While mouse models have provided crucial platforms to study lunch stromal immunobiology, including settings of fibrosis, there are clear differences between mouse and human lungs that limit the generalizability of insights derived from the murine system. The human lung is architecturally more complex, possessing anatomic segments that are missing from the mouse lung; further, the epithelial differentiation trajectories between orthologous stem cell populations in mouse and human lungs are not always conserved. We have identified many shared stromal and immune subsets/states in scRNAseq analysis of healthy human and diseased lungs; however, we critically lack an understanding of the spatial relationships (topography) of stromal and immune cells in human lung fibrosis, with a focus on patients with the two most common causes of lung fibrosis: (1) Idiopathic pulmonary fibrosis (IPF), and (2) scleroderma (systemic sclerosis/SS).

While previous efforts have defined potential ligand-receptor interactions, spatial transcriptomics and 3D imaging will allow us to define likely interactions between immune and stromal cells. We hope to define these stromal-immune communities in human lungs in health and how they are altered with fibrosis. We believe that an understanding of human lung fibrosis can also provide a road map, when integrated with emerging data from other organs and diseases, to define stromal-immune interactions that will provide key targetable pathways applicable across diverse categories of disease, including sterile injury, cancer, autoimmunity, infection, and aging.

Funded by the Bakar ImmunoX Initiative

Autoimmune hepatitis (AIH) is an understudied, poorly understood chronic liver disease that disproportionately affects women and people of color and is increasing in incidence and prevalence. In 2018, we established a longitudinal cohort study, Prospective Observational Study to Understand Liver Diseases (POSULD), at Zuckerberg San Francisco General and UCSF. POSULD now has approximately 300 participants, 60 of whom have AIH, most of whom are women of color. Autoantibodies are important in the diagnosis of AIH but it is unclear what the autoantigen in Type I AIH might be. Multiple immune cell types have been implicated in the disease, and hepatocytes are typically infiltrated by lympoplasmacytic cells at the interface of portal and lobular areas on liver biopsy. We identified AFF3 as a potential autoantigen expressed on a subset of hepatocytes and showed that myeloid, B and T cells are particularly active in AIH. In particular, we identified a role for CD40 and its ligand in the recruitment and activation of B cells by specific subpopulations of T cells.

We aim to spatially characterize hepatocyte and immune cells of AIH livers. We will use existing liver biopsies from POSULD participants with AIH and other liver diseases and perform spatial transcriptomics. We will focus in particular on spatial relationships between AFF3+ hepatocytes, CD40+ B cells and CD40L+ T cells near the portal region. We will complement the transcriptome approach with multiplexed immunofluorescence studies with antibodies to AFF3, CD40 and CD40L. Lastly, we will compare the immune profiles of blood and liver compartments.

Funded by the Bakar ImmunoX Initiative

Cutaneous squamous cell carcinoma (cSCC) and its pre-malignant precursor in-situ lesion (cSCCis) arise from keratinocytes in the skin, a vast and highly active immune organ. An important immune regulatory pathway in cSCC is TNFa-induced inflammation via NF-κB signaling, whose inhibition is associated with cSCC development and progression2,3. However, the consequences of TNFa inhibitors (TNFai) in the spatial organization of cSCC immune microenvironment remain unknown.

We aim to leverage a cSCC patient cohort we identified with either concurrent or non-concurrent exposure to TNFai at time of their cSCC excision. Patients required TNFai therapy during their clinical course to treat their autoimmune disease with similar baseline characteristics, but differed whether they were actively on TNFai therapy at time of tumor excision or not. Leveraging this cohort, we will evaluate the impact of TNFa blockade on cytokine signaling and cell-cell interactions within the tumor microenvironment. We will test the central hypothesis that concurrent TNFai reshapes cellular interactions via suppression of NF-κB-induced cytokine and cell adhesion molecules, restructuring the cSCC and cSCCis immune organization to favor tumor progression. Upon successful completion of this pilot project, we anticipate expansion of the study to a larger cohort of patients as well as prospective, longitudinal tissue collection from individual patients.

Funded by the Bakar ImmunoX Initiative

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 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 - please contact us

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

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