Juvenile idiopathic arthritis (JIA) is an umbrella term used to describe a group of arthritides which occur in children under the age of 16 yrs (Ravelli & Martini, 2007). Fortunately, arthritis in children is rare and only 1 in 1000 children are affected resulting in 12,000 children in the UK being diagnosed with JIA each year (Malone, 2009). The term JIA is a relatively new term devised by the International League of Associations for Rheumatology (ILAR) and has since been adopted to encompass the old nomenclature of Still‟s disease, Juvenile Chronic Arthritis or Juvenile Rheumatoid Arthritis (Ravelli & Martini, 2007). This chronic and debilitating disease is characterised by inflammation of the synovial joints which may resolve spontaneously or exist as a precursor to Rheumatoid arthritis (RA) in later life. Unlike its adult counterpart however, JIA affects larger peripheral joints, particularly the knee. Involvement of the axial joints such as the shoulder, hip spine or smaller joints in the fingers and toes have also been reported, however these presentations are less common (Friswell & Southwood, 2004). In addition to pathology in the joints, Kumar and Clark (2009) claim that some children also present with a significantly high fever (>39 degrees°C ) accompanied by a pink, maculopapular rash. Friswell and Southwood (2004) also list anorexia, listlessness and weakness as other symptoms in some children. The diverse nature of JIA has led to its classification into various distinct subgroups. Systemic disease, oligoarthritis and polyarthritis (either positive or negative for rheumatoid factor) are the three major subgroups (Cassidy & Petty, 2000). Other subgroups include extended oligoarthritis, enthesitis related arthritis or psoriatic juvenile idiopathic arthritis. The classification of JIA is very much dependant on clinical signs and symptoms and the genetic background of the individual. Systemic arthritis generally has an equal prevalence in both males and females and can occur at any age (Ravelli & Martini, 2007). This form of JIA is still referred to as Still‟s disease by some authors and accounts for 10% of all JIA cases (Kumar & Clark, 2009). Stills disease more often occurs before the age of 5 yrs at which time


boys and girls are affected equally, however, after 5 yrs of age prevalence of this form of the disease increases amongst girls. Adult onset Stills disease can also occur but this form is rare. Diagnosis of systemic arthritis is made with the onset of inflammation of one or more joints accompanied by a persistent fever. According to Ravelli & Martini (2007), a „typical evanescent, non-fixed erythmatous rash’ coinciding with a fever in addition to other symptoms such as pleurisy, hepatosplenomegaly, pericarditis or lymphadenopathy further aid diagnosis. High Erythrocyte Sedimentation Rate (ESR), C-Reactive protein serum levels and microcytic anaemia are also common features observed in laboratory investigations and Ravelli and Martini (2007) highlight the difference between this anaemia and that of RA noting its relationship to „interleukin6 induced iron sequestrian in the reticuloendothelial system.’ Children affected with this form of the disease often have a poorer prognosis and 58% of those inflicted can go onto develop the life threatening condition referred to as Macrophage activation syndrome (Kumar & Clark, 2009). The excessive proliferation of T-cells and macrophages in this condition induces active phagocytosis of haemopoietic bone marrow cells (Sawhney et al, 2001). JIA which is confined to fewer than 4 joints is classified as oligoarthritis. As the most common form of JIA, oligoarthritis is estimated to account for more than 50% of all cases of JIA. The knee joint is a prime location for manifestation of oligoarthritis and is evident in more than 75% of cases (Cassidy & Petty, 2000). Children who fall into this category are also at increased risk of developing uvetitis, which if left untreated can lead to significant visual disturbance or even blindness. A study by Zeggini et al (2006), demonstrates the linkage between oligoarthritis and uvetitis and their association with HLA-DRB1. The polyarticular form of arthritis gives rise to a symmetrical pattern of arthritis affecting numerous joints predominantly the knees, wrists and ankles (Klippel et al, 1999). In certain children, this form is positive for rheumatoid factor and mimics the disease process seen in adult RA. This form primarily affects adolescent girls and results in the destruction of joints in addition to the extra non-articular features of RA.


To achieve this a strong element of data triangulation has been used. 2001). much work has been done at the cellular level in an attempt to elucidate disease pathogenesis and progression for the various subgroups of JIA. Although the pathogenesis of this condition is still not completely understood. Data for this literature review has therefore been drawn from a range of sources. Sciencedirect and Med-line for papers in the English Language between the years 1995 and 2010.Despite the recent classification of JIA. these study designs are generally more effective for comparing certain drug interventions as they combat „confounding by indication’. The main aim of this literature review is to examine the evidence on the pathogenesis of JIA. Databases searched included the Cochrane library. Studies which aim to determine disease aetiology or pathogenesis are not usually subjected to such confounding and therefore case-control studies are often preferential (Rosendaal. Papers to be discussed include a number of case control and cohort studies. “childhood arthritis” and “arthritis in children” individually and in combination. including reports from professional journals and academic books related to this topic. the pathogenesis of this disease is still not completely understood. 3 . Search terms included “juvenile idiopathic arthritis”. “juvenile chronic arthritis”. Although randomised controlled trials are considered the gold standard. “juvenile rheumatoid arthritis”.

many researchers have been concerned with investigating the specific cytokines and other mediators responsible for the initiation of T and B cells involved in JIA and the diversity of cellular activity in the different subgroups of the disease. These peptides act as messengers. According to Niehues et al (2008). 2009. the majority of researchers would agree that the disorder is an autoimmune disease in which the body‟s natural defences mistakenly trigger an inflammatory reaction causing destruction of its own tissues (De Jager et al. dysregulation of both the innate and the acquired immune system play a role in the autoimmune response in JIA and this dysregulation leads to the initiation of humoral factors which are found in the serum. Equipped with this knowledge. 4 . destruction of the cartilage and bone resorption (Agarwal et al. Despite the uncertainty surrounding this area however. 2009). Humoral factors include the complement and coagulation systems in addition to other chemical mediators such as interferons and interleukins (Mayer. Rang & Dale. 2006. 2008). Much of the literature is also focused on genetic factors contributing to JIA susceptibility. JIA is characterised by the activation of T and B lymphocytes. 2009). 2008). The interleukins and chemokines are the main cytokines of the immune system and are particularly important in the pathogenesis of JIA. As with any autoimmune disorder. In JIA these cells infiltrate the synovium of joints and release mediators referred to as cytokines and chemokines as well as degradative enzymes all of which contribute to synovitis. released in order to change the function of other cells (Kumar & Clark. Cytokines which appear to play a role in the pathogenesis of JIA are polypeptides which are largely found in the immune system as well as other organ systems.LITERATURE REVIEW The pathogenesis of Juvenile idiopathic arthritis (JIA) remains something of a medical enigma. Kamphuis et al.

1996). IL-1 production is often induced by cells such as macrophages. This study consisted of three different parts in order to emphasise the role of IL-1 in sJIA. Peripheral blood mononuclear cells (PBMCs) and sera were taken from 23 patients with systemic JIA and 19 healthy controls.INTERLEUKINS At present there are 35 known interleukins and according to Vastert et al (2009) interleukin 1 (IL-1). fibroblasts and monocytes in response to contact with a foreign body and primarily initiates the inflammatory response (Mallardo et al. 2008). In 5 . IL-6 and IL-18 are the predominant cytokines involved in the disease activity of systemic JIA. Pascual et al performed a study which attempted to show the relevance of IL-1 in the pathogenesis of systemic JIA (sJIA). IL-1 IL-1 is the name given to both IL-1 beta and IL-1 alpha and was the first inflammatory and regulatory cytokine of the interleukin family to be discovered (Bazan et al. IL-1Ra was administered to 2 patients and their response to treatment was monitored over a twelve month period. 2005. Of the 23 subjects in the test group systemic JIA 15 were females and 8 male. 1996). Both patients experienced complete resolution of all symptoms and inflammatory markers were decreased. The release of IL-1 leads to a number of events including the secretion of chemokines from capillary endothelial cells. 1994). whilst the control group consisted of 12 children and 7 adults. The activity of interleukin-1 was first researched by Verbsky et al in 2004 and various researchers have since investigated its action in JIA (Fitzgerald et al. replication of itself in other monocytes which thus reinforces the inflammatory process and the release of matrix metalloproteinases (MMPs) by fibroblasts which in turn degrade the extracellular matrix (ECM) (Biliau. Lequerre et al. In 2005. It is this degradation of the ECM which leads to joint destruction associated with JIA. In this case study. Verbsky (2004) was the first researcher to perform a study whereby IL-1Ra was administered to patients with systemic JIA (sJIA) to indicate the role of IL-1 in sJIA as well as the efficacy of IL-1Ra as a treatment.

03) and IL1R2 (p value=0. leucocytosis (0. Using non-parametric Mann-Whitney t U-tests. Further tests were carried out to show the difference in IL-1b production by sJIA PBMCs and those of healthy controls after activation with PMA-ionomycin. 2005). the authors showed a significant difference in the expression of both IL-1b (p value=0. a mitogen which stimulates production of interleukins and finally IL-1Ra an antagonist of IL-1b was administered to nine patients with active sJIA with the view that any reduction in symptoms or remission would substantiate IL-1 activity in JIA pathogenesis.001) between healthy sera and sJIA sera incubated with PBMCs.018) (Pascual et al. Anakrina (an IL-1 inhibitor (IL-1Ra)) was administered to 9 patients suffering from sJIA. 6 . without culture and for 6 hrs with serum from 4 patients with active JIA and were then processed using Affymetrix oligonucleotide microarrays in order to examine gene transcription rates.006). These patients had previously shown resistance to other forms of treatment with 7 having systemic symptoms and 8. The incubation of healthy PBMCs with sJIA sera produced up-regulation of 46 different genes including interleukin 1‟s which were increased more than two fold. PBMCs were incubated for 6 hrs with autologous serum.001). Finally in order to further confirm their findings. IL-1a and the receptors IL-1R1 and IL-1R for interleukin activation were also increased in sJIA cultures as compared to the controls. In addition. (p=0. Transcription of IL-1b was particularly apparent being increased from 4. the authors then investigated the ability of PBMCs from patients with sJIA to secrete IL1b when triggered by PMA-ionomycin and again there was a significant difference between the results obtained for healthy controls and those with sJIA (p -40 fold in all four sJIA cultures. fever (0.order to show the increased expression of IL-1 in systemic JIA. unremitting arthropathy ranging from 5-125 months.007). All showed a positive response to the treatment with symptoms remitting in 7 and improving significantly. Having determined that sJIA sera induced increased expression of these genes. Patients were seen prior to initiation of Anakrina (IL-1Ra) and every 2 months for the following year and the level of symptoms recorded on each occasion.

As there are no parameters or confidence interval with this test it is difficult to establish how much difference actually exists between the control group and patients with sJIA in each case. they generally require a larger sample size to reject a false hypothesis. the sample size in each group is very low and this reduces its reliability. This paper merely discusses IL-1Ra as an effective treatment. the small sample size observed in Pascual‟s (2005) study appears to be a common problem in the majority of studies. The non parametric Mann Whitney U-test is also used and although such tests have less restrictive assumptions than their parametric counterparts. The section of Pascual‟s (2005) study concerned with the efficacy of IL-1Ra for the treatment of sJIA only uses patients with the disease. As a result. In Verbsky et als (2004) study. IL-6 Preceding the investigation of IL-1 as a significant inflammatory marker in JIA. the radical improvement in symptoms and reduction in inflammatory markers witnessed by each subject in all three studies is increases the validity of the work and provides evidence that IL-1 plays a large part in the pathogenesis of sJIA and that IL-1Ra is thus an effective treatment. 7 . much of the research focused on other cytokines such as interleukin-6 (IL-6) (Rooney et al. only two patients were used and thus Pascual et als (2005) study is perhaps more accurate using 9 patients but conversely less precise than a similar study carried out by Lequerre et al (2008) in which IL-1Ra was administered to 20 patients with sJIA. progress in determining the pathogenesis of JIA has always proven difficult due to controversy surrounding the classification of the disease. in addition to the small percentage of people afflicted with the condition. however whereas Pascual et al (2005) focuses on the role of IL1 in the pathogenesis of sJIA. A more effective study could have been performed using a placebo group and making the study double blinded in order to prevent bias. Although there are controls included in the trials. Regardless of the flaws mentioned however. this work is limited on a number of levels.These studies demonstrated the significance of interleukin-1 in the pathogenesis of sJIA. however. Unfortunately however.

one trial performed by Fishman et al (1998) hypothesised that the impaired levels of IL-6 in plasma of patients with sJIA were due to a polymorphism in the cytokine‟s gene. Plasma was also taken from 102 8 . 2005). in order to inspect for any polymorphisms at the 5‟ flanking region of the IL-6 gene. IL-6 is a predominant cytokine in the acute phase of inflammation initiating the release of acute phase proteins such as serum amyloid A (SAA) and C-reactive protein (CRP) (Gabay. Although both studies acknowledged both IL-1 and Tumour Necrosis Factor (TNF) as important markers in sJIA. however when there is impaired regulation of IL-6 chronic inflammation can occur with the recruitment of monocytes and macrophages and thus destruction of the body‟s tissues ensues (Gabay. The acute phase of inflammation involves the infiltration of polymorphonuclear cells and is a limited yet beneficial response to some infectious agent. 1988) from the blood of 92 children with sJIA as well as from a control group of 383 healthy caucasian males and females. 2006). This proposal was further emphasised by the multicentre study performed by Ogilvie et al in 2003. more recent research has been done to determine any genetic link associated with these varying levels of IL-6. It is also responsible for the stimulation of T cells and the differentiation of B cells. Trials of this nature however are often difficult due to the rarity of JIA. As a result it is difficult to devise a study in which there are a significant number of subjects to achieve any significant statistical power. Produced by various cells such as fibroblasts and macrophages. IL-6 like Il-1 may act as a pro-inflammatory or anti-inflammatory mediator and has been found to be involved in many inflammatory and infectious diseases such as Rheumatoid arthritis (RA) (Rooney et al. 2006). In Fishman‟s (1998) trial the genonomic DNA was extracted by the „salting out‟ method (Miller et al. Following research by Rooney et al (1995) and De Benedetti et al (1994) which confirmed the increased levels of plasma IL-6 in patients with sJIA. The gene construct from each subject was then subjected to a sequence of laboratory investigations including the comparison of each 5‟ flanking region in a luciferase reporter vector ephemerally transfected into heLA cells and the genotype at the IL-6 -174 nucleotide for each subject was then recorded. these studies were more concerned with the relationship between the fever associated with sJIA and the alternating levels of IL-6.1995). In spite of this.

Ogilvie‟s Multicentre study in 2003 which used similar methods to determine the frequency of different genotypes but included 3 cohorts of JIA families from France (27 families).79 for those children over 6 yrs.07) P=0.01 . This therefore illustrated that the normal CC genotype was reduced in those children under 5 and thus the null hypothesis that IL-6 expression was due to chance rather than a gene polymorphism could be rejected.healthy controls and analysed using an Enzyme-linked immunosorbent assay (ELISA) test to check the levels of IL-6.38) 169 (0.17) Caucasian controls (n=383) 144 (0. Statistical analysis of results was made using the X2 test with Yates correction to compare the distribution of the C allele in the various groups.02.50) 6 (0.29) 36 (0. Furthermore.44) 70 (0.33) 18 (0.01 for those patients under 5 and a p value of 0. controls Table 1: Various genotypes observed in the different subgroups. Fishman divided the group of sJIA into two categories: 56 sJIA patients with an onset<5yrs and 36 sJIA patients with an onset>6yrs and obtained a p value of 0. DNA was extracted from each child with JIA and either one or both parents. Britain (100 families) and America (95 families) supported Fishman‟s findings but is perhaps a more reliable study.18) 16 (0.64) 4 (0. in addition to the SPSS ANOVA test. GENOTYPE sJIA onset < 5yrs (n=56) GG GC CC Patients vs. the plasma from 102 patients was tested and it was found that those patients with a GG homozygote had two times the amount of circulating IL-6 giving rise to a significant p value of 0. using either 9 sJIa onset> 6yrs (n=36) 12 (0. to demonstrate the different levels of plasma IL-6 coinciding with the various genotypes. Using the X2 test. A polymerase chain reaction (PCR) was then performed for each DNA sample after genotyping of the -174 nucleotide variant. In Ogilvie‟s group of cohorts. Several genotypes were observed at the IL-6 -174 nucleotide for each subject including the normal CC genotype and the homozygous GG and heterozygous GC polymorphisms (Table 1).

This is particularly evident in the work by Terry et al (2000) which concluded that „genetic polymorphisms in the promoter influence IL6 transcription not by a simple additive mechanism but rather through complex interactions determined by the haplotype. „heteroduplex analysis‟ and „allelic discrimination’ using various primers. The Transmit program used the „HardyWeinberg equilibrium‟ meaning the assumed genotypes for those parents not involved in the study could also be included. the validity of Fishman‟s results are perhaps not as steadfast as those obtained by Ogilvie. On the other hand Ogilvie used the TDT family based measure which therefore quantifies and corrects for stratification. 10 .041) and an underrepresentation of the CC phenotype.‟ With these conflicting views. more research on genetic links will inevitably be required in the future. these studies may give rise to confounding by population stratification and thus bias particularly through admixture. studies carried out by Pignatti et al (2001) and Donn et al (2001) did not replicate their findings and in Donn‟s (2001) study there was no association between a polymorphism and IL-6 expression in a UK cohort. has identified a more complex genetic regulation of IL-6. By using a case-control study. Fishman‟s study differs from Ogilvie‟s study in that it is a case-control study in contrast to Ogilvie‟s Multi-centre study which included a large number of families from different populations. Although both Fishman and Ogilvie arrived at a similar conclusion. Although casecontrol studies are often used to study genetic epidemiology. This admixture occurs when there is genetic mixing of two or more distinct genetic groups in the past meaning variations in allele frequencies between both cases and controls may simply be due to differences in genetic ancestry.’ This test indicates which allele is more likely to be transmitted from a parent to the affected child and was performed using the Transmit program. Statistical analysis was then carried out using TDT which according to Ewans and Spielman (1995) „is a valid test for linkage and association. The bootstrap stimulation procedure of Transmit was then applied and the results showed a significant excess in the G allele (P=0.„restriction fragment length polymorphism (RFLP)‟ which uses restriction enzymes to cut DNA at precise location and to a precise length. More recent research however. even when the association is caused by population subdivision and admixture.

interleukin 18 is observed at the site of chronic inflammation. Jelusic et al. in several auto-immune diseases and also in various cancers. 2007. Lotito et al. Kawaguchi et al. Knee articular puncture was performed and synovial fluid and sera extracted from each patient was then analysed by ELISA to determine the levels of the above mentioned cytokines. there were higher levels of all markers in patients with JIA than healthy controls. Previously known as interferon-y (IFN-y) inducing factor. 2001). IL-6 and IL-18 in the synovial fluid and serum of patients with the various forms of JIA. The study included a total of 75 subjects including 50 with JIA (13 systemic. IL-1Ra. Following statistical analysis. 2007. 2001. which according to Maeno et al (2004) is „pathogenically identical to systemic JIA’ more work has been performed to validate its role in the pathogenesis of JIA (Maeno et al. Lotito et al performed a study to determine the increased expression of IL1b. 11 .IL-18 Interleukin 18 (IL-18) which has also been implicated as an important mediator in the pathogenesis of JIA¸ plays a role in both the innate and acquired immune systems (Gracie et al. IL-18 is expressed by various cells including macrophages. C-reactive protein levels and radiological findings (Table 2). 2003). In 2007. the production of cytokines and CXC chemokines and cytotoxicity.0001). Since researchers have confirmed an increased expression of IL-18 in adult-onset Still‟s disease (AOSD) (Kawashima et al. 2004. 2009). According to Gracie et al (2003). 13 polyarticular and 24 oligoarticular) and 25 healthy controls. Lotito‟s (2007) study also highlighted much higher levels of both IL-6 and IL-18 in systemic JIA as compared to the other subgroups (p < 0. De Jager et al. osteoblasts and synovial fibroblasts and is involved in the maturation of NK cells which are lymphocytes that induce apoptosis. This was of particular significance for IL-18 which showed a positive correlation between the levels of IL-18 and disease severity namely the number of joints affected.

(Lotito et al. Both studies are case-controlled.48 0. one during the active phase of the disease and one during remission.39 0. therefore indicating that the pathogenesis of oligoarticular JIA is more likely due to other tissue factors and not IL-18. Although the results in both studies are akin. 2007) Lotito‟s (2007) study therefore concurred with research by Jelusic et al (2007). statistical analysis of Jelusic‟s (2007) results were made using ANOVA to compare the various different groups. Spearman‟s p to evaluate the bivariate relationships and the Student‟s t test which was used to investigate differences between active phase and inactive phase results.47 0. This study also demonstrated that IL18 levels remained high during the inactive phase in patients with systemic JIA and that levels of IL-18 in synovial fluid correlated directly with levels in the serum in those patients with oligoarticular JIA.37 Serum IL-18 p <0. both vary slightly in their methodology. who examined PBMC‟s from 81 children with the various subgroups of JIA and from 18 randomly selected healthy children. Analysis of PBMC‟s and synovial fluid was then performed. Correlation between serum and synovial fluid IL-18 levels and measures of disease activity/damage with inflammatory cytokines. in addition to synovial fluid taken from 16 patients with oligoarticular JIA.50 0. In contrast to Lotito (2007) however. to determine IL-18 levels.0001 0.0001 <0.42 p 0.Synovial Fluid IL-18 rs Number of active joints C-reactive protein Radiological score 0. Jelusic‟s (2007) work concluded that expression of IL-18 correlated with the disease state (active or inactive) and also that IL-18 levels were higher in those patients with systemic JIA than the other groups (p<0.001).008 Table 2. however controls participating in Jelusic‟s (2007) 12 . Two blood samples were taken from each JIA patient.003 rs 0.0001 0.03 <0.

The number of patients with systemic JIA in both is low and in Jelusic‟s (2007) study only the IL-18 cytokine is investigated. despite the fact that there are other cytokines and chemokines which interact with IL18 in the pathogenesis of JIA. 2004). Both studies are subject to limitations. therefore such an approach does not improve the validity of this study. Whereas randomisation is often considered as the gold standard for clinical trials. 13 . randomisation is assigned to the 18 healthy controls. this study design is generally applied to studies investigating certain treatment interventions. however for randomisation to be of any benefit large sample sizes are required. In Jelusic‟s (2007) study. balancing confounding factors and reducing were randomly picked after being admitted to hospital for non-inflammatory related conditions. Nonetheless. the findings of both authors strongly indicate that IL-18 is involved in the systemic subgroup of JIA and these findings have been replicated by numerous other authors (Chen et al.

these small proteins primarily act as chemoattractants. CXCR3. In addition to mediating chemoattraction. 2006). CXCL10 and CXCL16 as important inflammatory markers. These receptors are denoted by „R‟such as CXCR2 and certain ligands bind to certain receptors to produce the end cellular function. 2008). CCL5. Receptors are found on the surface of the cells and these „seven transmembrane-domain. At present there are more than 50 known chemokines. attracting leucocytes along a chemical concentration gradient of high to low. According to Kumar et al (2009). The accumulation and trafficking of immune cells and particularly T cells is the vital step in the pathophysiology of JIA and according to several researchers the majority of these events are regulated by the chemokines (Luster et al. provided the first evidence that interactions between the CXCL10 ligand and the CXCR3 receptor played an important role in the recruitment 14 . the chemokines can also activate leucocytes and in doing so stimulate the maturation of dendritic cells and thus the migration of T cells into an inflamed joint (Pharoah et al. Rollins et al. 1997). CXCR6. Martini et al. 2008). For instance both the CXCL6 and CXCL8 ligands bind to the CXCR2 receptor to initiate the chemotaxis of neutrophils (Davenport. 1998. where X denotes any other amino acid) (Davenport. Like cytokines the chemokines are pleiotropic meaning they produce many effects and have the ability to stimulate immune cells. G protein-coupled receptors‟ regulate the biological activity of the various chemokines. CXC and CXXXC. CC.CHEMOKINES The chemokines are a group of secreted peptides which play a role in both pathology and normal physiology (Davenport. In 2006. all of which are divided into 4 distinct groups according to variations in a shared cysteine (C. Various different chemokines have been indicated in the pathogenesis of JIA and researchers have investigated the role of CCL3. 2008).

Since then research has been carried out on other chemokines suspected to be involved in the pathogenesis of JIA. Other research on the area previously noted the migration of T cells towards CCL3 (Gattorno et al. Statistical analysis for results was then carried out using the paired student‟s t test. data was first analysed to verify a normal distribution. whereby levels were significantly increased in SF. RNA was then extracted from both PBMC‟s and SFMC‟s in order to evaluate mRNA levels of chemokines in each group. In addition multiplex immunoassays were performed to detect the levels of chemokines in SF and analysis was made by ELISA and flow cytometry. PBMC‟s were isolated from blood samples by centrifugation.of T cells to inflamed synovial joints. However they may also have a direct action against anti-viral agents (Nakayama et al. Pharoah et al (2006) performed the first research study to investigate the expression of the chemokines CCL5. thus suggesting a gradient between blood and SF for both of these chemokines. CCL3 and their ability to stimulate migration of CXCL10 (an activated T cell) in the joints of patients with JIA. This was particularly evident in the increased levels of CD8+T cells which produce CCL5. Following statistical analysis. In both cases. the results showed a significant difference between the levels of CCL3 and CCL10 in both SF and PB plasma. Both CCL3 and CCL5 are double cysteine ligands and mainly act as chemotactic cytokines. Analysis of mRNA for CCL5 in SF also showed an increased expression in both forms of JIA. In Pharoah‟s (2006) study peripheral blood and synovial fluid were obtained from 50 children with either oligoaricular or poyarticular JIA and 19 controls (5 adults and 14 children). 2005). in order to compare any difference between chemokine levels in blood and SF samples and the unpaired t test to compare the different findings amongst the different patient sets. whilst Hyaluronidase was added to synovial fluid to isolate SF mononuclear cells (SFMN). 15 . 2006). There was also a significant increase in levels of all three chemokines in the plasma of patients with JIA as compared to the controls (Table 3). cDNA was then generated using several primers and observed for the various genotypes denoting the different chemokines.

The conclusions obtained in this study have also been paralleled by other authors (Volin et al. In contrast to other methods such as microscopy. 1998. Both SF and PB cells were assayed by ELISA and flow cytometry was used to measure the cells in samples. therefore improving the understanding of how T cells are recruited in JIA. 1996). Prior to performing any statistical analysis Pharoah et al (2006). ensured that their data had a normal distribution and therefore avoided the risk of unreliable results. 2006). As flow cytometry measures individual cells. This method of measuring cells is more advantageous than other conventional methods as it takes heterogeneity into account and therefore does not make the assumption that all cells in a population are acting in a similar manner (Davey. demonstrates not only increased expression of the chemokines under investigation but also a gradient in their levels from blood to joint.s-1’ (Davey. through an inappropriate statistical method. This results in a smaller error term and therefore a larger t value. flow cytometry measures cells on a more realistic time scale at a rate of „1000 cells.This study by Pharoah (2006). 1996). 16 . Haringman et al. The paired sample t test used to interpret results between SF and PBMC‟s has the advantage of being a more powerful test. Because each individual is used as his/her own control then differences which would have inevitably occurred between individuals has been ruled out. The methods and statistical methods employed in this study undoubtedly improve its validity. it has the potential to recognise subpopulations of cells.

158 (± 2. 2. unpaired samples.730) 21.1 (± 12.0003 <0.174) 743 (± 675) <0.001 65.0001 87.096 (± 222.297 (± 1.402. paired samples.2) <0.962) <0.148) 211.451 (± 3.0001 <0.618) 1. (Pharoah et al.Comparison of plasma of patients and controls.006 55.) 1.9 <0.2 (± 63.Protein levels of chemokines in plasma and synovial fluid measured in 14 patients with juvenile idiopathic arthritis and 14 age matched healthy control children Chemokine Patients (± SD) Synovial fluid Mean levels (pg/ml) Controls (± SD) Plasma Plasma p2 CCL3 CXCL10 CCL5 p1 3.829) 6.05 *(TABLE 3. 2006) 17 .035 (± 10.8 (± 184.Comparison of patient plasma to synovial fluid.

Numerous chemokines have also been implicated in the pathogenesis and the interaction between chemokines and their receptors is the crucial step in the trafficking and accumulation of T cells into the joints in children with JIA. Therefore large and rigorous studies will be required in the future in order to further investigate any other cytokines involved in the pathogenesis of JIA as well as the interactions between them. The majority of studies were limited to the action of one or two mediators whereas it is known that the interactions between cytokines and chemokines are complex.Conclusion The new classification of JIA into its various subgroups was devised in order to delineate this disease group into relatively homogenous. 18 . Despite these new findings however. Continuous advancements have been made in the understanding of the mechanisms associated with the inflammatory process and immune response and particularly with regards to the role of cytokines. This review concludes that the role of IL-1. the case-control and cohort studies used in this review were drawn from small numbers of studies with a low number of participants. IL-6 and IL-18 as well as various chemokines have been studied and have shown to have a fundamental role in the pathogenesis of JIA. This continued progression in knowledge will inevitably provide new insights into the pathogenesis of JIA as well as the therapeutic approach. Since then more research has been performed to determine the different cellular activity in the different subgroups. But expression of these cytokines varies amongst the various subgroups. which are classified depending on the various clinical and laboratory findings for each. exclusive categories for the purpose of research.

D...641-696.183-198. D. A.. (1994). D. F. pp. (2008). Interleukin 17 levels are increased in juvenile idiopathic arthritis synovial fluid and induce synovial fibroblasts to produceproinflammatory cytokines and matrix metalloproteinases. (1996). pp. 62. Davey.M. M. J... Microbiological reviews.. (1996).515-519.. Hsieh. Advancing Immunology. (1996). A. 31. R. Martini..References Agarwal. Interferon-gamma: biology and role in pathogenesis.L. Aggarwal. P.Y. J. S.L. Misra. T.. pp:61-130 Chen.Y. Proinflammatory cytokine profiles in sera and pathological tissues of patients with untreated adult-onset still‟s disease. pp. Massa. A newly defined interleukin-1? Nature. pp. (93)5.. pp. Novick... Kastelein.. Billau. (2008). Serum soluble interleukin 6 (IL-6) receptor and IL-6/soluble receptor complex in systemic juvenile rheumatoid arthritis. S. Flow cytometry and cell sorting of heterogenous microbial populations: the importance of single cell analyses. Timans...2114-2119. De Benedetti. Journal of Clinical Investigation.F.. Albani. H. Kell. J.. Lan.591. (2004). The Journal of Rheumatology..B. F... pp. Davenport. 19 .. Lin. 35(3).A. R. The Journal of Rheumatology. R.2189-2198. S. An introduction to chemokines and their role in transfusion medicine. 379.D.C. 60. Bazan.. Pignatti. 96.. Vox Sanguinis.

S. L.Martini.1369-1376. Beekman. J. S. S.A. Vastert.. 20 . W. (1995).De Jager. 60(9).E. (2005). A. R. Jeffery. Fahran. D. American Journal of Human Genetics.A...J.P. 44. 57. W. Homik. A.(2005).. leclercq. Inherited autoinflammatory syndromes: an expanding new group of chronic inflammatory diseases.A... J. 102. 23. McInnes. Cytokine gene polymorphisms and susceptibility to juvenile idiopathic arthritis. pp. Faulds. et al (2009). S.M.. Humphries. Arthritis Rheum. (2003)...E.. A. Defective Phosphorylation of Interleukin-18 Receptor beta Causes Impaired Natural Killer Cell Function in Systemic-Onset Juvenile Idiopathic Arthritis. Pepper. Yan. pp. Fitzgerald.1794-1803..213-224. P. pp. Fishman... Kuis.. J.. S.A.B. R. Ewen. Stopford. pp. Gattorno.. Yudkin. Barrett. N.. Dinarello. Journal of Leukocyte Biology. I. M. Arthritis rheum. J.802-10.. Rapid responses to anakinra in patients with refractory adults-onset still‟s disease. 73. Donn.S. A. Arthritis and Rheumatism..455–464.A. pp..J. and an association with systemic-onset juvenile chronic arthritis. J. C.M. 52.. Gracie. Robertson.. subdivision and admixture.. Wulfraat.2782-2793. W. G.H. R.133-136. Woo. Interleukin-18... et al.. (1998). pp. Mohamed-Ali... The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels. Spielman. V. The transmission/disequilibrium test: history. Journal of Clinical Invetigation. Clin Exp Rheumatol. pp. and the British Paediatric Rheumatology Study Group (2001)..

Haringman.T. Kawaguchi.. pp.. London: Mosby. Yamauchi. Kawashima. T. Alaoui.K. Dubravcic. Y.. P. Reinders-Blankert. Chemokine and chemokine receptor expression in paired peripheral blood mononuclear cells and synovial tissue of rheumatoid arthritis. Hara. pp. Silva. J. M.H... K.. Ferri.... Interleukin18 as a novel diagnostic marker and indicator of disease severity in adult-onset still‟s disease. J. M.. C. P.F. L. Harigai. F.. Kamatani.. H. (2007).J. De Bandt. Yamamura. Jelusic. (2001).13321334.. Arthritis Rheum. Interleukin 18 as a Marker of Disease Activity and Severity in Patients with Juvenile Idiopathic Arthritis... 34(4). pp. M. (2001).. D. Smeets. 26. 46. Taniai. M. I..2539-2541. T. A. Terajima. Interleukin-18 as a mediator of systemic juvenile idiopathic arthritis. (2008).P. H. 65.. M... Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult-onset still‟s disease: preliminary experience in France.. et al. & Dieppe..J. Bukovac. M. 21 .. Annals of Rheumatic Diseases..A. (1999).1716-1718. Lequerre. Rosellini. P. Clinical Rheumatology. Kiss. 44. N.302-308. T. pp. Levels of interleukin-18 and its binding inhibitors in the blood circulation of patients with adult-onset Still‟s disease..294–300.. pp. Lotito. (2006). F. Klippel. Tak. Lukic... M. Annals of the rheumatic diseases. Mello. A.P. M.. 67. et al. The Journal of Rheumatology. Arthritis Rheum. (2007). osteoarthritis and reactive arthritis patients.. Primary care rheumatology. pp. Tanimoto. Quartier.823. P.

Juvenile idiopathic arthritis... M. H. Mertens. 350(2)... Giordano. G. Singh J.. (2004). (2006). Imanaka. Dykes.Luster. Kawano. 22 . Mallardo. 50(6).. K. Increased interleukin-18 expression in bone marrow of a patient with systemic juvenile idiopathic arthritis and unrecognised macrophage-activation syndrome. (1988).268-276. Kuriwaki. Arthritis and Rheumatism.. Hieshima.. Quinto. Miller.. Nakayama. Novel antiviral activity of chemokines. Martini. M. and interleukin-6 transcripts and the production of the relative proteins. E. pp. New England Journal of Medicine.DNA damaging agents increase the stability of interleukin-1 alpha.. S. Polesky. Mechanisms of Disease: Chemokines-Chemotactic Cytokine That Mediate inflammation. J. D. Shibano.1215. Calabrese. 2009. (2009) . pp. August issue. Yamamoto. Issue 1. 269. pp. (2008). CXCR6-CXCL 16 interaction in the pathogenesis of Juvenile Idiopathic arthritis. (1998). (2009). I. M.436-445. H. pp.. Nucleic Acids Research. F.. A.. A simple salting out procedure for extracting DNA from human nucleated cells. Shirane. Oda... K. Y. Dragonetti.Anakinra for rheumatoid arthritis. S.. G. H.. et al. Scala. V. Takei... 129.. S. Carraro.. pp. The Journal of Biological Chemistry.. M.14899-14904.1935-1938.. A.A. (1994).. pp.D.D. K.. Maeno N. T. Podiatry Now.. interleukin-1 beta.484-492. 338(7).. Virology.F. Malone. M. Cabrelle. Cochrane Database of Systematic Reviews. Watanabe.A.. Clinical Immunology. 16(3).

D. 201. 90. (2008). F. E. Banchereau. De Benedetti. David. M. 67(2). A. Punaro. Ravelli. Lancet. J...3202-3206. Pignatti. Fife. Blood. Abnormal regulation of interleukin 6 in systemic juvenile idiopathic arthritis. P. F. G.. S. Rollins. V. Thompson.. A. E.R. 369. F. Inflammatory Cytokine Responses in Juvenile Chronic Arthritis.. Juvenile idiopathic arthritis. 909-928. et al. M.767-778.. Woo.S. Martini. Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade. (1995). Ogilvie. pp. Arce.. Allantaz.Niehues. pp. Feyen. T. Arthritis Rheum.. Chemokines.. pp. (2003). (2007). P. H.. Varsani. pp. Concepts on the pathogenesis of juvenile idiopathic arthritis.. 34.. Bridging case-control studies and randomised trials. O. Martini. M. Pascual. M. T.. J. The -174G allele of the interleukin-6 confers susceptibility to systemic arthritis in children: a multicenter study using simplex and multiplex juvenile idiopathic arthritis families. Rosendaal...1-8.. The Journal of Experimental Medicine.. Telieps. (2005).M. A.1670-1676.. Current Control Trials Cardiovascular Medicine. The Journal of Rheumatology. Meazza. B. (1997).. C...109-110.. 52.. pp. F. (2001).454-460.111-116. pp. Rizzolo.. 23 .. J. Di Giovine. Vivarelli. pp. Paediatric Rheumatology: Original Article. (2001). pp. 2(3). 28. British Journal of Rheumatology. Symons.. The Journal of Rheumatology.. Rooney.

Green. 45(8). Systemic JIA: new developments in the understanding of the pathophysiology and therapy. (2001). A... W. F.. Loukaci. (1998). Arch Dis Child. Wordsworth. 24 . pp.972. 23.V..M. W.. (2006). The Journal of Rheumatology. Grom..R. Murray. Association of HLA-DRB1*13 with susceptibility to uveitis in juvenile idiopathic arthritis in two independant data sets. Tokuhira M. 31(10). Verbsky. Journal Biol Chem. Volin M.W. Zeginni. Woo.. Kuis. Cooperative influence of genetic polymorphisms on interleukin 6 transcriptional regulation. pp.. Donn. 89. Woods J. pp.J..E. P. K.Sawhney.. pp. E. Rheumatology.J.. S. Clin Immunol Immunopathol.655-664. C.A. Vastert. Best Practice and Research Clinical Rheumatology..F. Haines G. Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders..421-426. R. Terry.K. S. Packham..18138-18144. A.... pp.. White. P. Shah M. (2000). Effective use of the recombinant interleukin 1 receptor anakinra in therapy resistant systemic onset juvenile rheumatoid arthritis. (2009).. 275.2071-2075... pp. J.. (2004).. V.. RANTES expression and contribution to monocyte chemotaxis in arthritis.J. J.R. 85. Thomson. A.44–53. Hall. Koch A.

3rd ed. (2004). Philadelphia: Elseiver.. H. A Colour Atlas of Rheumatology.. J. Southwood. Introduction to Podopediatrics. Volpe. & Clark. Rang and Dale’s Pharmacology. pp.Bibliography Cassidy. M. ABC Rheumatology. 4th ed. Kumar. 7th ed. 2nd ed. (2009). R.. R... Wolfe Publishing. T.68-74.J. 25 . Philadelphia: WB Saunders Company. Elseiver.R.. P. Friswell M. (2008). Dale. (2000). R. flower.. Rang. Thomson. Clinical Medicine. In Snaith ML. Juvenile idiopathic arthritis.editor. 6th ed. Ritter. P. London: BMJ publishers. Philadelphia: Elseiver. M. J. Shipley.M. England. (1993).P. Textbook of paediatric rheumatology.M. M... Petty... Philadelphia. (2001)..

. H. Novel self-epitopes derived from aggregan. 8(6). (Accessed 17th February.. 26 . Klein. (2006). CCL3 and CXCL10 in juvenile idiopathic arthritis. (Online). (2006) (Accessed 17th February.R. C. Hrafnkelsdóttir. de Jager.. 8(2) Available at: http://www.nlm. M. Available at: http://arthritis-research. et al.H. 2010)... M... Arthritis Research and Therapy. Expression of the inflammatory chemokines CCL5. and demonstration of CCL5 production by an atypical subset of CD8+ T cells. et al. Varsani. (2006). Pharoah. (Online). S.. K.. (Online). Arthritis research and therapy. 8(2). Interleukin-6 and chronic inflammation. and matrix metalloproteinase-3 drive distinct autoreactive T-cell responses in juvenile idiopathic arthritis and in health. (Accessed 17 February 2010). fibrillin. Kamphuis.. Newton. Tatham. 2010). W. de Jager.Online Journals Gabay.. Available at: http://arthritis-research. Arthritis Research and Therapy. R. K. Haverkamp.

27 .

Master your semester with Scribd & The New York Times

Special offer for students: Only $4.99/month.

Master your semester with Scribd & The New York Times

Cancel anytime.