The aging process is accompanied by qualitative and quantitative changes in the immune system, which are grouped under the term immunesenesence.1 Consequently, the elderly show increased susceptibility to neoplasms, infections, and autoimmune diseases.2 In this sense, aging is accompanied by the appearance of some age-related diseases, and one of the best examples is giant cell arteritis (GCA), a granulomatous systemic vasculitis with a preference for large and medium caliber arteries.3 The clinical manifestations of cranial GCA symptoms ranges from the classic aortic arch syndrome or less specific manifestations such as fever, weight loss or polymyalgia syndrome.4–7 Polymyalgia rheumatica (PMR) is a syndrome characterized by pain and stiffness of the neck, pelvic girdle and also affects only elderly individuals.8 Although PMR occurs normally in the absence of GCA, some patients may also develop arteritis during the disease.9 Moreover, it has been suggested that PMR and rheumatoid arthritis in the elderly (Eora), especially the seronegative variety, have much in common.10

The T cell-derived cytokine profile of inflammatory diseases associated with aging suggests that it is primarily mediated by a Th1 response. This may be due to an increase in Th1 cytokine expression, such as IFN-γ that plays a crucial role in the development of GCA,11 or in a defect in regulation by activated Th2 cytokines.

In recent years there have been numerous studies of cytokine gene polymorphisms in PMR and GCA.12 However, these studies have focused on pro-inflammatory cytokines rather than Th1 and Th2 cytokines. Th2 immune response is characterized by expression of IL-4, IL-5, IL-9, and IL-13. Theoretically a decrease in the activity of these Th2 cytokines may be accompanied by greater severity of these diseases while Th2 increased activity could be associated with a milder clinical picture. There is only one previous study conducted by Amoli et al.13 in which there was a marginally significant association between GCA and some IL-4 single nucleotide genetic polymorphisms (SNPs).

IL-13 is an immunoregulatory protein produced mainly by activated Th2 cells14 and is involved in the maturation and differentiation of B cells. It promotes expression of CD23 and class histocompatibility molecules, IL15 and isotype switching to IgE in B cells.16 Furthermore, IL-13 decreases the activity of macrophages, thus inhibiting production of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α, among others. Recently, numerous polymorphisms in the gene for IL-13 have been identified and have been associated with IgE levels and/or allergic diseases.17 One of the SNPs located in exon 4 at position 2044 (switch from G to A, denominated G2044A) causes a change of the amino acid (arginine for glutamine at codon 130, denominated R130Q) and possibly affects ligand-receptor interaction.18,19

The aim of this study was to investigate the association between the R130Q polymorphism of the gene for IL-13 and susceptibility to GCA and 2 other inflammatory diseases associated with aging such as PMR and Eora.

IL-13 is an immunoregulatory protein produced mainly by activated Th2 cells14 and is involved in the maturation and differentiation of B cells.15 This cytokine is considered part of the Th2 immune response and a reasonable hypothesis is that the imbalance in the Th1/Th2 balance could be involved in the pathogenesis of chronic diseases associated with age and are the result of a dysfunction in immune system regulation. According to this hypothesis, a genetic predisposition in the expression of genes coding for Th2 cytokines could influence the severity and/or susceptibility of these 3 diseases. There is only one previous study conducted by Amoli et al.13 in which there was a marginally significant association between GCA and some SNPs for IL-4. However, these results were more significant when considering only those patients HLA-DRB1*04, suggesting an interaction between HLA-DRB1 and IL-4 contributing to increased susceptibility for the disease.13

Therefore, taking into consideration the failure of previous studies in determining the influence of Th2 cytokine genes, we analyzed for the first time the influence of the rs20541 (R130Q) polymorphism in the gene encoding the IL-13 in a large series of patients with inflammatory diseases associated with aging.

The data shows an association of this polymorphism with susceptibility to GCA. Although the differences found in this study are significant only for patients with GCA, PMR patients show a similar trend. However, the study's statistical power for comparisons in allele frequencies and genotype of patients with PMR is low, ranging between 12% and 34%, so the results should be taken with caution and confirmed in studies containing a higher number of patients. Although this study shows a significant association between the analyzed polymorphism and GCA we cannot exclude that other polymorphisms within this gene or its receptor may be associated with susceptibility and/or severity of these diseases. In fact, the polymorphism studied in this work is more clearly associated with asthma and atopy, especially in children. In contrast, the association of other polymorphisms in the gene for IL-13, such as rs20541 (R130Q), rs1800925 (IL13-1055), and rs2243204 have been described in other inflammatory rheumatic disease, which we did not evaluate.26–28

Moreover, SNPs may have different biological effects depending on the cell type upon which the cytokine acts or the inflammatory environment in which the effect develops.29 In this regard, functional studies conducted in the rs20541 (R130Q) SNP have demonstrated functional consequences on transcriptional activity, increased activity or signaling through its protein, or changes in serum protein levels in different cell types.30,31 Therefore, in this study we not only investigated the possible genetic association between the R130Q polymorphism and genetic susceptibility to disease but also its correlation with circulating levels of IL-13. It has been suggested that patients homozygous for the mutation of this IL-13 gene exhibit increased levels of circulating IL-1332. It appears that the presence of the AA genotype is associated with decreased levels of serum IL-13 in both healthy controls and in patients with GCA and Eora. In contrast, in PMR this relationship is the opposite, with a higher level of circulating IL-13 in heterozygous subjects, which corresponds to what is published.32 In any case, this data should be taken with caution because of the low frequency of this genotype and the absence of similar studies.

Serum and synovial fluid IL-13 have been found increased in patients with various types of arthropathies, including RA.32,33 In addition, serum levels of IL-13 have been correlated with the presence of autoantibodies, such as RF.33 In our study, although no significant differences with healthy controls were seen, patients with Eora had a tendency to have higher circulating levels of IL-13, which remained despite treatment. Although we found a significant correlation between levels of circulating IL-13 and autoantibody characteristic of RA, our study clearly differs from the above33 in regards to the study population, Eora only, and therefore on the frequency of these autoantibodies.

The association of the GA genotype with a lower rate of relapse/recurrence, and therefore with a shorter duration and cumulative dose of corticosteroid treatment in patients with GCA is of interest given the current lack of prognostic markers for this disease, but should be confirmed in a larger series of patients.

In summary, the rs20541 (R130Q) polymorphism of the IL13 gene is associated with susceptibility to GCA. The utility of this gene to predict prognosis in GCA should be confirmed in studies with more patients. Further studies are needed regarding Th2 cytokine genes that allow us to clarify this issue.

Protection of human and animal subjects. The authors declare that the procedures followed were in accordance with the regulations of the responsible Clinical Research Ethics Committee and in accordance with those of the World Medical Association and the Helsinki Declaration.

Confidentiality of Data. The authors declare that they have followed the protocols of their work centre on the publication of patient data and that all the patients included in the study have received sufficient information and have given their informed consent in writing to participate in that study.

Right to privacy and informed consent. The authors have obtained the informed consent of the patients and /or subjects mentioned in the article. The author for correspondence is in possession of this document.

This study has been financed with grants from the Fundación Marqués de Valdecilla-IFIMAV and the Fondo de Investigación Sanitaria (PI050475 and PI080098). Lorena Álvarez-Rodríguez was financed with a research grant from the Fundación Marqués de Valdecilla-IFIMAV. Iñaki Beares and Marta González (financed by the Fundación Marqués de Valdecilla-IFIMAV) and Carolina Santa Cruz (financed through a research grant from Schering-Ploug, Spain).

None.