Kelly Brown
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Biography
In Canada, rheumatic conditions are the most common chronic illness of childhood, affecting as many as 10 000 of our children and youth. Examples of rheumatic diseases are juvenile idiopathic arthritis, lupus, vasculitis and autoinflammatory conditions. The common denominator for all is pain and / or inflammation in joints, muscles, and critical organs. Some diseases are life- or organ- threatening and all have significant potential for lifelong poor health and disability. There are no cures and remarkably few treatments that are specific and safe for a growing child. My research program is designed to generate an evidence base for clinical decisions that ultimately improve outcomes for Canadian children and families affected by rheumatic disease.
Research Methodology
Recruitment
We are a highly collaborative, multidisciplinary team of scientists that are motivated to improve diagnosis, treatment and outcomes for children and youth with a rheumatic disease through the discovery of driving mechanisms and prognostic biomarkers. Priority rheumatic diseases are: vasculitis - which develops when blood vessels carring oxygen to critical organs in the body (inclusive of the brain, kidneys and lungs) are damaged by inflammation, and systemic autoinflammatory diseases (SAID) - which are caused by unprovoked, recurrent and uncontrolled attacks of inflammation and fever. Specifically, trainees work towards the i) validation and prospective testing of biomarkers for diagnosis and assessment of overall and organ-specific disease activity, and ii) unravel the contribution of innate and adaptive processes to disease onset, severity, and response to treatment.
Ideal team members are basic scientists (BSc, MSc, PhD) that are passionate about improving child health through a translational, 'team science' approach. They may have foundational training in a variety of scientific disciplines (immunology, biochemistry, genetics, computing science). Individuals should be highly motivated and have prior research experience. Strong interpersonal skills and the ability to communicate with scientists, clinicians and patients/families is essential.
All researchers based at the BC Children's Hospital require a Criminal Record Check (CRC) and must provide proof of full vaccination against COVID-19. We encourage applications from members of groups that have been marginalized on any grounds enumerated under the B.C. Human Rights Code, including sex, sexual orientation, gender identity or expression, racialization, disability, political belief, religion, marital or family status, age, and/or status as a First Nation, Metis, Inuit, or Indigenous person.
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Graduate Student Supervision
Doctoral Student Supervision
Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.
Chronic primary systemic vasculitis (PSV) describes a diverse group of debilitating and potentially life-threatening diseases, characterized by inflammation of blood vessels within various organs such as the kidneys, lungs, brain, eyes, and skin. Subtypes of the small- to medium-sized vessel vasculitides are particularly challenging to classify due to many overlapping clinical symptoms. Their differentiation is important, however, as there is evidence that different subtypes benefit from different treatment approaches. The rarity of vasculitis in children has limited pediatric-specific PSV studies and the clinical approach to pediatric PSV is adapted primarily from adult studies. Not surprisingly, adult-derived classification criteria are imperfect for children and consequently, fail to classify up to two thirds of children with small- to medium-vessel PSV. The objective of this dissertation is to identify genetic markers and select, circulating biomarkers to better our understanding and clinical approach to managing the disease and to improve outcomes of children with chronic PSV. Using biological samples and clinical metadata from a worldwide cohort of children with chronic PSV, this dissertation reports (1) genetic associations specific to pediatric autoimmune vasculitis through employing a genome-wide association study; (2) a high prevalence of autoantibodies to lysosome associated membrane protein-2 in pediatric PSV that correlate to vasculitis-associated kidney dysfunction; and (3) the identification of nine patients, originally diagnosed with chronic PSV, harbouring novel and/or rare variants in adenosine deaminase 2 (ADA2) – these genetic data alongside having abrogated ADA2 enzyme activity have led to their reclassification as having a new monogenic form of vasculitis, deficiency of adenosine deaminase 2. This dissertation reports the first large-scale genotype and biomarker study of primary vasculitis focusing solely on pediatric cases. Improved classification is critical for timely therapeutic intervention, for identification of appropriately classified children for clinical trials, and for research, all of which will improve our understanding of the disease and the quality of life of children suffering from chronic PSV.
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Hyaluronan (HA) is a glycosaminoglycan that in its natural, high molecular mass (HMM) form, promotes tissue repair and homeostasis. With inflammation, enhanced HA metabolism results in HMM HA fragmentation to low molecular mass (LMM) fragments that may act as a damage-associated molecular pattern to initiate innate immune responses. However, the responsiveness of myeloid cells to HA is controversial and largely unknown for neutrophils. Here, I investigated if and how HA can directly affect key immune functions of neutrophils and potentially contribute to the dysregulated neutrophil activation observed in childhood-onset rheumatic diseases. For this investigation, peripheral blood cells from healthy donors were incubated ex vivo with pharmaceutical grade HA of different molecular mass (HMM, LMM and HA fragments
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Master's Student Supervision
Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.
Juvenile idiopathic arthritis (JIA) is the most common cause of youth disability in Canada, characterized by chronic joint inflammation and bone degradation. Common JIA treatment regimens include nonsteroidal anti-inflammatory drugs (NSAIDs), and disease-modifying agents. Currently, there are no reliable means to identify those children with JIA at risk of a more severe or progressive or frequently relapsing disease. Platelets are blood cells with well characterized roles in hemostasis and increasingly recognized contributions to inflammation in chronic inflammatory disease. Specifically, the presence of platelet factor 4 (the most abundant platelet-derived chemokine) and activated platelets have been associated with inflammation in rheumatoid joints in adults. However, the role of platelet-derived proteins in juvenile arthritis has not yet been evaluated. This patient-based study evaluated platelet factor 4 (PF4) as a potential subclinical marker of disease activity in JIA and explored a possible cross-talk with neutrophils and neutrophil-derived S100A proteins (S100A8/9 and S100A12) that have been shown to track with JIA disease activity. Results demonstrated that intracellular (within platelets) and extracellular (in plasma) PF4 was significantly more abundant in healthy children compared to adults, and release of PF4 from thrombin receptor-activated platelets was enhanced with prior exposure to S100A12 and S100A8/9. In contrast, PF4 did not stimulate pro-inflammatory responses (release of reactive oxygen species or S100A protein) by neutrophils. Early in JIA disease course and in the absence of NSAID treatment, there was a moderate correlation between circulating concentrations of PF4 and both disease activity and concentrations of S100A12. For patients in remission, circulating PF4 concentrations were higher in children who relapsed, correlated with the time to first flare, and had a similar probability of predicting a flare compared to S100A12. Overall, this study helped to advance our understanding of the role of platelets in chronic inflammation and provided preliminary evidence for PF4 as a subclinical marker for JIA disease activity.
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Publications
- Autoantibodies Against Lysosome Associated Membrane Protein-2 (LAMP-2) in Pediatric Chronic Primary Systemic Vasculitis (2021)
Frontiers in Immunology, 11 - Children with systemic autoinflammatory diseases have multiple, mixed ethnicities that reflect regional ethnic diversity (2021)
Clinical and Experimental Rheumatology, 39 (5), S124-S128 - Different Disease Endotypes in Phenotypically Similar Vasculitides Affecting Small-to-Medium Sized Blood Vessels (2021)
Frontiers in Immunology, 12 - Galectin-3 Modulates Microglia Inflammation in vitro but Not Neonatal Brain Injury in vivo under Inflammatory Conditions (2021)
Developmental Neuroscience, 43 (5), 296-311 - Latent gammaherpesvirus exacerbates arthritis and requires age-associated B cells (2021)
bioRxiv, - Latent gammaherpesvirus exacerbates arthritis through modification of age-associated b cells (2021)
eLife, 10 - Adenosine deaminase 2 activity negatively correlates with age during childhood (2020)
Pediatric Rheumatology, 18 (1) - Anti‐neutrophil cytoplasmic antibodies (ANCA): Antigen interactions and downstream effects (2020)
Journal of Leukocyte Biology, - Consensus treatment plans for periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome (PFAPA): A framework to evaluate treatment responses from the childhood arthritis and rheumatology research alliance (CARRA) PFAPA work group (2020)
Pediatric Rheumatology, 18 (1) - Hyaluronan primes the oxidative burst in human neutrophils (2020)
Journal of Leukocyte Biology, - Comparable type I interferon score determination from PAXgene and Tempus whole blood RNA collection and isolation systems (2019)
BMC Research Notes, 12 (1) - Complexity in unclassified auto-inflammatory disease: A case report illustrating the potential for disease arising from the allelic burden of multiple variants (2019)
Pediatric Rheumatology, 17 (1) - Identification of Novel Adenosine Deaminase 2 Gene Variants and Varied Clinical Phenotype in Pediatric Vasculitis (2019)
Arthritis and Rheumatology, 71 (10), 1747-1755 - Methods for type I interferon detection and their relevance for clinical utility and improved understanding of rheumatic diseases. (2019)
Clinical and experimental rheumatology, 37 (6), 1077-1083 - Monocyte-Derived Interleukin-1β As the Driver of S100A12-Induced Sterile Inflammatory Activation of Human Coronary Artery Endothelial Cells: Implications for the Pathogenesis of Kawasaki Disease (2019)
Arthritis and Rheumatology, 71 (5), 792-804 - Periodic fever syndromes: beyond the single gene paradigm. (2019)
Pediatric rheumatology online journal, - The Value of Creativity for Enhancing Translational Ecologies, Insights, and Discoveries. (2019)
Frontiers in psychology, - S100A12 Serum Levels and PMN Counts Are Elevated in Childhood Systemic Vasculitides Especially Involving Proteinase 3 Specific Anti-neutrophil Cytoplasmic Antibodies. (2018)
Frontiers in pediatrics, - Clinical practice variation and need for pediatric-specific treatment guidelines among rheumatologists caring for children with ANCA-associated vasculitis: an international clinician survey. (2017)
Pediatric rheumatology online journal, - Elevated Mitochondrial Reactive Oxygen Species and Cellular Redox Imbalance in Human NADPH-Oxidase-Deficient Phagocytes (2017)
Frontiers in Immunology, 8 - Measles Lymphadenopathy in a Child With PFAPA Syndrome. (2017)
Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society, - The importance of considering monogenic causes of autoimmunity: A somatic mutation in KRAS causing pediatric Rosai-Dorfman syndrome and systemic lupus erythematosus. (2017)
Clinical immunology (Orlando, Fla.), - Endotoxin free hyaluronan and hyaluronan fragments do not stimulate TNF-α, interleukin-12 or upregulate co-stimulatory molecules in dendritic cells or macrophages (2016)
Scientific Reports, 6 - Purified hyaluronan and hyaluronan fragments do not stimulate pro-inflammatory cytokine production in dendritic cells or macrophages (2016)
Scientific Reports, - Temporal Characterization of Microglia/Macrophage Phenotypes in a Mouse Model of Neonatal Hypoxic-Ischemic Brain Injury. (2016)
Frontiers in cellular neuroscience, - Pediatric vasculitis: advances in treatment. (2015)
Current opinion in rheumatology, - The Where, When, How, and Why of Hyaluronan Binding by Immune Cells (2015)
Frontiers in Immunology, 6 - Innate defense regulator peptide 1018 protects against perinatal brain injury. (2014)
Annals of neurology, - Cathelicidins (2013)
Handbook of Biologically Active Peptides, , 77-84 - Host Defence (Antimicrobial) Peptides and Proteins (2013)
eLS, - Increased intracellular oxygen radical production in neutrophils during febrile episodes of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome. (2013)
Arthritis and rheumatism, - Anti-Inflammatory/Analgesics: An In-Depth Look at p38 MAP Kinases (2011)
Pharmaceutical Sciences Encyclopedia, - Differential use of chondroitin sulfate to regulate hyaluronan binding by receptor CD44 in Inflammatory and Interleukin 4-activated Macrophages. (2011)
The Journal of biological chemistry, - Galectin 3 aggravates joint inflammation and destruction in antigen-induced arthritis. (2011)
Arthritis and rheumatism, - Host defense peptide LL-37 selectively reduces proinflammatory macrophage responses. (2011)
Journal of immunology (Baltimore, Md. : 1950), - On the road to discovery in periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome. (2011)
Proceedings of the National Academy of Sciences of the United States of America, - G-protein-coupled receptor independent, immunomodulatory properties of chemokine CXCL9 (2010)
Cellular Immunology, 261 (2), 105--113 - Intracellular generation of superoxide by the phagocyte NADPH oxidase: how, where, and what for? (2010)
Free radical biology & medicine, - Profile of blood cells and inflammatory mediators in periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome. (2010)
BMC pediatrics, - Robust TLR4-induced gene expression patterns are not an accurate indicator of human immunity. (2010)
Journal of translational medicine, - Treating neonatal brain injury - promise and inherent research challenges. (2010)
Recent patents on inflammation & allergy drug discovery, - Divergent effects on phagocytosis by macrophage-derived oxygen radicals. (2009)
Journal of innate immunity, - Galectin-3 functions as an opsonin and enhances the macrophage clearance of apoptotic neutrophils. (2009)
Glycobiology, - Manual annotation and analysis of the defensin gene cluster in the C57BL/6J mouse reference genome (2009)
BMC Genomics, 10 (1), 606 - The host defense peptide LL-37 selectively permeabilizes apoptotic leukocytes. (2009)
Antimicrobial agents and chemotherapy, - Antimicrobial Host Defence Peptides of Human Neutrophils – Roles in Innate Immunity (2008)
Anti-Infective Agents in Medicinal Chemistry, 7 (3), 155--168 - Is Innate Host Defense the Answer? (2008)
Current Opinions in Biotechnology, - Novel anti-infectives: is host defence the answer? (2008)
Current Opinion in Biotechnology, 19 (6), 628-636 - Phagocyte-derived reactive oxygen species as suppressors of inflammatory disease. (2008)
Arthritis and rheumatism, - ROS-deficient monocytes have aberrant gene expression that correlates with inflammatory disorders of chronic granulomatous disease (2008)
Clinical Immunology, 129 (1), 90--102 - Antimicrobial, Host Defence Peptides and Proteins (2007)
eLS, - Complexities of targeting innate immunity to treat infection (2007)
Trends in Immunology, 28 (6), 260--266 - Enhanced inflammatory responses of chronic granulomatous disease leukocytes involve ROS-independent activation of NF-κB (2007)
European Journal of Immunology, 37 (4), 1087--1096 - Bovine and human cathelicidin cationic host defense peptides similarly suppress transcriptional responses to bacterial lipopolysaccharide. (2006)
Journal of leukocyte biology, - Cathelicidins: Cationic Host Defense and Antimicrobial Peptides (2006)
Handbook of Biologically Active Peptides, , 67--74 - Cationic host defense (antimicrobial) peptides (2006)
Current Opinion in Immunology, 18 (1), 24--30 - Host defence peptides from invertebrates--emerging antimicrobial strategies. (2006)
Immunobiology, - IRAK-4 mutation (Q293X): rapid detection and characterization of defective post-transcriptional TLR/IL-1R responses in human myeloid and non-myeloid cells. (2006)
Journal of immunology (Baltimore, Md. : 1950), - Modulation of the TLR-mediated inflammatory response by the endogenous human host defense peptide LL-37. (2006)
Journal of immunology (Baltimore, Md. : 1950), - Expression of N-acetylglucosamine 6-O-sulfotransferases (GlcNAc6STs)-1 and -4 in human monocytes: GlcNAc6ST-1 is implicated in the generation of the 6-sulfo N-acetyllactosamine/Lewis x epitope on CD44 and is induced by TNF-alpha. (2005)
Glycobiology, - Regulation of hyaluronan binding by F-actin and colocalization of CD44 and phosphorylated ezrin/radixin/moesin (ERM) proteins in myeloid cells. (2005)
Experimental cell research, - Role of sulfation in CD44-mediated hyaluronan binding induced by inflammatory mediators in human CD14(+) peripheral blood monocytes. (2001)
Journal of immunology (Baltimore, Md. : 1950), - A role for the cell adhesion molecule CD44 and sulfation in leukocyte-endothelial cell adhesion during an inflammatory response? (2000)
Biochemical pharmacology, - Assaying phage-borne peptides by phage capture on fibrinogen or streptavidin. (1997)
Biological chemistry,
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