HELENA ERLANDSSON HARRIS GROUP

Pediatric rheumatology

About

Our research aims at improving the knowledge regarding disease-causing mechanisms active during rheumatic diseases in children as well as in adults. The obtained knowledge forms a basis for the development of new, targeted anti-rheumatic therapy. We are especially interested in the group of self-molecules termed Alarmins. These are molecules with defined functions inside cells and a common function outside of cells; to alert the body to danger, cell death or cell stress due to infection or trauma, and induce an inflammatory response. A prototype alarmin is HMGB1 and we are studying its inflammation-inducing features, its role in rheumatic diseases and it’s potential as a target for new therapy. 

Our research programme can be divided into three related projects:

1. Studies of the proinflammatory functions of HMGB1 and their regulation

2. The role of HMGB1 in the immunopathogenesis of juvenile idiopathic arthritis (JIA). To perform these studies we have established a biobank (JABBA) of patient samples coupled with a quality register, Swedish Pediatric Rheumatology Registry, and are using molecular, cellular and in vitro/in vivo models.

Additionally we are also interested in studying the role of HMGB1 in other inflammatory conditions, including stroke and have an ongoing project (COUNTERSTROKE) to identify HMGB1 inhibitors that could be used in therapy.

Links:

National research school in chronic inflammation http://www.researchschool.nu/

 

Projects

Cecilia Aulin, PhD, assistant professor

Pre-clinical studies of inflammation and pain in osteoarthritis – Development of local therapies using injectable polymer materials

Osteoarthritis (OA) is the most common form of arthritis, with pain and joint destruction as the primary symptoms.

Inflammation is a contributing factor to the development of OA, but in contrast to the successful anti-inflammatory treatments established for rheumatoid arthritis neutralization of TNF and  IL-1 have demonstrated modest or no effects in OA. This has led us to study other inflammatory mediators such as alarmins and oxidative stress related products that may contribute to inflammation and enhancing the catabolic processes in the joint. 

 

Our overall aim is to develop local therapies targeting inflammation and pain. This is done by utilizing injectable materials, developed in collaboration with Ångström Laboratory in Uppsala. The materials could be designed either to neutralize harmful products by functionalizing the material itself, or by functioning as a drug delivery vehicle for anabolic or anti-inflammatory cues.

 

By combining cell studies, mouse models and analysis of patient material, I aim to study the role of inflammatory mediators in OA, their association to pain as well as their neutralization using materials designed as polymeric scavengers as a potential therapy. This is a first step in development of combination therapies directed against alternative inflammatory mediators with the possibility of cartilage regeneration.

 

Current projects:

  • Investigate the effect of oxidative stress and LPO products in chondrocytes

  • Evaluate therapeutic blockade of LPO products  in experimental OA with regards to pain and joint destruction

  • Study the role of the alarmin HMGB1 in OA and its potential as therapeutic target

  • Develop therapies inducing cartilage regeneration

 

Mia Olsson, assistant professor

The genetics behind rheumatic and autoinflammatory syndromes in children

My main research questions revolve around the onset and progression of rheumatic and autoinflammatory diseases in children.

 

As a molecular geneticist, I use genome-wide association studies, high-throughput DNA and RNA sequencing to define innate changes associated with these diseases. I am also interested in the role of alarmins in the abnormal inflammation seen in these patients. The intention behind my studies is to identify new molecular targets to use in prognostics and treatment, and thereby improve care and life quality of patients.  

 

Current projects:

  • The genetics behind Juvenile idiopathic arthritis (JIA) 

JIA is a term to describe a heterogeneous group of diseases in children and adolescents characterized by joint inflammation of unknown origin. In this genome wide association study, the aim is to identify genetic risk factors linked to JIA as a group, and also to stratify sub-groups of JIA.

  • Sequencing of a periodic fever syndrome

PFAPA is an acronym for ‘periodic fever, aphthous stomatitis, pharyngitis, adenitis´ and is the most common autoinflammatory disease in Swedish children. In this study, high-throughput sequencing has been performed to find genetic variants linked to PFAPA. This is a joint project with collaborators at Uppsala University and Queen Silvia’s Children’s Hospital.

  • The role of degraded HA in inflammation

The potency of HA fragments to initiate or regulate inflammation is investigated in vitro using ex vivo human immune cells.

 

Hannah Aucott, post-doc

Studies of HMGB1 as a central mediator of neuroinflammation

Neuroinflammation contributes to the pathogenesis of several diseases affecting the CNS, including stroke. It is well known that alarmins, such as HMGB1, can be released from stressed and dying brain cells and can initiate inflammatory responses. The aim of my research is to investigate how HMGB1 and other alarmins can induce neuroinflammation and blood brain barrier disruption.

 

Current projects:

  • Dissecting how the different redox isoforms of HMGB1 can induce neuroinflammation and modulate blood brain barrier permeability

  • Investigating the role of anti-microbial peptides in the development of neuroinflammation

  • Elucidating HMGB1-receptor interactions, specifically the interaction with TLR2, using in vitro binding experiments and cell assays

  • HMGB1 is able to form pro-inflammatory complexes with endogenous and exogenous molecules. I am using cell experiments and structural biology techniques to investigate the interaction between HMGB1 and IL-1β.

To perform these experiments I am using a number of different methods including cryo-sectioning and immunohistochemistry/ immunofluorescence, cell culturing, ELISA and general molecular biology techniques.

 

Agnieszka (Agnes) Sowinska, PhD student

HMGB1 functional regulation and release mechanisms

Activated immune cells and immunogenic modes of cell death strongly contribute to inflammatory disease by releasing proinflammatory molecules, i.e. alarmins. HMGB1 is a prototypical alarmin as it, upon entering extracellular space, interacts with multiple receptors and induces cell migration and production of proinflammatory mediators. The capacity to bind and signal through different receptors has been strongly associated with posttranslational modifications to HMGB1.

 

In my PhD studies, I am employing basic laboratory techniques to:

  • clarify HMGB1 release mechanisms and their impact on function

  • study receptor usage of different redox isoforms of HMGB1

  • investigate down-regulatory mechanisms of HMGB1 activity

 

Henna Salo, PhD student

The role of the alarmin HMGB1 in neuroinflammation and stroke

Stroke remains a leading cause of death and disability around the world. Stroke can be caused either by a blood cloth or by a ruptured vessel leading to blood leakage. HMGB1 is an interesting target molecule for therapy since it is a key mediator of inflammation and blocking of HMGB1 has been shown to alleviate the neuro-inflammation initiated by stroke.

 

In my PhD project I’m using cell culturing, animal models and immunohistochemistry, among other methods to:

  • Describe the immune activation caused by the different HMGB1 redox isoforms, specifically in microglia cells. This is performed by Nanostring analysis.

  • Investigate cellular sources of HMGB1 in stroke-induced neuroinflammation

  • Study HMGB1-neutralisation as a therapeutic option for stroke

  • To study the induction of neuroinflammation and blood-brain-barrier leakage mediated by cerebral injections of different HMGB1 redox isoforms

 

 

Raya Saleh, PhD student

Immunological and genetic studies of juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children and adolescents characterized by articular and extra-articular manifestations. JIA encompasses all forms of arthritis that begin before a patient is aged 16 years that persist for more than 6 weeks and are of unknown origin.

 

Although conventional therapies for JIA has proved to improve the quality of life for many patients but heterogeneity in JIA causes that not all of the patients benefit from current treatments. Without appropriate treatment, patients may get severe complications, such as developing joint destruction, growth retardation, impaired mobility, permanent disability or blindness from chronic uveitis. Furthermore, some children with JIA carry an active disease into adulthood life.

 

Thus, it is desirable to find new biomarkers for early diagnosis of JIA to enable early treatment and also to distinguish patients with transient JIA from those at risk of developing chronic, destructive arthritis as early as possible. To explore immunopathogenetic mechanisms active during JIA and to better understand mechanisms involved in joints destruction of JIA patients is also important.

 

Current projects:

  • Anti-citrullinated protein/peptide antibodies (ACPA) in JIA

ACPA have been suggested to have a pathogenic and inducing role in Rheumatoid Arthritis. Involvement of ACPA is not well established in JIA.

  • Genetics of JIA

We aim to detect gene polymorphisms associated with increased risk of JIA

  • Biomarkers for bone and cartilage destruction in JIA

JIA is associated with joint degeneration. The loss of articular cartilage is irreversible and current diagnosis methods are unable to detect early stages of joint degeneration. Thus, there is a need for better diagnosis methods, such as biomarkers for cartilage and bone destruction.

 

Lena Klevenvall, BMA

I am working as a biomedical analyst (BMA) and am invovled in a number of projects ongoing within the lab. I am using many different methods including ELISA, cell culture experiments, immunofluroscence stainings and general molecular biology techniques. I am also processing and analysing samples from patients as part of our clinical studies.

 

Erik Sundberg, MD PhD

Translational research in the field of Pediatric Rheumatology combining patient characteristics and outcome measures with molecular medicine.

Children and adolescents with rheumatic disease suffer not only from organ symptoms, most often arthritis, but also from functional disability, fatigue and psycho social consequences due to chronic disease. Organ damage may occur and be reversible or irreversible.

My research aim is to increase the knowledge of immune pathologic mechanisms, diagnostic and prognostic factors in order to optimize clinical monitoring and therapy to prevent organ damage and disease suffering at earliest possible time point. This research is made possible by patient generous donations of biologic speciments for research use.

 

Current projects:

  • Anti-citrullinated protein/peptide antibodies (ACPA) in JIA

ACPA have been suggested to have a pathogenic and inducing role in Rheumatoid Arthritis. Involvement of ACPA is not well established in JIA.

  • Genetics of JIA

We aim to detect gene polymorphisms associated with increased risk of JIA

  • Biomarkers for bone and cartilage destruction in JIA

JIA is associated with joint degeneration. The loss of articular cartilage is irreversible and current diagnosis methods are unable to detect early stages of joint degeneration. Thus, there is a need for better diagnosis methods, such as biomarkers for cartilage and bone destruction.

  • HMGB1 as a prognostic factor in Pediatric Rheumatic Disease (PRD)

Proinflammatory Alarmin HMGB1 is studied as a possible prognostic factor of disease progression and damage outcome in PRD.

 

Selected Publications

Lundbäck P, Lea JD, Sowinska A, Ottosson L, Fürst CM, Steen J, Aulin C, Clarke JI, Kipar A, Klevenvall L, Yang H, Palmblad K, Park BK, Tracey KJ, Blom AM, Andersson U, Antoine DJ, Erlandsson Harris H. A novel high mobiliy group box 1 neutralizing chimeric antibody attenuates drug-induced liver injury and postinjury inflammation in mice. Hepatology. 2016 Nov;64(5):1699-1710. Epub 2016 Sep 1.

Aulin C, Lundbäck P, Palmblad K, Klareskog L, Erlandsson Harris H. An in vivo cross-linkable hyaluronan gel with inherent anti-inflammatory properities reduced OA cartilage destruction in female mice subjected to cruciate ligament transection. Osteoarthritis Cartilage. 2017 Jan;25(1):157-165. Epub 2016 Aug 29.

Assadi G, Saleh R, Hadizadeh F, Vesterlund L, Bonfiglio F, Halfvarson J, Törkvist L, Eriksson AS, Harris HE, Sundberg E, D'Amato M. LACC1 polymorphisms in inflammatory bowel disease and juvenile idiopathic arthritis. Genes Immun. 2016 Jun;17(4):261-4. Epub 2016 Apr 21.

Lundbäck P, Stridh P, Klevenvall L, Jenkins RE, Fischer M, Sundberg E, Andersson U, Antoine DJ, Harris HE. Characterisation of the inflamamtory properties of actively released HMGB1 in Juvenile Idiopathic Arthritis.  Antioxid Redox Signal. 2016 Apr 20;24(12):605-19. Epub 2015 Feb 6.

Palmblad K, Schierbeck H, Sundberg E, Horne AC, Harris HE, Henter JI, Antoine DJ, Andersson U. High systemic levels of the cytokine-inducing HMGB1 isoform secreted in severe macrophage activation syndrome. Mol Med. 2015 Jan 27;20:538-47. 

Nyström S, Antoine DJ, Lundbäck P, Lock JG, Nita AF, Högstrand K, Grandien A, Erlandsson-Harris H, Andersson U, Applequist SE. TLR4 activation regulates damage-associated molecular pattern isoforms released during pyroptotic cell death. EMBO J. 2013 Jan 9;32(1):86-99.

Lu B, Nakamura T, Inouye K, Li J, Tang Y, Lundbäck P, Valdes-Ferrer SI, Olofsson PS, Kalb T, Roth J, Zou Y, Erlandsson-Harris H, Yang H, Ting J P-Y, Wang H, Andersson U, Antoine DJ, Chavan SS, Hotamisligil GS, Tracey KJ. Novel role of PKP in inflammasome activation and HMGB1 release. Nature. 2012 Aug 30;488(7413):670-4.

Hreggvidsdóttir HS, Lundberg AM, Aveberger AC, Klevenvall L, Andersson U, Harris HE. High Mobility group box protein 1 (HMGB1)-partner molecule complexes enhance cytokine production by signalling through the partner molecule receptor. Mol Med. 2012 Mar 27;18:224-30. 

Yang H, Hreggvidsdottir HS, Palmblad K, Wang H, Ochani M, Li J, Lu B, Chavan S, Rosas-Ballina M, Alabed Y, Akira S, Bierhaus A, Erlandsson-Harris H, Andersson U, Tracey KJ. A critical cysteine is required for HMGB1 binding to TLR4 and activation of macrophage cytokine release.  Proc Natl Acad Sci U S A. 2010 Jun 29;107(26):11942-7.

Kokkola R, Sundberg E, Ulfgren AK, Palmblad K, Li J, Wang H, Ulloa L, Yang H, Yan XJ, Furie R, Chiorazzi N, Tracey KJ, Andersson U, Erlandsson Harris H. High Mobility group box chromosomal protein 1 (HMGB1): A novel proinflammatory mediator in synovitis.  Arthritis Rheum. 2002 Oct;46(10):2598-603.