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.


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

Despite the uncertainty surrounding this area however. 2009. As with any autoimmune disorder. 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. destruction of the cartilage and bone resorption (Agarwal et al. Kamphuis et al. Humoral factors include the complement and coagulation systems in addition to other chemical mediators such as interferons and interleukins (Mayer. JIA is characterised by the activation of T and B lymphocytes. 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. 4 . 2009). The interleukins and chemokines are the main cytokines of the immune system and are particularly important in the pathogenesis of JIA. Equipped with this knowledge. These peptides act as messengers. 2008). 2008). 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. 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. 2006.LITERATURE REVIEW The pathogenesis of Juvenile idiopathic arthritis (JIA) remains something of a medical enigma. Much of the literature is also focused on genetic factors contributing to JIA susceptibility. Rang & Dale. According to Niehues et al (2008). released in order to change the function of other cells (Kumar & Clark. 2009). 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.

Pascual et al performed a study which attempted to show the relevance of IL-1 in the pathogenesis of systemic JIA (sJIA). 1996). IL-6 and IL-18 are the predominant cytokines involved in the disease activity of systemic JIA. Lequerre et al. Peripheral blood mononuclear cells (PBMCs) and sera were taken from 23 patients with systemic JIA and 19 healthy controls. fibroblasts and monocytes in response to contact with a foreign body and primarily initiates the inflammatory response (Mallardo et al. 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. 1994). 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. IL-1Ra was administered to 2 patients and their response to treatment was monitored over a twelve month period. In 2005. In this case study. In 5 . This study consisted of three different parts in order to emphasise the role of IL-1 in sJIA. IL-1 production is often induced by cells such as macrophages. It is this degradation of the ECM which leads to joint destruction associated with JIA. whilst the control group consisted of 12 children and 7 adults. 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. 2005. 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. 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.INTERLEUKINS At present there are 35 known interleukins and according to Vastert et al (2009) interleukin 1 (IL-1). 2008). 1996). Of the 23 subjects in the test group systemic JIA 15 were females and 8 male.

These patients had previously shown resistance to other forms of treatment with 7 having systemic symptoms and 8. Transcription of IL-1b was particularly apparent being increased from 4. Finally in order to further confirm their findings. PBMCs were incubated for 6 hrs with autologous serum. 2005).006). fever (0. (p=0.03) and IL1R2 (p value=0. Using non-parametric Mann-Whitney t U-tests. 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. the authors showed a significant difference in the expression of both IL-1b (p value=0. In addition.order to show the increased expression of IL-1 in systemic JIA. 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. 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. 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.001). IL-1a and the receptors IL-1R1 and IL-1R for interleukin activation were also increased in sJIA cultures as compared to the controls.018) (Pascual et al. 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.001) between healthy sera and sJIA sera incubated with PBMCs. 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 value=0. All showed a positive response to the treatment with symptoms remitting in 7 and improving significantly. Anakrina (an IL-1 inhibitor (IL-1Ra)) was administered to 9 patients suffering from -40 fold in all four sJIA cultures. leucocytosis (0.007). Having determined that sJIA sera induced increased expression of these genes. unremitting arthropathy ranging from 5-125 months.

Unfortunately however. As a result. much of the research focused on other cytokines such as interleukin-6 (IL-6) (Rooney et al. 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. in addition to the small percentage of people afflicted with the condition. they generally require a larger sample size to reject a false hypothesis. In Verbsky et als (2004) study.These studies demonstrated the significance of interleukin-1 in the pathogenesis of sJIA. the small sample size observed in Pascual‟s (2005) study appears to be a common problem in the majority of studies. 7 . this work is limited on a number of levels. 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. 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. 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. progress in determining the pathogenesis of JIA has always proven difficult due to controversy surrounding the classification of the disease. the sample size in each group is very low and this reduces its reliability. however. Although there are controls included in the trials. The non parametric Mann Whitney U-test is also used and although such tests have less restrictive assumptions than their parametric counterparts. Regardless of the flaws mentioned however. This paper merely discusses IL-1Ra as an effective treatment. 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.

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. It is also responsible for the stimulation of T cells and the differentiation of B cells. Produced by various cells such as fibroblasts and macrophages. 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. This proposal was further emphasised by the multicentre study performed by Ogilvie et al in 2003. these studies were more concerned with the relationship between the fever associated with sJIA and the alternating levels of IL-6. In spite of this. more recent research has been done to determine any genetic link associated with these varying levels of IL-6. 2006). Trials of this nature however are often difficult due to the rarity of JIA. 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. Plasma was also taken from 102 8 . In Fishman‟s (1998) trial the genonomic DNA was extracted by the „salting out‟ method (Miller et al.1995). 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. The acute phase of inflammation involves the infiltration of polymorphonuclear cells and is a limited yet beneficial response to some infectious agent. 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. 2006). 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. 1988) from the blood of 92 children with sJIA as well as from a control group of 383 healthy caucasian males and females. 2005). in order to inspect for any polymorphisms at the 5‟ flanking region of the IL-6 gene. 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.

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.79 for those children over 6 yrs. to demonstrate the different levels of plasma IL-6 coinciding with the various genotypes. GENOTYPE sJIA onset < 5yrs (n=56) GG GC CC Patients vs. Britain (100 families) and America (95 families) supported Fishman‟s findings but is perhaps a more reliable study.02.64) 4 (0. 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). A polymerase chain reaction (PCR) was then performed for each DNA sample after genotyping of the -174 nucleotide variant.38) 169 (0. Using the X2 test. in addition to the SPSS ANOVA test.07) P=0.17) Caucasian controls (n=383) 144 (0. Furthermore.18) 16 (0. controls Table 1: Various genotypes observed in the different subgroups.01 .healthy controls and analysed using an Enzyme-linked immunosorbent assay (ELISA) test to check the levels of IL-6. 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.33) 18 (0. DNA was extracted from each child with JIA and either one or both parents. 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. In Ogilvie‟s group of cohorts.01 for those patients under 5 and a p value of 0. 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). 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 0.50) 6 (0.44) 70 (0.29) 36 (0.

Statistical analysis was then carried out using TDT which according to Ewans and Spielman (1995) „is a valid test for linkage and association. these studies may give rise to confounding by population stratification and thus bias particularly through admixture.‟ With these conflicting views. Although both Fishman and Ogilvie arrived at a similar conclusion. By using a case-control study. 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.„restriction fragment length polymorphism (RFLP)‟ which uses restriction enzymes to cut DNA at precise location and to a precise length.041) and an underrepresentation of the CC phenotype. more research on genetic links will inevitably be required in the future. 10 . has identified a more complex genetic regulation of IL-6. 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. the validity of Fishman‟s results are perhaps not as steadfast as those obtained by Ogilvie. 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. On the other hand Ogilvie used the TDT family based measure which therefore quantifies and corrects for stratification. Although casecontrol studies are often used to study genetic epidemiology. The Transmit program used the „HardyWeinberg equilibrium‟ meaning the assumed genotypes for those parents not involved in the study could also be included. even when the association is caused by population subdivision and admixture. 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.’ 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. The bootstrap stimulation procedure of Transmit was then applied and the results showed a significant excess in the G allele (P=0. More recent research however. „heteroduplex analysis‟ and „allelic discrimination’ using various primers.

In 2007. the production of cytokines and CXC chemokines and cytotoxicity.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. Jelusic et al. 2004. 2001). 13 polyarticular and 24 oligoarticular) and 25 healthy controls. 2007. IL-18 is expressed by various cells including macrophages. 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. Since researchers have confirmed an increased expression of IL-18 in adult-onset Still‟s disease (AOSD) (Kawashima et al. Lotito et al. Kawaguchi et al. C-reactive protein levels and radiological findings (Table 2). 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. According to Gracie et al (2003). Following statistical analysis. IL-1Ra. De Jager et al. Previously known as interferon-y (IFN-y) inducing factor. 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. 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. osteoblasts and synovial fibroblasts and is involved in the maturation of NK cells which are lymphocytes that induce apoptosis. 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. 2007. Lotito et al performed a study to determine the increased expression of IL1b. 2003). 11 . in several auto-immune diseases and also in various cancers. 2001. interleukin 18 is observed at the site of chronic inflammation. 2009).0001).

who examined PBMC‟s from 81 children with the various subgroups of JIA and from 18 randomly selected healthy children. (Lotito et al.03 <0. Analysis of PBMC‟s and synovial fluid was then performed.008 Table 2. 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. 2007) Lotito‟s (2007) study therefore concurred with research by Jelusic et al (2007).39 0.48 0. one during the active phase of the disease and one during remission.0001 0.42 p 0. both vary slightly in their methodology. Although the results in both studies are akin.37 Serum IL-18 p <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. In contrast to Lotito (2007) however. 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.50 0. Both studies are case-controlled. in addition to synovial fluid taken from 16 patients with oligoarticular JIA.003 rs 0. however controls participating in Jelusic‟s (2007) 12 .47 0. therefore indicating that the pathogenesis of oligoarticular JIA is more likely due to other tissue factors and not IL-18.0001 <0. Correlation between serum and synovial fluid IL-18 levels and measures of disease activity/damage with inflammatory cytokines.Synovial Fluid IL-18 rs Number of active joints C-reactive protein Radiological score 0.001). Two blood samples were taken from each JIA patient.0001 0. statistical analysis of Jelusic‟s (2007) results were made using ANOVA to compare the various different groups. to determine IL-18 levels.

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

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

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

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

2) <0.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 3.730) 21.0003 <0.297 (± 1.05 *(TABLE 3.402.829) 6.174) 743 (± 675) <0.2 (± 63.006 55.451 (± 3.0001 87.Comparison of plasma of patients and controls.035 (± 10.618) 1.0001 <0.1 (± 12. (Pharoah et al.096 (± 222.9 <0.8 (± 184.158 (± 2.) 1.001 65. paired samples. 2006) 17 .962) <0. 2. unpaired samples.Comparison of patient plasma to synovial fluid.148) 211.

Since then more research has been performed to determine the different cellular activity in the different subgroups. which are classified depending on the various clinical and laboratory findings for each.Conclusion The new classification of JIA into its various subgroups was devised in order to delineate this disease group into relatively homogenous. exclusive categories for the purpose of research. 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. 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 continued progression in knowledge will inevitably provide new insights into the pathogenesis of JIA as well as the therapeutic approach. Despite these new findings however. But expression of these cytokines varies amongst the various subgroups. the case-control and cohort studies used in this review were drawn from small numbers of studies with a low number of participants. This review concludes that the role of IL-1. 18 . 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. 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. 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.

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