We invite you to meet the talented and dedicated scientists who are at the forefront of arthritis research. Each year, our esteemed Scientific Advisory Board carefully selects these emerging leaders based on their innovative research proposals and potential to make significant contributions to the field.
These scholars represent a diverse group of researchers working in prestigious laboratories and institutions around the world. Their work spans various aspects of arthritis and autoimmune disease research, from understanding the underlying mechanisms to developing new treatments and therapies.
By supporting these exceptional scientists, you are directly contributing to groundbreaking research that brings us closer to finding a cure. Explore their profiles to learn more about their backgrounds, research interests, and the impactful work they are doing.
“The Role Of IL-7R+ Progenitor CD8 T Cells in the Development of Rheumatologic IRAES After aPD-1 Immunotherapy”
Carl F. Ware Fellowship
“The Role of Trained Immunity as a Pathogenic Trigger in Psoriatic Arthritis”
Bristol Myers Squibb Psoriatic Arthritis Fellow
“Defining Tissue-Specific T cell Dysfunction in Juvenile Idiopathic Arthritis”
“The Prevalence and Consequences of Somatic Mutations in Auto-Inflammatory Disease”
Elizabeth D. Mellins Memorial Fellowship
“Transcriptional Profiling of Synovial Immune Cells in Juvenile Idiopathic Arthritis”
Postdoctoral Research Fellowship
“SPP1+ Macrophages as Targets in Regulating Rheumatoid Arthritis”
Gale “Morrie” Granger Fellowship
“Epigenetic Dysregulation of the Inactive X Chromosome in B Cells and its Contribution to the Female Sex Bias of Systemic Sclerosis”
“Thermogenic Adipose Remodeling in Post-traumatic Osteoarthritis”
“Characterization of synovial T peripheral helper cell autoantigens in RA”
“Leveraging the Nr4a Family to Dissect Thymic Tolerance and its Links to Autoimmune Disease”
“Exploring the Pathogenesis of Juvenile Systemic Sclerosis”
Rheum for Kids: Pediatric Skin and Joint Grant in collaboration with PeDRA
“Identification of Gene Dysregulation and Therapeutic Targets for Psoriatic Arthritis Using Novel Machine Learning Approaches”
Johnson & Johnson Innovative Medicine PsA Fellowship
“Assessing parenchymal signaling as a mechanism of peripheral tolerance in lupus pathogenesis”
“Investigating the Role of Pathogenic CD8+ T cells in HLA-B27 Positive Juvenile Spondyloarthritis”
“Signaling pathways governing the development of hip osteoarthritis”
“Activation of Antigen-Presenting Plasmacytoid Dendritic Cells in Autoimmune Disease”
“Exploiting Spondyloarthritis TCR:pHLA-B*27 Interaction for Therapeutic Development”
“Defining the Role of UBA1 in Autoimmune Disease”
Gale “Morrie” Granger Fellowship
“Virus-induced Predisposition to Lupus after TLR7 Stimulation”
Carl F. Ware Fellowship
“An Articular Cartilage Stem Cell Mediating Cartilage Regeneration for The Treatment of Osteoarthritis”
“Inflammatory Mediators of Synovial Resident Memory T Cell Formation”
“The Role of Neuroimmune Metabolic Crosstalk in the Onset and Progression of Pain in Osteoarthritis”
“The Prevalence and Consequences of Somatic Mutations in Auto-Inflammatory Disease”
Elizabeth D. Mellins Memorial Fellowship
“Activation and Repertoire of Autoreactive B cells in Systemic Lupus Erythematosus”
“A Non-Coding Genetic Risk Variant That Controls T-Reg Abundance”
“Characterization of synovial T peripheral helper cell autoantigens in RA”
“Identification of Self-Reactive T Cell Antigens in Systemic Sclerosis”
“Assessing parenchymal signaling as a mechanism of peripheral tolerance in lupus pathogenesis”
“Signaling pathways governing the development of hip osteoarthritis”
“Activation of Antigen-Presenting Plasmacytoid Dendritic Cells in Autoimmune Disease”
“Exploiting Spondyloarthritis TCR:pHLA-B*27 Interaction for Therapeutic Development”
“Deciphering Complement-Dependent Phagocytic Myeloid Phenotypes in Human Autoimmune Arthritis Using Single-Cell Computational Omics”
Sontag Foundation Fellow
“The Role of Neutrophils and NETs in the Pathogenesis of Scleroderma”
“Defining the Role of UBA1 in Autoimmune Disease”
Gale “Morrie” Granger Fellowship
“Virus-induced Predisposition to Lupus after TLR7 Stimulation”
Carl F. Ware Fellowship
“An Articular Cartilage Stem Cell Mediating Cartilage Regeneration for The Treatment of Osteoarthritis”
“The Role of Cytokines in Monocytes During Macrophage Activation Syndrome”
“Inflammatory Mediators of Synovial Resident Memory T Cell Formation”
“The Role of Neuroimmune Metabolic Crosstalk in the Onset and Progression of Pain in Osteoarthritis”
“Adipose Tissue as a Memory T Cell Storage Site in Inflammatory Arthritis”
“Activation and Repertoire of Autoreactive B cells in Systemic Lupus Erythematosus”
“A Non-Coding Genetic Risk Variant That Controls T-Reg Abundance”
“Identification of Self-Reactive T Cell Antigens in Systemic Sclerosis”
“Mechanisms of Th1.17 Cell Development in Polyarticular Juvenile Idiopathic Arthritis”
Staci Stringer Valiant Women Fellow
“Role of A20 in Restricting Psoriatic Skin and Joint Disease”
Janssen Immunology Psoriatic Arthritis Fellow
“Deciphering Complement-Dependent Phagocytic Myeloid Phenotypes in Human Autoimmune Arthritis Using Single-Cell Computational Omics”
Sontag Foundation Fellow
“The Role of Neutrophils and NETs in the Pathogenesis of Scleroderma”
“Elucidating the Role of miR-126-3p in Osteoarthritis”
“Removal of Apoptotic Cells in Inflammatory Arthritis”
Synthetically regulated cell-based therapeutics for targeted articular cartilage regenerative medicine
“The Role of Cytokines in Monocytes During Macrophage Activation Syndrome”
“Epigenetic Mechanisms of Macrophages during Gouty Inflammation”
Platelets as neutrophil amplifiers in systemic sclerosis
“Adipose Tissue as a Memory T Cell Storage Site in Inflammatory Arthritis”
Splicing Disruption in Systemic Lupus Erythematosus
mTORC1 in the pathogenesis of systemic juvenile idiopathic arthritis
Type I Interferon Pathway Activity Informs TNF-inhibitor Treatment Response in Rheumatoid Arthritis
Understanding how the CARD9-neutrophil-Th17 axis controls ankylosing spondylitis
Mechanistic Insights into Organ-Specific Manifestations of Spondyloarthritis
“Mechanisms of Th1.17 Cell Development in Polyarticular Juvenile Idiopathic Arthritis”
“Role of A20 in Restricting Psoriatic Skin and Joint Disease”
Microparticle-assisted modulation of regulatory T cells in rheumatoid arthritis
Molecular reprogramming of Rheumatoid arthritis synovial fibroblasts by interleukin 6
Metabolic regulation of chondrocytes by Sirt5 and protein malonylation in osteoarthritis development
Mechanisms of infection-induced autoimmunity in COVID-19 and beyond
Characterize the role of AIM2 in the autoimmune disease Systemic Lupus
Synthetically regulated cell-based therapeutics for targeted articular cartilage regenerative medicine
Platelets as neutrophil amplifiers in systemic sclerosis
Splicing Disruption in Systemic Lupus Erythematosus
The Function & Autoreactivity of Th1 Polarized & Clonally Expanded Tregs in Oligo JIA
Analysis of the NOD-RIPK2 signaling pathway in osteoarthritis
mTORC1 in the pathogenesis of systemic juvenile idiopathic arthritis
Mechanisms by which clonal hematopoiesis augments inflammation and atherosclerosis in rheumatoid arthritis
Understanding how the CARD9-neutrophil-Th17 axis controls ankylosing spondylitis
Elucidating mechanisms of methotrexate metabolism by the human microbiome in rheumatoid arthritis
Mechanistic Insights into Organ-Specific Manifestations of Spondyloarthritis
The role of TNF and TNFR1 in breaking B cell tolerance
Microparticle-assisted modulation of regulatory T cells in rheumatoid arthritis
Molecular reprogramming of Rheumatoid arthritis synovial fibroblasts by interleukin 6
Immune Checkpoint Inhibition Induced Inflammatory Arthritis Correlates with Imbalance Between T-cell Exhaustion and Senescence
Investigating the role of gene Creb5 in lubricin expression during the development of osteoarthritis
Metabolic regulation of chondrocytes by Sirt5 and protein malonylation in osteoarthritis development
Mechanisms of infection-induced autoimmunity in COVID-19 and beyond
Characterize the role of AIM2 in the autoimmune disease Systemic Lupus
Investigating the role of resident stem cell populations in the regeneration of cartilage and in OA progression
Identifying why some children outgrow JIA whereas others develop chronic disease.
Investigate how such OCs form and how they lead to joint tissue destruction in arthritis.
Hypothesizes that mutations in specific genes as found in OA susceptible families may underlie the enhanced joint inflammation that is a hallmark of OA progression.
Evaluating the impact of mutations in the gene TET2 in RA since her previous work demonstrated that such mutations result in accelerated CVD development.
Characterize the microbiomes and Methotrexate (MTX) metabolites of a number of RA patients to more fully understand how specific bacterial genes may influence the activity of MTX in RA patients.
Investigating how TNF affects the generation of autoreactive B cells.
Understand how this specific DNASE1L3 polymorphism leads to the development of scleroderma
The genetics of antinuclear antibodies and the risk of lupus
Analyze ICI patient samples to determine the mechanisms that lead to the development of this form of arthritis following ICI therapy.
Investigating the role of gene Creb5 in lubricin expression during the development of osteoarthritis
Decoding rheumatoid arthritis using a unique tool to identify arthritogenic T cells
A Chemical Niche to Regenerate and Rejuvenate Cartilage in Osteoarthritis
Megakaryocytes as neutrophil amplifiers in inflammatory arthritis
Identification of pathogenic lymphocytes in ankylosing spondylitis
Identification of inhibitory receptors involved in establishing the Lyn-SHP-1 axis in B cell tolerance
Origins of synovial osteoclasts in inflammatory arthritis
Epigenetics at the intersection of trauma, aging, and osteoarthritis
Characterization of a CD8 T Cell Subset Enriched in Blood of Patients with Rheumatoid Arthritis
The genetics of antinuclear antibodies and the risk of lupus
The influence of the surrogate light chain protein λ5 on bone health and arthritis in aging
Mitochondrial-mediated inflammation and autoimmunity in rheumatoid arthritis
Understanding a shared mechanism for genetic risk in childhood arthritis
Sontag Foundation Fellow
Type I Interferon Pathway Activity Informs TNF-inhibitor Treatment Response in Rheumatoid Arthritis
Targeting Platelet-Derived Growth Factor Receptor-α (PDGFRα) in Rheumatoid Arthritis
Pathogenic effects of DNASE1L3 R206C polymorphism in systemic sclerosis
Derivation and phenotype of ANA+ plasma cells in SLE
Functional diversity of iNKT subsets in Rheumatoid Arthritis
Characterization of a novel epigenetic regulator of Th17 differentiation
Signaling and repertoire differences in arthritogenic T cells
Genetic reprogramming of OA chondrocytes to improve cartilage repair
Megakaryocytes as neutrophil amplifiers in inflammatory arthritis
Cellular senescence as a driver and therapeutic target for osteoarthritis
Epigenetics at the intersection of trauma, aging, and osteoarthritis
Characterization of a CD8 T Cell Subset Enriched in Blood of Patients with Rheumatoid Arthritis
The influence of the surrogate light chain protein λ5 on bone health and arthritis in aging
Role of IL36α in Osteoarthritis progression
Identifying Novel Mechanotransduction Targets for Treating Osteoarthritis
Targeting Platelet-Derived Growth Factor Receptor-α (PDGFRα) in Rheumatoid Arthritis
The Role of TNF and TNFR1 in Breaking B Cell Tolerance
The role of matricellular protein CYR61 in fibrosis and angiogenesis in scleroderma
Validating STAT3 as a Therapeutic Target in Arthritis
Characterization of a novel epigenetic regulator of Th17 differentiation
Comparing the Regulatory Networks Underlying Inflammation in Arthritis & Aging
The function of SENP6 desumoylase in preventing articular chondrocyte senescence and osteoarthritis development
Cells for Regenerating Articular Cartilage
Cellular senescence as a driver and therapeutic target for osteoarthritis
Mechanisms Underlying TACI-dependent activation of immature transitional B cells in BAFF-driven humoral autoimmunity
Therapeutic targeting of GPCR Gbetagamma-GRK2 signaling in osteoarthritis
Thrombo-inflammatory role of neutrophils in lupus
Activin A regulation of T follicular helper cell biology in Rheumatoid Arthritis
Identifying Novel Mechanotransduction Targets for Treating Osteoarthritis
Predicting tissue growth potential using high-throughput screening for cell mechanics
Genetic and Epigenetic Covariance of Gout, Hyperuricemia and its Comorbidities
Personalized approach to enhance prediction of psoriatic arthritis
The role of matricellular protein CYR61 in fibrosis and angiogenesis in scleroderma
Validating STAT3 as a Therapeutic Target in Arthritis
Comparing the Regulatory Networks Underlying Inflammation in Arthritis & Aging
Deborah R. Winter, PhD is the Sontag Foundation Fellow for 2017-2018.
The Intriguing Role of Macrophages in Rheumatoid Arthritis
The function of SENP6 desumoylase in preventing articular chondrocyte senescence and osteoarthritis development
Research: Rheumatoid Arthritis
Project Title: Identifying Cellular and Molecular Mechanisms of Microbiome-Driven Inflammatory Arthritis
Research: Psoriatic Arthritis
Understanding the Cause of Psoriatic Arthritis
Research: Osteoarthritis
Cells for Regenerating Articular Cartilage
Research: Osteoarthritis
Elucidating the function of musculoskeletal promoting small molecules for osteoarthritis
Research: Lupus
Mechanisms underlying TACI-dependent activation of immature transitional B cells in BAFF-driven Systemic Lupus Erythematosus (SLE)
Research: Lupus
Thrombo-inflammatory role of neutrophils in lupus
Research: Adult and Pediatric Rheumatoid Arthritis
High-throughput experimental interrogation of GWAS loci in adult and pediatric arthritis
Research: Gout
Genetic and Epigenetic Covariance of Gout, Hyperuricemia and its Comorbidities
Research: Autoimmunity
Role of the transcription factor Ikaros in development of autoimmune disease
Research: Autoimmunity
The innate immune adaptor STING regulates age-dependent bone homeostasis and remodeling.
Research: Rheumatoid Arthritis
Unraveling a novel mechanism of action of PTPN22, a major RA gene
Research: Psoriatic Arthritis
Personalized approach to enhance prediction of psoriatic arthritis
Research: Lupus
Regulation of Treg metabolism and stability by PTEN in autoimmune diseases
Microbiome-Driven Inflammatory Arthritis: Studying Bacteria as Cause of RA
How Joint-Protecting Cells Transform into Joint-Destroying Cells
Osteoarthritis (OA) study could lead to new treatment
Inherited Immune Cell Defects May Hold Key to Understanding
Genetic Mechanisms in Inflammatory Arthritis
Understanding the Cause of Psoriatic Arthritis
Co-Funded Grant with National Psoriasis Foundation
Study to prevent or reverse damaged Osteoarthritis joints
Skin Rash Triggers Kidney Inflammation
Gene Study may provide targeted treatment for RA, JIA patients
Gene could provide key to understanding autoimmunity
Understanding initiation of bone loss may yield new targets for treatment
Genetic study may lead to targeted treatment
Laying a foundation for new OA therapy
Damage in joints of patients with rheumatoid arthritis (RA) is induced by the patient’s immune system attacking its own joint tissues. However, a portion of this damage is caused by “resident” normal cells in the joint that have become altered during and after the immune attack. The altered resident cells undergo abnormal growth and healing which results in scarring, disfigurement and joint immobilization.
Studying joint tissue from human RA patients and mice, Dr. Bartok has discovered how the normal joint cells become altered by the immune attack. Her important findings can lead to the development of new methods to block this destructive cellular response. This can lead to new drugs and treatments to prevent and stop the progressive destruction of joint tissues in RA patients.
Rheumatoid arthritis is a common joint disease causing distress and disability in the affected individuals. Abnormal changes in specialized cells lining the joint surfaces, known as the fibroblasts-like synoviocytes, are one of the major causes of this disease. In healthy joints fibroblasts-like synoviocytes are critical for the maintenance of joint integrity. They produce molecules that lubricate joints and help to protect joints from wear and tear. However, in rheumatoid arthritis, these specialized cells transform into cancer-like cells. They increase in numbers and act as a source of molecules that destroy the joints.
Despite this knowledge, incomplete understanding of the genes and pathways that regulate fibroblasts-like synoviocytes has limited the development of treatment strategies that can target these cells. This study focuses on uncovering the roles of a group of genes that belong to the SOX family, in transforming the healthy joint protecting cells into joint destroying cells. The signaling pathways that are under the control of these SOX genes could be targeted to treat and limit the joint damage in rheumatoid arthritis.
Osteoarthritis is the most common form of arthritis that affects approximately 27 million people in U.S. alone. Current treatments are however limited to pain management mainly because of a lack of understanding of the initiation and early stages of the disease. No disease-modifying OA drug is available as a result. OA is marked by joint dysfunction and particularly cartilage degeneration caused by the native cartilage cells themselves. Dr. Bhutani’s recent studies have identified that normal and OA cartilage cells from patients differ greatly in the function of a novel family of enzymes. These enzymes are responsible for modifying the DNA and such ‘epigenetic’ modifications affect widespread gene expression; therefore, these enzymes can be central regulators of the gene expression changes in OA.
Dr. Bhutani’s research will identify the genes that are regulated by these particular enzymes in OA cartilage to understand how they affect the initiation and progression of OA. Using mice that lack these enzymes, she will test how the absence of this regulator will modulate OA. Lastly, Dr. Bhutani will evaluate whether a pharmacological manipulation of these enzymes (and its targets) has the potential to be therapeutic in OA.
Dr. Bhutani is the ANRF-AFAR Grant Recipient – a special grant on aging co-funded by ANRF and the American Federation for Aging Research.
While acute inflammation is mostly beneficial, unchecked or dysregulated inflammation can have devastating consequences leading to a wide range of diseases including Rheumatoid Arthritis, Systemic Lupus Erythematous, and Cancer. Thus, given the significance of these devastating diseases, new approaches towards understanding pathology and gene mechanism are urgently needed.
It has been over a decade since the human genome was sequenced. Since then, there have been huge improvements in our ability to carry out sequencing. The classical understanding of the genome was that DNA is transcribed into RNA, which makes proteins that carry out various biological functions. However, sequencing studies have shown that only a small portion (2%) of the genome results in protein, yet there are very large amounts of RNA being produced (85% of the genome). The major class of RNA molecules produced from the genome are called long noncoding RNA (lncRNA). These RNA molecules are emerging as fundamental mediators of innate immune signaling pathways.
Dr. Carpenter’s research has identified lincRNA-Cox2 as a highly inducible gene in response to inflammatory stimuli and functions to repress interferon stimulated gene (ISG) expression while also being required for the induction of other inflammatory genes such as IL-6. She has identified functional interactions between lincRNA-Cox2 and the heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP-A2/B1), also known as RA33, an auto-antigen in rheumatoid arthritis.
This project aims to understand how lincRNA-Cox2 and RA33 are involved in the pathogenesis of inflammatory arthritis. Obtaining a better understanding of the role of these RNA molecules in inflammatory conditions could lead to the development of new biomarkers for disease and unveil new therapeutic targets.
Articular cartilage is a type of connective tissue that covers the surfaces of bones within synovial joints. Articular cartilage injury and the lack of cartilage regeneration often lead to osteoarthritis. Recent studies carried out by Dr. Evseenko and his lab and others have shown that stem/progenitor cells can partially repair damage cartilage, but more work is needed to increase the efficiency of this therapy. Unfortunately, limited survival and degeneration of implanted stem/progenitor cells, as well as excessive collagen type I (COL I) deposition leading to formation of mechanically inferior tissue, are the standard outcomes of currently used cell-based cartilage restoration techniques.
Dr. Evseenko proposes a novel approach based on his recent findings and the development of an essential model to test this and subsequent therapeutic methods. He will use a highly purified population of cartilage stem cells identified in his lab’s recent studies of normal human cartilage development. His team will also manipulate signaling driven by the small biogenic lipid LPA, having recently shown that LPA is highly expressed in the site of cartilage injury driving COL I deposition, which in turn leads to fibrosis and limits the expansion and survival of implanted stem cells. In rat studies, his team has also shown that pharmacological inhibition of the LPA-signaling reduces fibrosis and results in enhanced production of neocartilage at the site of injury.
During this second year of ANRF support, Dr. Evseenko will access this novel approach in a large animal model of joint injury and apply a highly innovative robotic approach to assess the biomechanical properties of repaired joints, in addition to the routine histological tests. The ultimate objective of the proposed project is to develop new therapeutic approaches for articular cartilage restoration, which in turn will reduce the morbidity from acute cartilage injuries and degenerative joint disease.
Dr. Evseenko is this year’s James Klinenberg Scholar as his work at UCLA closely aligns with that of Dr. Klinenberg.
Systemic lupus erythematosus (SLE or lupus) is a severe autoimmune disorder that can adversely affect many organs, including the skin, kidney, blood and joints. This organ damage can result in substantial morbidity or even death. In patients suffering from lupus, their disease course is characterized by “flares” of increased disease activity that require treatment with aggressive immunosuppressive medications. Often, these flares can be heralded by the presence of a lupus rash. However, how this rash relates to systemic disease development remains unclear.
In most murine models of lupus, the onset of disease is a gradual process, and it has been difficult to model how a flare occurs. In her work, Dr. Kahlenberg has developed a model in which lupus-prone female mice develop a rapid flare of kidney disease following skin injury. This project proposes to determine the mechanisms by which skin injury can lead to a rapid flare of kidney inflammation in these mice. She will investigate this by undertaking a systematic exploration of the inflammatory cell populations present in the kidney and relate this to simultaneous changes in the skin and blood of the mice. Additionally, she and her team will target the cytokine IL-18 to determine whether induction of flares of kidney inflammation by skin injury requires this cytokine.
She anticipates this work will show that skin injury rapidly increases the inflammatory cell populations in the kidney and that blocking IL-18 may modulate this. This work will benefit the scientific community by increasing knowledge of how the skin and kidney may cross-talk in lupus, thus leading to development of novel therapies that may help to prevent flares of lupus nephritis and reduce the need for immunosuppressive medications in lupus patients.
Dr. Evseenko is this year’s Eng Tan Scholar as her work most closely aligns with that of Dr. Tan.
Rheumatoid arthritis (RA) affects 0.5-1% of the general population and is characterized by joint inflammation (arthritis) and increased mortality, primarily due to heart attack and stroke. Scientific breakthroughs during the last 20 years have enriched our therapeutic “medicine chest” with biologic therapies and kinase inhibitors, leading to a dramatic improvement in patients’ quality of life. Despite this progress there are still unmet needs including the low rates of sustained disease remission and the inadequate response to therapy in about 1/3 of RA patients. In this context, it is necessary to implement more individualized treatment protocols and identify safer and more effective therapies. The path to achieve these goals is to understand in depth the molecular events implicated in RA pathogensis.
Dr. Kalliolias uses novel technologies to characterize the role of synovial fibroblasts (SF) in RA pathogenesis. SF are resident cells of the normal joint that become activated in RA. Although their implication in the inflammatory and destructive processes of RA has been considered for a long time, none of the existing therapies for RA targets SF. His previous studies have shown that SF display an uncontrolled inflammatory response to factors found in abundance within the inflamed joint of RA patients. These findings led to the hypothesis that SF of RA patients lack the appropriate “brakes” that should turn off inflammatory responses. Currently, Dr. Kalliolias is testing this hypothesis with an ultimate goal to identify strategies to terminate or block the production of inflammatory and tissue destructive mediators by SF. His long-term goal is to set the stage for the development of drugs for RA patients that will target SF, supplementing the existing therapies that target the immune system.
Dr. Kalliolias was named the first Gale A. Granger Scholar, as his work most closely aligned with that of Dr. Granger, former ANRF grant recipient and board member who initially discovered tumor necrosis factor (TNF) and its receptors.
Antiphospholipid syndrome (APS) is a serious autoimmune clotting disorder in which the immune system mistakenly attacks a self-protein in the blood. The “auto antibodies” that attack self molecules in blood are found in certain patients with rheumatoid arthritis, lupus and other autoimmune diseases. When the auto antibodies react with self molecules they form clots in the blood stream that can lodge in tissues causing stroke, heart attack and death. What induces the patient’s immune system to react against these self molecules is not known.
Dr. Kriegel has found that certain bacteria living in the digestive tract of patients with APS trick the immune system to react against the self molecules. These are important findings for they reveal 1) how this disease starts which may serve as a model of how other types of autoimmune disease can start and, 2) how to diagnose, prevent and stop the progression of this particular disease.
Nutrition can have a profound effect on disease development. Most current studies have focused on how macro-nutrition (calorie, carbohydrate, fat, and protein) affects diseases, but very little is known about the role that early life micro-nutrition plays in diseases such as rheumatoid arthritis (RA). Micronutrients such as folic acid and methionine produce methyl donors that can attach to DNA. The amount of protein produced by a gene can be increased or decreased by the amount of methyl donors attached to that gene’s DNA. When this happens, the gene is considered “methylation sensitive.”
Tissue damage in rheumatoid arthritis is caused by certain pro-inflammatory genes, and many of these genes are methylation sensitive. A subset of white blood cells, CD4+ T cells, contributes to RA by producing high levels of many pro-inflammatory proteins, and disease severity can be adjusted by controlling the methylation level of several of these genes. Feeding mice a diet rich in methyl donors during pregnancy affects expression of many of these genes in CD4+ T cells in their offspring mice (F1 methyl supplemented), compared to the offspring of pregnant mice that were fed a regular diet (F1 control). Genes favoring inflammation are expressed at lower levels in F1 methyl supplemented mice and, in a model of atherosclerosis (heart disease), F1 methyl supplemented mice had less severe disease than F1 control mice.
Dr. Patel predicts F1 methyl supplemented mice will have less severe rheumatoid arthritis, compared to F1 control mice, as well. His team has shown, in the collagen induced arthritis model, F1 methyl supplemented mice have decreased paw swelling compared to F1 control mice. To explain this, he expects that CD4+ T cells will express lower levels of pro-inflammatory mediators, and higher levels of anti-inflammatory mediators, in F1 methyl supplemented mice compared to F1 control mice.
These results have the potential to transform our understanding of how genes and the environment interact in RA and other chronic inflammatory diseases, and to identify a new paradigm in understanding and potentially treating inflammation and disease with pre-natal nutrition.
Neutrophils are white blood cells which are important for the body’s defense against infectious agents. However, these same cells enter the joint in rheumatoid arthritis in large numbers and over time cause swelling, pain and tissue damage.
Dr. Wang has identified the mechanism of how neutrophils leave the blood stream and migrate into joint tissues. These are important findings for blocking the migration of neutrophils into the joint can prevent the onset of the disease and stop tissue damage. These results can lead to new methods to prevent and control RA and other forms of inflammatory arthritis.
Current osteoarthritis (OA) treatment focuses on symptom relief but does not materially alter disease progression. OA prevention and treatment continue to be a clinical challenge due to the limited self-healing capacity of joint cartilage. Searching for cell sources capable of being mobilized and providing functional descendants in joint cartilage is of paramount importance to osteoarthritis prevention and treatment.
Dr. Yang and his team recently identified a population of cartilage progenitors/stem cells that express an enzyme called cathepsin K in joints; these cells are capable of forming cartilage and this function is enhanced in the absence of a certain protein, tyrosine phosphatase SHP2. The goal of this study is to further understand the role of this population of stem cells in joint cartilage development and homeostasis and the molecular mechanism through which this protein modulates the capability of the stem cells to form cartilage. Dr. Yang’s long-term objective is to develop strategies to inhibit cartilage degeneration and promote its regeneration by mobilizing this population of stem cells and/or modifying SHP2-regulated signaling pathway(s).
Systemic lupus erythematosus (SLE or lupus) is an autoimmune disease in which the immune system turns against parts of the body it is designed to protect. With lupus, instead of producing protective antibodies, the immune system makes autoantibodies, which attack the patient’s own tissues and cause widespread tissue and organ injury. These autoantibodies are secreted by large number of plasma cells, which are differentiated from a type of leukocytes (white blood cells) called B cells, and are heavily mutated on the antigen-binding domain and class-switched to mainly IgG isotype.
The pathogenesis of autoimmune diseases, including lupus, can be traced to both genetic elements and epigenetic modifications arising from exposure to the environment. Epigenetics involves genetic control by factors other than an individual’s own DNA sequence. Epigenetic factors, such as DNA methylation, histone modifications and microRNAs, can switch genes on or off and determine which proteins impact cell function. Like many other autoimmune diseases, lupus preferentially affects women during their reproductive years, suggesting that the female hormone estrogen, which promotes autoantibody response, plays an important role in causing lupus.
In Dr. Zan’s study, he and his team utilizes FDA-approved and widely-used epigenetic modulators to selectively inhibit the generation of pathogenic autoantibodies to prevent, treat or even cure lupus. With the second year support from Arthritis National Research Foundation, he will develop therapeutic approaches including combined treatment that target both estrogen receptor, which is important for effects of estrogen, and epigenetic factors, or target multiple epigenetic factors to synergistically dampen autoantibody responses, thereby, treat lupus more effectively. He will also attempt to gain further insight into B cell-intrinsic epigenetic mechanisms in the pathogenic lupus autoantibody response, and to unveil modulation of the epigenetic factors by estrogen.
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