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Principal Investigator: Anna Helena Jonsson
Organization: UNIVERSITY OF COLORADO DENVER
Fiscal Year: 2024
Award: $167,875
Funding agency: National Institute of Arthritis and Musculoskeletal and Skin Diseases
Project Summary/Abstract
This proposal is a five-year research and training plan with a scientific focus on interactions between CD8 T
cells and fibroblasts in synovial tissue from patients with rheumatoid arthritis (RA). We have found that the
majority of CD8 T cells in RA synovium have an unusual phenotype characterized by low expression of classic
cytotoxic proteins such as granzyme B, perforin, and granulysin. Instead, these cells express high amounts of
granzyme K, which induces synovial fibroblasts to produce pro-inflammatory factors such as IL-6. Based on
our preliminary data, we believe that granzyme K does more than simply activate synovial fibroblasts. We
believe that granzyme K activates the complement system to induce so-called inflammatory priming of synovial
fibroblasts, characterized by metabolic reprogramming and augmented activation to stimuli.
The specific aims proposed here will investigate the interactions of CD8 T cells and synovial fibroblasts in three
complementary ways. Aim 1 interrogates whether human granzyme K induces the metabolic reprograming
associated with inflammatory priming and whether complement mediates the downstream effects of granzyme
K. Aim 2 uses imaging mass cytometry, traditional immunofluorescence, and spatial transcriptomics to
evaluate granzyme K+ CD8 T cells and their relationship with fibroblast subsets and complement deposition
within the context of human synovial tissues. Aim 3 uses mouse models of inflammatory arthritis to determine
the effects of granzyme K on clinical and cellular measures in inflammatory arthritis.
This study combines mechanistic studies, patient-derived samples, mouse models, and cutting-edge
transcriptomic technologies to provide the candidate new training in several key aspects of translational
immunology. The candidates immediate career development goals are to gain experience with microscopy
techniques, spatial transcriptomics, cellular metabolism, mouse models of autoimmune diseases, and
bioinformatic analysis. A specific career development plan is described by both the candidate and her mentor
Dr. Michael Brenner, MD, an expert in lymphocyte biologic and synovial inflammation. She also has the
support of an Advisory Committee of experts in the areas in which she will build her skills. The candidate’s
long-term goal is to attain a tenure-track faculty position pursuing research that integrates high-dimensional
analysis of patient samples with detailed mechanistic studies to characterize cellular interactions within tissues
in rheumatologic diseases, with the ultimate goal of identifying new cellular and molecular candidates for
diagnosis and treatment of autoimmune diseases.
Terms: <(TNF)-α><519 protein><Active Oxygen><Advisory Committees><Animal Model><Animal Models and Related Studies><Architecture><Area><Atrophic Arthritis><Autoimmune Diseases><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Bio-Informatics><Bioinformatics><Biological><Body Tissues><CCL2><CCL2 gene><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><COVID-19 infection><COVID-19 virus infection><COVID19 infection><Cachectin><Cell Body><Cells><Chemokine, CC Motif, Ligand 2><Clinical><Collagen Arthritis><Collagen-Induced Arthritis><Complement><Complement Activation><Complement Proteins><Computational Biology><Core Facility><Crohn disease><Crohn's><Crohn's disease><Crohn's disorder><Cytometry><D2S69E><Data><Deposit><Deposition><Development Plans><Diagnosis><Disease><Disorder><Doctor of Philosophy><Engineering / Architecture><Exhibits><FK506 Binding Protein 12-Rapamycin Associated Protein 1><FKBP12 Rapamycin Complex Associated Protein 1><FRAP1><FRAP1 gene><FRAP2><Faculty><Fibroblasts><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Frequencies><GNLY><Goals><Granulomatous Enteritis><Granzyme><HPGF><Hepatocyte-Stimulating Factor><Histology><Human><Hybridoma Growth Factor><IFN-beta 2><IFNB2><IL-6><IL6 Protein><Image><Immunofluorescence><Immunofluorescence Immunologic><Immunology><In Situ><Inflammation><Inflammatory><Inflammatory Arthritis><Interleukin-6><Intermediary Metabolism><Investigators><Kidney><Kidney Urinary System><LAG-2><LAG2><Laboratories><Lavage><Link><Liquid substance><Lung><Lung Respiratory System><Lupus Glomerulonephritis><Lupus Nephritis><Lymphatic cell><Lymphocyte><Lymphocytic><MCAF><MCP-1><MCP1><MGI-2><Macrophage-Derived TNF><Measures><Mechanistic Target of Rapamycin><Mediating><Mediator><Membrana Synovialis Capsulae Articularis><Mentors><Mentorship><Metabolic><Metabolic Processes><Metabolism><Mice><Mice Mammals><Microscopy><Modeling><Modern Man><Molecular><Monocyte Chemoattractant Protein-1><Monocyte Chemotactic Protein-1><Monocyte Chemotactic and Activating Factor><Monocyte Chemotactic and Activating Protein><Monocyte Chemotactive and Activating Factor><Monocyte Secretory Protein JE><Monocyte-Derived TNF><Murine><Mus><Musculoskeletal Pain Disorder><Myeloid Differentiation-Inducing Protein><NKG5><Oxygen Radicals><Pathogenesis><Pathway interactions><Patients><Ph.D.><PhD><Phenotype><Plasmacytoma Growth Factor><Play><Position><Positioning Attribute><Pro-Oxidants><Production><Proliferating><Proteins><RAFT1><RNA Seq><RNA sequencing><RNAseq><RT-PCR><RTPCR><Reactive Oxygen Species><Reporting><Research><Research Personnel><Researchers><Reverse Transcriptase Polymerase Chain Reaction><Rheumatic Diseases><Rheumatism><Rheumatoid Arthritis><Rheumatologic Diseases><Rheumatologic Disorder><Rheumatology><Role><SARS-CoV-2 infection><SARS-CoV2 infection><SCYA2><Sampling><Severe acute respiratory syndrome coronavirus 2 infection><Small Inducible Cytokine A2><Stimulus><Synovia><Synovial Fluid><Synovial Membrane><Synovitis><Synovium><T-Cell Subsets><T-Cells><T-Lymphocyte><T-Lymphocyte Subsets><T-lymphocyte activation gene 519><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><TLA519><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Task Forces><Techniques><Technology><Time><Tissue Sample><Tissue imaging><Tissues><Training><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Ulcerated Colitis><Ulcerative Colitis><Wild Type Mouse><advisory team><autoimmune condition><autoimmune disorder><autoimmunity disease><biobank><biologic><biorepository><bowel inflammation><career><career development><complement pathway regulation><complement system><complementation><computer biology><coronavirus disease 2019 infection><cytotoxic><dimensional analysis><eleocolitis><experience><experiment><experimental research><experimental study><experiments><flow cytophotometry><fluid><gene signatures><genetic signature><granulysin><gut inflammation><high dimensionality><imaging><improved><in vivo><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><inflamed bowel><inflamed gut><inflamed intestine><inflamed synovial tissue><inflamed synovium><inflammation marker><inflammatory marker><instructor><interferon beta 2><intestinal inflammation><lavage therapy><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><liquid><lymph cell><lymphocyte pore-forming protein><mTOR><mammalian target of rapamycin><metabolism measurement><metabolomics><metabonomics><model of animal><mouse model><murine model><pathway><perforin><pulmonary><regional enteritis><renal><reverse transcriptase PCR><rheumatic arthritis><scRNA-seq><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><skills><social role><synovial inflammation><tenure process><tenure track><thymus derived lymphocyte><transcriptome sequencing><transcriptomic sequencing><transcriptomics><translational immunology><wildtype mouse>