a defined tissue compartment, suggesting the involvement of anatomically conscribed fibroblast populations. We recently characterized a novel subset of fibroblasts in mouse and human skin called Th2-interacting fascial fibroblasts (TIFFs). In mice, TIFFs are located in the fascial layer and can be stimulated by Th2 cytokines to proliferate and deposit extracellular matrix. We identified two populations of cells in human skin that transcriptionally resemble murine TIFFs and occupy two skin layers. Murine models of TIFF inflammation resemble human eosinophilic fasciitis (EF), in which Th2-skewed inflammation causes fibroinflammatory disease of subcutaneous fascia. EF exists on a clinical spectrum with morphea, which involves more superficial layers of skin but shares overlapping clinical features with EF. 

We seek to use single-cell and spatial transcriptomics to compare immune and fibroblast composition of EF and morphea and to define the involvement of TIFFs in these diseases. We hypothesize that distinct subsets of TIFFs are the fibrogenic precursor cells in both EF and morphea. Looking beyond TIFFs, this project will also generate a rich dataset that will enable the identification of other fibrosis-associated fibroblast and immune subsets. 

Funded by the Bakar ImmunoX Initiative 

Although antiretroviral therapy (ART) prolongs life, it is expensive and potentially toxic, and delivering therapy to a global population for decades pose major challenges. Thus, HIV cure has emerged as an important research priority. 

The overall goal of the study is to elucidate the immune cell subsets and phenotypes that drive viral control and host immune responses at the earliest stages of HIV infection and during HIV reservoir establishment. Findings from this study will have considerable clinical and immunologic significance since early ART initiation is associated not only with enhanced post-treatment control, but also reduced immune activation, inflammation, morbidity, and mortality 

Funded by the Bakar ImmunoX Initiative 

The Immune Cell Census aims to determine how much variation exists in normal immune systems, and importantly - how much variation exists in even a single person’s immune system at various times. We'll be profiling transcriptomes, epigenomes, and a subset of the proteome at the single-cell level to understand the composition and function of individual immune systems. Funded by the Bakar ImmunoX Initiative and the Chan Zuckerberg Initiative.

SICCA is built upon a 10-year enrollment of patients with signs and symptoms of Sjögren's Syndrome (SS) from 9 research centers in 7 countries over 4 continents into a cohort with well characterized phenotypic features of SS, and a comprehensive biorepository with 3,514 participants with genome-wide genotyping performed on all participants. The overarching goal of the SICCA NextGen study is to generate transcriptome and methylation profiles to explore diversity across subsets of SICCA participants with characterized epigenetic and genetic profiles across cell and tissue types and to explore correlations between omics profiles and signs of severe disease manifestations.

Funded by the National Institute of Dental and Craniofacial Research

The Human-Mouse Cancer Translator Project aims to Immunoprofile a series of common and exceptional models of cancer in mice.  Models will be studied in various environmental backgrounds such as variation in diet and age. The goal of the project is to create a rational translation between the classes of immune systems in cancers as revealed in Immunoprofiler and other UCSF datasets. Funded by the Bakar ImmunoX Initiative.

The AutoImmunoprofiler team is analyzing tissue and blood samples from patients with various forms of autoimmune disease to identify autoimmune archetypes that underlie these diseases. Autoimmune diseases being studied include type 1 diabetes, systemic lupus erythematosus,  Sjögren’s syndrome, ulcerative colitis, Crohn’s disease and scleroderma. Initial funding comes from a research alliance with Eli Lilly and Company.

Industry Partners: Eli Lilly, (Open for enrollment)

The UCSF Immunoprofiler Initiative coordinates the handling of valuable human biopsy samples taken from cancer patients and performs a series of tests for immune composition, immune cell gene expression, and immune interaction biology. We propose that cancers are discrete forms of immunopathologies. By understanding the nature of the immune response, we will determine how to treat cancers and provide new targets for the next round of immunotherapies.

Industry Partners: Bristol-Myers Squibb, Amgen, Abbvie, Pfizer, Anonymous

The goal of this study is to elucidate how in utero inflammation imprints the developing human fetal immune system and alters the composition of the meconium microbiome. We propose to address this question by interrogating the cord blood immune profile and the meconium microbiome in two neonatal cohorts: one of infants born preterm (<34 weeks) and a second of term infants with gastroschisis. 

Funded by the Bakar ImmunoX Initiative

The goal of this project is to delineate at the single cell level the evolution of the developing human immune system through its functional transition from a program of predominant tolerance to one of protective immunity. Our proposal leverages our unique access to and experience with fetal and organ donor tissue to address critical gaps in our knowledge regarding: (1) the relationship between immune cell populations from different tissues within a single donor, (2) the age-dependent maturation of innate and adaptive immune cells during the critical early life window spanning in utero gestation to late childhood, and (3) the role of metabolism in shaping immune cell fate and function across different tissues and developmental stages. These studies are poised to elucidate the development of human immune cellular identities, functional phenotypes and metabolic capacities and dependencies unique to fetal and pediatric tissue, with key implications for understanding and treating infectious, allergic, and autoimmune conditions of early life onset.

Funded by the Bakar ImmunoX Initiative

Our long-term goal is to unravel the mechanisms by which the microbiome influences immunity and immunotherapy responsiveness. We will generate a comprehensive multi-omic dataset featuring longitudinal immune and microbiome data from a healthy cohort and perform integrative analysis to model how the microbiome influence the immune system. Our central hypothesis is that the microbiome is responsible for shaping and priming distinct immune setpoints across the population. These setpoints influence the susceptibility to disease and the severity of underlying pathologies, but also the capacity for the immune system to be modulated through therapeutic interventions. 

Funded by the Bakar ImmunoX Initiative

The aim of this project is to characterize the fetal immune response to malaria and to CMV by performing Cytof and scRNAseq on cord blood cells from already banked from an extremely well-characterized cohort of Ugandan infants. We will broadly examine differences in immune cell populations in cord blood and identify transcriptional changes in response to infection

Funded by the Bakar ImmunoX Initiative

COMET is a multi-institutional study to collect detailed clinical, laboratory, and radiographic data in coordination with biologic sampling of blood and respiratory secretions and viral shedding in nasal secretions in order to identify immunophenotypic features of COVID-19 -related susceptibility and/or progression in order to generate hypotheses for effective host-directed therapeutic interventions.

Funded by the National Institute of Allergy and Infectious Diseases

The Chronic Viral Infection project aims to evaluate the immunological context of anti-viral and anti-tumor immune response by assessing local (liver) and peripheral (PBMC) immune repertoires in uninfected patients, patients with active viral replication (HBV, HCV) and patients with drug-induced viral suppression and/or clearance in the presence and absence of liver cancer. We'll be profiling transcriptomes and a subset of the proteome both in bulk and at the single-cell level to identify novel targets for therapy to augment viral clearance in chronic viral infection and control of liver cancer through immunomodulation. Funded by the Bakar ImmunoX Initiative.

Our central hypothesis is that granulomatous inflammation of sarcoidosis is orchestrated by a complex interaction of lymphocytes and innate cells reacting to antigenic stimuli of unknown etiology. Leveraging our cohorts, our study aims to determine the patterns of lymphocyte and innate cell differentiation trajectories and TCR/BCR diversity regulated by flares of sarcoidal granulomatous inflammation using single cell CITEseq and measurement of the TCR/BCR repertoire. We will also decipher cell-cell communication between circulating lymphocyte subsets and innate cells in longitudinal samples taken over the disease course from sarcoidosis patients and determine chromatin-accessibility signatures in purified CD4 T cells from patients representing each clinical phenotype and will perform a meta-dimensional analysis to identify biologic blood markers that predict the clinical course in each cohort. and perform prediction modeling to find those markers that carry the most prognostic importance with the long-term goal of moving biomarkers into clinical practice.

Funded by the Bakar ImmunoX Initiative