Elsevier

Human Immunology

Volume 68, Issue 7, July 2007, Pages 603-609
Human Immunology

Interleukin-1 gene complex polymorphisms in systemic sclerosis patients with severe restrictive lung physiology

https://doi.org/10.1016/j.humimm.2007.03.005Get rights and content

Summary

Increased concentrations of interleukin-1 (IL-1) were observed in bronchoalveolar lavage fluids from patients with systemic sclerosis (SSc), and their levels were correlated with the patients’ forced vital capacity (FVC). Because IL-1 production is regulated at the genetic level, we hypothesized that IL-1 gene complex single nucleotide polymorphisms (SNPs) might be relevant to the progression of ventilatory restriction in SSc. Two-hundred four Italian SSc patients were genotyped for the following IL-1 gene complex SNPs: IL-1α C–889T, IL-1β C+3962T, IL-1β C-511T, IL-1R Cpst1970T, and IL-1Ra Cmspal11100T, as well as for the following SNPs of cytokines with regulatory functions on IL-1 production: IFNγ AUTR5644T, TNFα A-308G, and IL-10 A-1082G. The SNPs were inserted in a Cox regression model with disease subset, gender, autoantibodies, age at onset of disease, and prior use of immunosoppresants as covariates and the presence of FVC < 55% of predicted values as outcome measure; p values were corrected for the number of pairwise comparisons. Twenty-five patients (12.3%) developed a severe ventilatory restriction after 6.8 ± 6.6 years (mean ± standard deviation) from diagnosis. In our model, the relative risk to develop a severe ventilatory restriction was increased by the antitopoisomerase I antibody (p = 0.01; HR = 14.67, CI95 = 1.87–114.92), the dcSSc subset (p = 0.007; HR = 3.14, CI95 = 1.36-7.21) and the IL-1β C+3962T SNP (p = 0.003 TT vs CC; HR = 6.61, CI95 = 2.28–19.15). The IL-1β C+3962T SNP is associated with the presence of severe restrictive lung physiology in Italian SSc patients.

Introduction

Interstitial pulmonary involvement with restrictive lung physiology is a common complication of systemic sclerosis (SSc) and it currently constitutes the leading cause of death related to scleroderma [1]. The pathogenesis of interstitial lung disease in SSc is currently unknown; while some evidence indicates that patients with lung inflammation are at increased risk for rapid progression of fibrosis [2], in animal models of bleomycin-induced alveolitis, lung inflammation is not always accompanied by the appraisal of fibrosis [3] and patients otherwise similar as far as therapeutical and baseline lung characteristics are concerned can progress at different rates toward ventilatory restriction [4]. Some authors thus hypothesized that the pathogenesis of interstitial lung disease secondary to SSc might be more complex, involving several factors and profibrotic cytokines subtly interlaced in a pathological network [5]. Individual predisposition and other currently unknown factors may then favor the activation or the deactivation of some key factors of the network, promoting or dampening the progression of interstitial lung disease.

Interleukin-1 (IL-1) is a proinflammatory cytokine with profibrotic properties that was implicated in the pathogenesis of interstitial lung diseases, promoting the deposition of collagen and tissue remodeling [6], [7]. The importance of IL-1 in scleroderma was also suggested by the demonstration that IL-1 induces the fibrogenic phenotypes of SSc fibroblasts, favoring their proliferation and collagen synthesis [8], and by the finding that IL-1 levels in bronchoalveolar lavage fluids (BALF) from SSc patients are increased, correlating with ventilatory restriction [9]. The interleukin-1 family is composed of several members: IL-1α and IL-1β are two different but related agonist polypeptide cytokines, which act by binding to one of the two IL-1 receptors (IL-1R) and whose action is counteracted by their natural antagonist, the IL-1 receptor antagonist (IL-1Ra) [10]. All members of IL-1 gene complex are located on chromosome 2q13–21 [11]; several polymorphisms were identified in this region, some of which can modify the function or the amount of IL-1 [12], [13], [14], [15] and are claimed to be relevant under many pathological conditions, including chronic inflammatory and autoimmune diseases [16], [17], graft-versus-host disease [18], pneumoconiosis, and other interstitial lung diseases [7], [19].

The current retrospective survival study was conducted to verify whether IL-1 cluster gene polymorphisms are relevant to the development of a severe restrictive lung physiology in a population of Italian SSc patients. The single nucleotide polymorphisms (SNPs) of the IL-1 cluster gene analyzed were those indicated as candidates for the cytokine polymorphism component at the 13th International Histocompatibility Workshop and Congress [20]. These SNPs are thought to be important to IL-1, IL-R, or IL-1Ra function and/or production, because they are located in the promoter or exon regions of the IL-1 family genes.

Section snippets

Patients and controls

Two-hundred four unrelated Italian SSc patients referred to our outpatient clinic, who provided written consent to have their DNA collected as well as their clinical data recorded and utilized for medical researches, were included. All patients fulfilled the classification criteria proposed by the American College of Rheumatology [21] and were categorized as having the limited (lcSSc) or the diffuse cutaneous (dcSSc) form of the disease according to LeRoy et al. [22]. Disease onset was

Genotyping

The distribution of the different genotypes of the selected SNPs in Italian SSc patients and healthy controls is shown in Table 1. In both populations the distribution of genotypes was consistent with the Hardy–Weinberg equilibrium and with the frequencies previously published in the Italian population [32]. No significant differences were observed between SSc patients and controls (pc = not significant for all SNPs), even though upon exploratory analysis a decreased frequency of the IL-10

Discussion

In the present study we illustrated an association between severe ventilatory restriction and the IL-1β +3962 TT genotype in scleroderma patients. Multivariate analysis by a Cox regression model (Table 3) demonstrated that only this genetic variant, among selected SNPs of the IL-1 complex gene, was relevant to the onset of severe restrictive lung physiology, independent of other well-known clinical and laboratory markers of interstitial lung involvement and functionally relevant SNPs of

Acknowledgments

The work was supported by a grant from the Fondazione CARIPLO (CAssa di RIsparmio delle Province LOmbarde) and by a grant from GILS, Gruppo Italiano per la Lotta alla Sclerodermia.

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