Overview

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.

Publications

Clinical practice variation and need for pediatric-specific treatment guidelines among rheumatologists caring for children with ANCA-associated vasculitis: an international clinician survey.
Pediatric rheumatology online journal
Westwell-Roper C, Lubieniecka JM, Brown KL, Morishita KA, Mammen C, Wagner-Weiner L, Yen E, Li SC, O'Neil KM, Lapidus SK, Brogan P, Cimaz R, for ARChiVe Investigators Network within the PedVas initiative
DOI: 10.1186/s12969-017-0191-z
PubMed: 28784150
08/2017

The importance of considering monogenic causes of autoimmunity: A somatic mutation in KRAS causing pediatric Rosai-Dorfman syndrome and systemic lupus erythematosus.
Clinical immunology (Orlando, Fla.)
Ragotte RJ, Dhanrajani A, Pleydell-Pearce J, Del Bel KL, Tarailo-Graovac M, van Karnebeek C, Terry J, Senger C, McKinnon ML, Seear M, Prendiville JS, Turvey SE
DOI: 10.1016/j.clim.2016.12.006
PubMed: 28043923
02/2017

Measles Lymphadenopathy in a Child With PFAPA Syndrome.
Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society
Terry J, Brown K, Hiebert J, Al-Rawahi GN, Moxham JP, Krajden M, Jassem AN, Tucker L
DOI: 10.1177/1093526617727970
PubMed: 28882091
01/2017

Elevated Mitochondrial Reactive Oxygen Species and Cellular Redox Imbalance in Human NADPH-Oxidase-Deficient Phagocytes
Frontiers in Immunology
Martina Sundqvist, Karin Christenson, Halla Björnsdottir, Veronica Osla, Anna Karlsson, Claes Dahlgren, David P. Speert, Anders Fasth, Kelly L. Brown, Johan Bylund
DOI: 10.3389/fimmu.2017.01828
2017

Temporal Characterization of Microglia/Macrophage Phenotypes in a Mouse Model of Neonatal Hypoxic-Ischemic Brain Injury.
Frontiers in cellular neuroscience
Hellström Erkenstam N, Smith PL, Fleiss B, Nair S, Svedin P, Wang W, Boström M, Gressens P, Hagberg H, Brown KL, Sävman K, Mallard C
DOI: 10.3389/fncel.2016.00286
PubMed: 28018179
2016

Purified hyaluronan and hyaluronan fragments do not stimulate pro-inflammatory cytokine production in dendritic cells or macrophages
Scientific Reports
PubMed: 27869206
2016

Pediatric vasculitis: advances in treatment.
Current opinion in rheumatology
Morishita K, Brown K, Cabral D
DOI: 10.1097/bor.0000000000000203
PubMed: 26147755
09/2015

The Where, When, How, and Why of Hyaluronan Binding by Immune Cells
Frontiers in Immunology
Sally S. M. Lee-Sayer, Yifei Dong, Arif A. Arif, Mia Olsson, Kelly L. Brown, Pauline Johnson
DOI: 10.3389/fimmu.2015.00150
04/2015

Innate defense regulator peptide 1018 protects against perinatal brain injury.
Annals of neurology
Bolouri H, Sävman K, Wang W, Thomas A, Maurer N, Dullaghan E, Fjell CD, Ek CJ, Hagberg H, Hancock RE, Brown KL, Mallard C
DOI: 10.1002/ana.24087
PubMed: 24339166
03/2014

Increased intracellular oxygen radical production in neutrophils during febrile episodes of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis syndrome.
Arthritis and rheumatism
Sundqvist M, Wekell P, Osla V, Bylund J, Christenson K, Sävman K, Foell D, Cabral DA, Fasth A, Berg S, Brown KL, Karlsson A
DOI: 10.1002/art.38134
PubMed: 23983059
11/2013

Host Defence (Antimicrobial) Peptides and Proteins
eLS
DOI: 10.1002/9780470015902.a0001212.pub3
05/2013

On the road to discovery in periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome.
Proceedings of the National Academy of Sciences of the United States of America
Brown KL, Wekell P, Karlsson A, Berg S
DOI: 10.1073/pnas.1107233108
PubMed: 21810991
08/2011

Differential use of chondroitin sulfate to regulate hyaluronan binding by receptor CD44 in Inflammatory and Interleukin 4-activated Macrophages.
The Journal of biological chemistry
Ruffell B, Poon GF, Lee SS, Brown KL, Tjew SL, Cooper J, Johnson P
DOI: 10.1074/jbc.m110.200790
PubMed: 21471214
06/2011

Host defense peptide LL-37 selectively reduces proinflammatory macrophage responses.
Journal of immunology (Baltimore, Md. : 1950)
Brown KL, Poon GF, Birkenhead D, Pena OM, Falsafi R, Dahlgren C, Karlsson A, Bylund J, Hancock RE, Johnson P
DOI: 10.4049/jimmunol.1002508
PubMed: 21441450
05/2011

Galectin 3 aggravates joint inflammation and destruction in antigen-induced arthritis.
Arthritis and rheumatism
Forsman H, Islander U, Andréasson E, Andersson A, Onnheim K, Karlström A, Sävman K, Magnusson M, Brown KL, Karlsson A
DOI: 10.1002/art.30118
PubMed: 21280000
02/2011

Anti-Inflammatory/Analgesics: An In-Depth Look at p38 MAP Kinases
Pharmaceutical Sciences Encyclopedia
DOI: 10.1002/9780470571224.pse446
2011

Intracellular generation of superoxide by the phagocyte NADPH oxidase: how, where, and what for?
Free radical biology & medicine
Bylund J, Brown KL, Movitz C, Dahlgren C, Karlsson A
DOI: 10.1016/j.freeradbiomed.2010.09.016
PubMed: 20870019
12/2010

Robust TLR4-induced gene expression patterns are not an accurate indicator of human immunity.
Journal of translational medicine
Brown KL, Falsafi R, Kum W, Hamill P, Gardy JL, Davidson DJ, Turvey S, Finlay BB, Speert DP, Hancock RE
DOI: 10.1186/1479-5876-8-6
PubMed: 20105294
01/2010

Treating neonatal brain injury - promise and inherent research challenges.
Recent patents on inflammation & allergy drug discovery
Sävman K, Brown KL
DOI: 10.2174/187221310789895586
PubMed: 19832696
01/2010

Profile of blood cells and inflammatory mediators in periodic fever, aphthous stomatitis, pharyngitis and adenitis (PFAPA) syndrome.
BMC pediatrics
Brown KL, Wekell P, Osla V, Sundqvist M, Sävman K, Fasth A, Karlsson A, Berg S
DOI: 10.1186/1471-2431-10-65
PubMed: 20819226
2010

G-protein-coupled receptor independent, immunomodulatory properties of chemokine CXCL9
Cellular Immunology
Jiang-Hong Gong, Erin F. Nicholls, Melissa R. Elliott, Kelly L. Brown, Karsten Hokamp, Fiona M. Roche, Charles Y.K. Cheung, Reza Falsafi, Fiona S.L. Brinkman, D.M.E. Bowdish, Robert E.W. Hancock
DOI: 10.1016/j.cellimm.2009.11.007
2010

The host defense peptide LL-37 selectively permeabilizes apoptotic leukocytes.
Antimicrobial agents and chemotherapy
Björstad A, Askarieh G, Brown KL, Christenson K, Forsman H, Onnheim K, Li HN, Teneberg S, Maier O, Hoekstra D, Dahlgren C, Davidson DJ, Bylund J
DOI: 10.1128/aac.01310-08
PubMed: 19075071
03/2009

Galectin-3 functions as an opsonin and enhances the macrophage clearance of apoptotic neutrophils.
Glycobiology
Karlsson A, Christenson K, Matlak M, Björstad A, Brown KL, Telemo E, Salomonsson E, Leffler H, Bylund J
DOI: 10.1093/glycob/cwn104
PubMed: 18849325
01/2009

Manual annotation and analysis of the defensin gene cluster in the C57BL/6J mouse reference genome
BMC Genomics
Clara Amid, Linda M Rehaume, Kelly L Brown, James GR Gilbert, Gordon Dougan, Robert EW Hancock, Jennifer L Harrow
DOI: 10.1186/1471-2164-10-606
2009

Divergent effects on phagocytosis by macrophage-derived oxygen radicals.
Journal of innate immunity
Brown KL, Christenson K, Karlsson A, Dahlgren C, Bylund J
DOI: 10.1159/000235583
PubMed: 20375614
2009

Phagocyte-derived reactive oxygen species as suppressors of inflammatory disease.
Arthritis and rheumatism
Björkman L, Dahlgren C, Karlsson A, Brown KL, Bylund J
DOI: 10.1002/art.23941
PubMed: 18821670
10/2008

ROS-deficient monocytes have aberrant gene expression that correlates with inflammatory disorders of chronic granulomatous disease
Clinical Immunology
Kelly L. Brown, Johan Bylund, Kelly L. MacDonald, George X. Song-Zhao, Melissa R. Elliott, Reza Falsafi, Robert E.W. Hancock, David P. Speert
DOI: 10.1016/j.clim.2008.06.005
10/2008

Antimicrobial Host Defence Peptides of Human Neutrophils – Roles in Innate Immunity
Anti-Infective Agents in Medicinal Chemistry
A. Bjorstad, K. Brown, H. Forsman, C. Dahlgren, A. Karlsson, J. Bylund
DOI: 10.2174/187152108784911278
07/2008

Is Innate Host Defense the Answer?
Current Opinions in Biotechnology
PubMed: 19000763
2008

Antimicrobial, Host Defence Peptides and Proteins
eLS
DOI: 10.1002/9780470015902.a0001212.pub2
07/2007

Complexities of targeting innate immunity to treat infection
Trends in Immunology
Kelly L. Brown, Céline Cosseau, Jennifer L. Gardy, Robert E.W. Hancock
DOI: 10.1016/j.it.2007.04.005
06/2007

Enhanced inflammatory responses of chronic granulomatous disease leukocytes involve ROS-independent activation of NF-¿B
European Journal of Immunology
Johan Bylund, Kelly L. MacDonald, Kelly L. Brown, Piotr Mydel, L. Vincent Collins, Robert E. W. Hancock, David P. Speert
DOI: 10.1002/eji.200636651
04/2007

IRAK-4 mutation (Q293X): rapid detection and characterization of defective post-transcriptional TLR/IL-1R responses in human myeloid and non-myeloid cells.
Journal of immunology (Baltimore, Md. : 1950)
Davidson DJ, Currie AJ, Bowdish DM, Brown KL, Rosenberger CM, Ma RC, Bylund J, Campsall PA, Puel A, Picard C, Casanova JL, Turvey SE, Hancock RE, Speert DP
DOI: 10.4049/jimmunol.177.11.8202
PubMed: 17114497
12/2006

Bovine and human cathelicidin cationic host defense peptides similarly suppress transcriptional responses to bacterial lipopolysaccharide.
Journal of leukocyte biology
Mookherjee N, Wilson HL, Doria S, Popowych Y, Falsafi R, Yu JJ, Li Y, Veatch S, Roche FM, Brown KL, Brinkman FS, Hokamp K, Potter A, Babiuk LA, Hancock RE
DOI: 10.1189/jlb.0106048
PubMed: 16943385
12/2006

Cationic host defense (antimicrobial) peptides
Current Opinion in Immunology
Kelly L Brown, Robert EW Hancock
DOI: 10.1016/j.coi.2005.11.004
02/2006

Modulation of the TLR-mediated inflammatory response by the endogenous human host defense peptide LL-37.
Journal of immunology (Baltimore, Md. : 1950)
Mookherjee N, Brown KL, Bowdish DM, Doria S, Falsafi R, Hokamp K, Roche FM, Mu R, Doho GH, Pistolic J, Powers JP, Bryan J, Brinkman FS, Hancock RE
DOI: 10.4049/jimmunol.176.4.2455
PubMed: 16456005
02/2006

Host defence peptides from invertebrates--emerging antimicrobial strategies.
Immunobiology
Hancock RE, Brown KL, Mookherjee N
DOI: 10.1016/j.imbio.2005.10.017
PubMed: 16697922
2006

Cathelicidins: Cationic Host Defense and Antimicrobial Peptides
Handbook of Biologically Active Peptides
NEELOFFER MOOKHERJEE and KELLY L. BROWN and ROBERT E.W. HANCOCK
DOI: 10.1016/b978-012369442-3/50015-5
2006

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.
Glycobiology
Tjew SL, Brown KL, Kannagi R, Johnson P
DOI: 10.1093/glycob/cwi050
PubMed: 15728736
07/2005

Regulation of hyaluronan binding by F-actin and colocalization of CD44 and phosphorylated ezrin/radixin/moesin (ERM) proteins in myeloid cells.
Experimental cell research
Brown KL, Birkenhead D, Lai JC, Li L, Li R, Johnson P
DOI: 10.1016/j.yexcr.2004.10.002
PubMed: 15652352
02/2005

Role of sulfation in CD44-mediated hyaluronan binding induced by inflammatory mediators in human CD14(+) peripheral blood monocytes.
Journal of immunology (Baltimore, Md. : 1950)
Brown KL, Maiti A, Johnson P
DOI: 10.4049/jimmunol.167.9.5367
PubMed: 11673554
11/2001

A role for the cell adhesion molecule CD44 and sulfation in leukocyte-endothelial cell adhesion during an inflammatory response?
Biochemical pharmacology
Johnson P, Maiti A, Brown KL, Li R
DOI: 10.1016/s0006-2952(99)00266-x
PubMed: 10660111
03/2000

Assaying phage-borne peptides by phage capture on fibrinogen or streptavidin.
Biological chemistry
Bonnycastle LL, Brown KL, Tang J, Scott JK
DOI: 10.1515/bchm.1997.378.6.509
PubMed: 9224931
06/1997

Research

Neonatal Hypoxic-Ischemic Brain Inflammation and Injury
Hypoxic-ischemic (HI) induced injury in infants can result from maternal infection or oxygen deprivation during birth and is an important contributor to neonatal mortality or permanent neurological impairment. The inflammatory response to HI is as important of a contributor to injury severity as is the initial period of oxygen deprivation. This collaborative project explores the mechanistic action of a novel immunomodulatory and neuroprotective peptide and aims to identify key inflammatory regulators that correlate with improved outcomes.

Inflammation and Cellular Redox States
It is well understood that highly toxic oxidants called ‘reactive oxygen species (ROS)’ are produced by phagocytic cells as part of the innate immune response to infection. In recent years, ROS and consequently the oxidation-reduction (redox) state of immune cells have been recognized as key players in the inflammatory response to both infectious and non-infectious cues. Pediatric diseases with inflammatory complications and signs of redox imbalance include chronic granulomatous disease (CGD), cystic fibrosis, and the autoinflammatory diseases SAPHO, PFAPA, TRAPS and FMF. Whether oxidants suppress or promote inflammatory signaling and to what extent they influence the biology of an inflammatory response remains controversial. This project aims to understand redoxsensitive signaling molecules in the context of inflammatory disease and their potential as novel therapeutic targets.

Childhood Autoinflammatory Diseases
The autoinflammatory family of diseases share features of unprovoked, recurrent attacks of inflammation with fever, rash, body pain/arthritis, and organ inflammation. The family includes a handful of defined monogenic diseases, but more than 80% of cases do not have a known cause. This collaborative project will establish a clinical home at BCCH for children with autoinflammatory disorders, and develop in parallel a robust, longitudinal collection of clinical data and biological samples for research. Laboratory initiatives will evaluate the clinical potential of previously identified, putative biomarkers of autoinflammation, and seek to uncover new disease etiologies.

Primary Childhood Vasculitis
Chronic primary vasculitis describes a group of rare, life-threatening diseases that have in common inflammation of blood vessels in vital organs such as kidneys, lungs and brain. The challenge in treating children with vasculitis is balancing the risk of under treating aggressive disease with the potential damaging side-effects of prolonged use of drugs. This project uses an established international web-based registry to collect clinical information from 50 or more centers worldwide, with approximately 20 centres contributing paired biological samples (DNA, RNA, plasma, serum, urine). The goal is to elucidate subclinical (molecular/cellular) features which help to classify, define and direct optimal treatment for children with vasculitis.

Research Group Members

Kristen Gibson
Felice Mizan, Research Coordinator
Iwona Niemietz
Lovro Lamot, Postdoctoral Fellow
Sarah Bowers
Sara Marrello