Improved knowledge of disease mechanism will help to identify potential targets for novel agents and the identification of new biomarkers of disease activity.
In JSLE the body’s immune system attacks its healthy cells (auto-immunity) instead of defending them, and this can cause organ damage. One of our main focuses as a group has been the role of neutrophils in the pathogenesis of autoimmune disease.
Neutrophils are very important members of the immune system as one of the first cells to respond to invasion from substances foreign to the body; however dysregulation in how these cells are activated or undergo cell death can result in the exposure of substances which are not usually found outside of the cell and therefore alerts other specialised parts of the immune system to respond, which in this situation may be one of the triggers to start the body attacking its own cells. We have shown increased neutrophil activation and death in JSLE which correlates with disease activity and can cause activation of the adaptive immune response.
By trying to understand how and why these processes go wrong potential therapeutic targets are indentified which may lead to more personalised therapies in the future for children with JSLE.
Biomarkers and Lupus Nephritis
Lupus affects many organs in the body, with significant numbers of both children and adults developing inflammation in the kidneys called lupus nephritis. This can cause long term kidney damage, in some cases requiring dialysis or kidney transplantation. Treatment of lupus nephritis often requires both high-dose steroids and other immunosuppressive agents which frequently have significant side effects.
We also want to discover more about how kidney cells are damaged in lupus. By highlighting key steps in this process we will identify potential targets for more specific and effective treatments.
At the moment there are only two options available to detect kidney inflammation:
- a urine dipstick test to look for blood or protein in the urine or
- an invasive test called the renal biopsy where a sample of kidney tissue is taken: this requires an operation.
By the time these tests are done there may already be some permanent damage to the kidney and we are keen to reduce this if at all possible.
We are currently trying to identify new and better biomarkers (tests) to help detect inflamed kidneys much earlier; this means that treatment can begin earlier, which may cause less kidney damage to occur.
Over the past few years urine samples have been collected from children who are looked after at two of the UK paediatric lupus centres – Alder Hey Children’s Hospital, Liverpool and Great Ormond Street Hospital, London . These samples have proved extremely useful because they show micro-proteins that can detect kidney disease about three months earlier than is possible using the current methods.
Experiments in the laboratory using kidney cells also look at what causes these micro-proteins to be released from kidney cells. Understanding what triggers the kidney to send out these early messages into the urine may lead to new treatments.
Publications
The development and assessment of biological treatments for children.
Smith EM, Foster HE, Beresford MW.
Br J Clin Pharmacol. 2014 Apr 21. doi: 10.1111/bcp.12406
Mucocutaneous manifestations in a UK national cohort of juvenile-onset systemic lupus erythematosus patients.
Chiewchengchol D1, Murphy R, Morgan T, Edwards SW, Leone V, Friswell M, Pilkington C, Tullus K, Rangaraj S, McDonagh JE, Gardner-Medwin J, Wilkinson N, Riley P, Tizard J, Armon K, Sinha MD, Ioannou Y, Mann R, Bailey K, Davidson J, Baildam EM, Pain CE, Cleary G, McCann LJ, Beresford MW; on behalf of the UK JSLE Study Group.
Rheumatology (Oxford). 2014 Mar 31
Predictors of access to care in juvenile systemic lupus erythematosus: evidence from the UK JSLE Cohort Study.
Smith EM, Foster HE, Gray WK, Taylor-Robinson D, Beresford MW; UK JSLE Study Group.
Rheumatology (Oxford). 2014 Mar;53(3):557-61
Urine biomarkers for monitoring juvenile lupus nephritis: a prospective longitudinal study.
Watson L, Tullus K, Pilkington C, Chesters C, Marks SD, Newland P, Jones CA, Beresford MW.
Pediatr Nephrol. 2014 Mar;29(3):397-405
New insights into the pathogenesis and management of lupus in children.
Midgley, A; Watson, L and Beresford M.W.
Arch Dis Child. 2014.
Th17 and T regulatory cells in Juvenile-onset Systemic Lupus Erythematosus.
Ballantine, L; Midgley, A; Ong, J; Watson, L; Flanagan, B; Beresford, MW.
Rheumatology Pediatric Jan 2014.
15-minute consultation: a structured approach to the management of hypermobility in a child.
Smith EM, Ramanan AV.
Arch Dis Child Educ Pract Ed. 2013 Dec;98(6):212-6
How to use lupus anticoagulants.
Sen ES, Beresford MW, Avcin T, Ramanan AV.
Arch Dis Child Educ Pract Ed 2012 Oct 6
The child with a limp: a symptom and not a diagnosis.
Smith E, Anderson M, Foster H.
Arch Dis Child Educ Pract Ed. 2012 Oct;97(5):185-93
Adding to complexity: co-morbidity in paediatric rheumatic disease.
Smith EM, Foster HE, Beresford MW.
Rheumatology (Oxford) 2012 Sep 28
Increased Serum Concentration of Sphingosine-1-phosphate in Juvenile-onset Systemic Lupus Erythematosus.
Watson L, Tullus K, Marks SD, Holt RC, Pilkington C, Beresford MW.
J Clin Immunol 2012 Oct.
Urine biomarkers in juvenile-onset SLE nephritis.
Watson L, Beresford MW.
Pediatr Nephrol 2012 May 16
Disease activity, severity, and damage in the UK Juvenile-Onset Systemic Lupus Erythematosus Cohort.
Watson L, Leone V, Pilkington C, Tullus K, Rangaraj S, McDonagh JE, Gardner-Medwin J, Wilkinson N, Riley P, Tizard J, Armon K, Sinha MD, Ioannou Y, Archer N, Bailey K, Davidson J, Baildam EM, Cleary G, McCann LJ, Beresford MW, UK Juvenile-Onset Systemic Lupus Erythematosus Study Group.
Arthritis Rheum 2012 Jul
Expression of Toll-like receptors and their detection of nuclear self-antigen leading to immune activation in JSLE.
Midgley A, Thorbinson C, Beresford MW.
Rheumatology (Oxford) 2012 May
Inactive disease and remission in childhood-onset systemic lupus erythematosus.
Mina R, Klein-Gitelman MS, Ravelli A, Beresford MW, Avcin T, Espada G, Eberhard BA, Schanberg LE, O'Neil KM, Silva CA, Higgins GC, Onel K, Singer NG, von Scheven E, Imundo LF, Nelson S, Giannini EH, Brunner HI.
Arthritis Care Res (Hoboken) 2012 May
Acceptability and practicality of pGALS in screening for rheumatic disease in Malawian children.
Smith E1, Molyneux E, Heikens GT, Foster H.
Clin Rheumatol. 2012 Apr;31(4):647-53
Preliminary criteria for global flares in childhood-onset systemic lupus erythematosus.
Brunner HI, Mina R, Pilkington C, Beresford MW, Reiff A, Levy DM, Tucker LB, Eberhard BA, Ravelli A, Schanberg LE, Saad-Magalhaes C, Higgins GC, Onel K, Singer NG, von Scheven E, Itert L, Klein-Gitelman MS, Punaro M, Ying J, Giannini EH.
Arthritis Care Res (Hoboken) 2011 Sep
Urinary monocyte chemoattractant protein 1 and alpha 1 acid glycoprotein as biomarkers of renal disease activity in juvenile-onset systemic lupus erythematosus.
Watson L, Midgley A, Pilkington C, Tullus K, Marks S, Holt R, Jones C, Beresford M.
Lupus 2012 Apr.
Cellular localization of nuclear antigen during neutrophil apoptosis: mechanism for autoantigen exposure?
Midgley A, Beresford MW.
Lupus 2011 May
Differential expression of factors involved in the intrinsic and extrinsic apoptotic pathways in juvenile systemic lupus erythematosus.
Midgley A, Mayer K, Edwards SW, Beresford MW.
Lupus 2011 Jan
An unusual cause of neonatal respiratory distress.
Smith E, Kumar R, Barron R, Bosman D.
BMJ Case Rep. 2010 Sep 20;2010
The role of neutrophil apoptosis in juvenile-onset systemic lupus erythematosus.
Midgley A, McLaren Z, Moots RJ, Edwards SW, Beresford MW.
Arthritis Rheum 2009 Aug
Endothelial nitric oxide synthase polymorphisms do not influence pulmonary artery systolic pressure at altitude.
Smith EM, Baillie JK, Thompson AA, Irving JB, Porteous D, Webb DJ.
High Alt Med Biol. 2006 Fall;7(3):221-7