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Rheumatology 2001; 40: 574-578
© 2001 British Society for Rheumatology

Paediatric Rheumatology

Hereditary predisposition to low interleukin-10 production in children with extended oligoarticular juvenile idiopathic arthritis

Paediatric Rheumatology/Series Editor: P. Woo

E. Crawley, S. Kon and P. Woo

Department of Molecular Pathology, University College London Medical School, London, UK

Abstract

Objective. To determine whether children with extended oligoarticular juvenile idiopathic arthritis (JIA) produce less of the anti-inflammatory cytokine interleukin-10 (IL-10) than those with persistent oligoarticular JIA.

Methods. We measured IL-10 production in the parents of children with oligoarticular or extended oligoarticular JIA, from whole-blood cultures stimulated with lipopolysaccharide.

Results. IL-10 production was lower in the parents of children with extended oligoarticular JIA compared with those of children with oligoarticular JIA (P=0.034). There was an increase in the percentage of ATA-containing genotypes (i.e. genotypes ATA/ATA, ATA/ACC or ATA/GCC) in the parents of children with extended oligoarticular JIA compared with healthy controls (P<0.02) but not in the parents of children with oligoarticular JIA.

Conclusions. As approximately 84% of the variation in IL-10 production is thought to be genetically regulated, these results suggest that stimulated IL-10 production would be lower in children with extended oligoarticular JIA. Because IL-10 is an anti-inflammatory cytokine, this may partly explain why this group of children has more severe disease.

KEY WORDS: JIA, Interleukin-10, Single nucleotide polymorphism, Genes, Hereditary, Oligoarticular.

The prevalence of arthritis in children in the UK is approximately 1 per 1000 [1]. Juvenile idiopathic arthritis (JIA) is defined as arthritis in a child under the age of 16 yr affecting one or more joints, lasting for at least 6 weeks and currently having no other known aetiology [2]. In addition to joint destruction, local inflammation results in accelerated growth of the epiphyses in the affected joints. Overall, an estimated 49% of affected children end up with severe functional limitation (classes III and IV in the Steinbroker classification) because of JIA [3].

JIA is not a homogeneous disease, and the various subtypes have been recently reclassified according to the ILAR proposals published in 1995 and revised in 1997 [4]. One subgroup is oligoarticular JIA, in which a child has arthritis affecting one to four joints during the first 6 months of disease. If the condition extends to involve more than four joints after the first 6 months of disease, the patient is considered to have extended oligoarticular JIA. The prognosis in this latter group is worse, but little of the pathological mechanism involved in differentiating between the two groups is understood. Our hypothesis is that a difference in regulatory cytokine production may partly explain why some children ‘extend’ and develop more severe disease. One of the key anti-inflammatory cytokines is interleukin 10 (IL-10). IL-10 acts mainly as an anti-inflammatory cytokine by inhibiting the production of proinflammatory cytokines [5–11] and antagonizing the effects of proinflammatory cytokines such as tumour necrosis factor {alpha} (TNF-{alpha}) [12, 13]. In addition, IL-10 down-regulates antigen-presenting cell function [14–17] and inhibits macrophage proliferation [18] and has many other anti-inflammatory actions [14, 19–23].

In animal models, IL-10 appears to be important in controlling the development of arthritis [3, 24–26]. Therefore, insufficient IL-10 in the presence of inflammation could be one of the mechanisms allowing joint inflammation to continue unchecked.

Studies to investigate whether the variability in IL-10 production is genetic have shown that the correlation of IL-10 production (stimulated with lipopolysaccharide) is 0.75 between monozygotic twins and 0.33 between siblings [27]. This suggests that the genetic contribution to variability in IL-10 production is 84%. There is no correlation between IL-10 production and the time spouses lived together [27], suggesting that a shared environment contributes little to the production of IL-10.

There is now some evidence that IL-10 production is controlled by the regulation of transcription [28–33]. Recent publications [34–40], including our own [41], have shown that single-nucleotide polymorphisms (SNPs) and microsatellites within the IL-10 5' flanking region are both functional and associated with disease.

There are two microsatellites between positions -4000 and -1200 [42] and three single-base-pair substitutions, at positions -1082 (G to A), -819 (C to T) and -592 (C to A) [34, 43]. There is linkage disequilibrium between the alleles, with the two downstream polymorphisms occurring in tandem, and only three out of four possible haplotypes have been described in Caucasian populations: GCC, ACC and ATA.

Initial in vitro work on peripheral blood mononuclear cell cultures has suggested that the GCC/GCC genotype is associated with higher IL-10 production than other genotypes [43], and we have shown that the ATA haplotype is associated with low IL-10 production in transient transfection studies and whole-blood culture [41]. In the same report, we showed that the ATA haplotype is associated with children with extended oligoarticular JIA and not those with oligoarticular JIA (P<0.05). If this association is biologically important, we would expect that children with extended JIA should produce less IL-10 during inflammation than children with oligoarticular JIA. IL-10 production cannot be measured in many children with arthritis because of the treatment they receive, which includes both glucocorticoids and methotrexate; these are both known to alter IL-10 production [44–53].

Parental IL-10 production was therefore measured as a marker for IL-10 production in the children, as approximately 84% of the variability in IL-10 production is genetically regulated [27]. This method has been used to estimate childhood cytokine production in other studies [27].

Materials and methods

Patient samples
Samples were collected from parents attending the out-patient department at Great Ormond Street Hospital. Ethical approval and informed consent was obtained.

Measurement of stimulated IL-10 production
Stimulated IL-10 production was measured by the enzyme-linked immunosorbent assay after using the whole-blood culture method as described previously [41].

Genotype analysis
Genotypes were assigned by polymerase chain reaction–sequence-specific oligonucleotide probing (PCR-SSOP) for the IL-10 5' flanking region SNPs, as described previously [41].

Statistical methods
If both parents were available, the value of IL-10 production in whole-blood culture from both the mother and the father was averaged. If only one parent was available the result from one parent was used. Parents of children with oligoarthritis and no eye disease were considered to be controls (for whole blood culture analysis). The Shapira–Wilk statistic showed that the data had a normal distribution. Comparisons of both groups and the control group were therefore made using Student's t-test.

The genotype data were compared as described using the {chi}2 test.

Results

Blood was cultured from the parents of 26 children with JIA. Fourteen of these children had extended oligoarticular JIA and 12 had oligoarticular JIA. Seven of the children had uveitis. Parents were excluded if they were on treatment that was known to affect IL-10 production or if they were suffering from a viral infection. IL-10 production was analysed in both parents of two of the children and in one parent of each of 24 children.

Stimulated IL-10 production was compared between parents of children with extended oligoarticular JIA and parents of children with oligoarticular JIA. The results are shown in Fig. 1Go. Mean (S.E.) IL-10 production (pg/ml) was lower in the parents of children with extended oligoarticular disease [2109.2 (251), n=14] compared with parents of children with oligoarticular JIA [3161.7 (411), n=12]; the difference was significant (P=0.034, 95% confidence interval 88–2016 pg/ml).



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  		FIG. 1. Average IL-10 production in parents of children with oligoarticular or extended oligoarticular JIA. The mean is shown as a horizontal bar. Each data point (•) represents the average IL-10 production corrected for monocyte and lymphocyte (m+l) count for one child with JIA. If a result was available from only one parent, this is plotted as a single point.

 
As there is some suggestion in the literature that uveitis may be associated with either high or low IL-10 production [54, 55], these children may therefore confound the results. The results were therefore reanalysed only for children who we knew did not have eye disease. The mean (S.E.) IL-10 production in parents of children with extended oligoarticular JIA was 1616.3 (534) pg/ml (n=5), whilst in parents of children with oligoarticular JIA it was 3019 (334) pg/ml (n=7). Although the numbers were lower, there was still a statistically significant difference between the two groups (P=0.05).

IL-10 production could be lower in this group of patients for many reasons, including a genotypic predisposition to low IL-10 production. We have already shown that the ATA haplotype and genotypes containing the ATA haplotype are associated with low IL-10 production [41]. We therefore genotyped the parents to ascertain whether this difference in parental IL-10 production could be accounted for by a difference in the distribution of IL-10 5' flanking region genotype or whether it was due to other factors, such as increased TNF production. For this analysis we used healthy controls unrelated to patients as described in our previous paper [41]. The results showed that the parents of children with extended oligoarticular JIA were more likely than controls to have an ATA-containing genotype (P=0.014), whilst there was no difference in the distribution of genotypes between the parents of children with oligoarticular JIA and controls. It was not possible to calculate whether there was a gene-dose effect as there was only one parent who was homozygous for ATA (Table 1Go ).


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  		TABLE 1. Genotype frequencies in parents of children with oligoarticular or extended oligoarticular JIA

 

Discussion

In this study, we have shown that stimulated IL-10 production was lower in the parents of children with extended oligoarticular JIA compared with parents of those with persistent oligoarticular JIA; by inference it was also lower in extended JIA patients, as 85% of IL-10 production is genetically determined. This observation is important as it suggests that the difference described is biological and not due to a difference in treatment received by the children. It also suggests that children who ultimately develop the extended form of oligoarticular JIA are predisposed to do so by low IL-10 production.

This observed difference may be due to differences in the production of other cytokines, such as TNF, or to a genetic predisposition to low IL-10 production in the parents of children with extended oligoarticular JIA. Because we have shown previously that the ATA haplotype of the IL-10 5' flanking region is associated with lower IL-10 production, we genotyped the parents. In this case–control study we have shown that parents of children with extended oligoarticular JIA are more likely to have an ATA-containing genotype. This is consistent with our previous work showing an association of extended oligoarticular JIA with ATA-containing genotypes. Taken together, these results suggest that children who develop extended oligoarticular JIA as opposed to persistent oligoarticular JIA may be genetically programmed to lower IL-10 production and therefore possess increased susceptibility to more severe disease.

Notes

Correspondence to: E. Crawley, Molecular Pathology, UCLMS, 3rd Floor, Windeyer Institute, 46 Cleveland Street, London W1T 4JF, UK. Back

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Submitted 4 July 2000; Accepted 11 December 2000


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