Abstract
IntroductionRepetitive episodes of ischemia and reperfusion (I/R) are a cardinal feature of the pathogenesis of systemic sclerosis (SSc), which precedes tissue fibrosis. The complement system is a key mediator of tissue damage after I/R, primarily by activation of the lectin pathway. This study investigated whether serum levels and polymorphisms of mannose-binding lectin (MBL) and ficolin-2 (FCN2), two pattern recognition receptors of the lectin pathway, are associated with the predisposition to and clinical features of SSc.MethodsA case-control study was undertaken involving 90 patients with SSc from a single SSc outpatient clinic and 90 age- and sex-matched blood donors. MBL and FCN2 levels and polymorphisms were measured in both groups, and in cases correlated with clinical data.ResultsMBL levels and genotypes were equally distributed in cases and controls while there were some significant differences in FCN2 polymorphisms. Median MBL levels were higher in SSc cases with diffuse disease compared with controls (2.6 versus 1.0 μg/ml, P <0.001).In cases, higher MBL levels were associated with the presence of clinical findings associated with vascular dysfunction and local tissue damage (digital ulcers, calcinosis and pitting). Moreover, MBL levels were associated with fibrotic disease manifestations as evidenced by the presence of diffuse disease (median 2.6 versus 0.8 μg/ml, P = 0.002), the modified Rodnan skin score (r = 0.39, P <0.001), and interstitial lung disease as measured by forced vital capacity (r = −0.33, P = 0.001). Importantly, MBL levels also correlated with the Scleroderma Health Assessment Questionnaire scores (r = 0.33, P = 0.002). The results for FCN2 levels were less striking. Phenotypic MBL results were largely confirmed by analysis of MBL polymorphisms. MBL levels were not associated with the presence of autoantibodies or hypocomplementaemia.ConclusionsOverall, predisposition to SSc was not influenced by the lectin pathway of complement in our matched case-control study. However, our preliminary data suggest that MBL, and to a lesser extent FCN2, may modulate disease manifestations of SSc, particularly in diffuse cutaneous disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-014-0480-6) contains supplementary material, which is available to authorized users.
Highlights
Repetitive episodes of ischemia and reperfusion (I/R) are a cardinal feature of the pathogenesis of systemic sclerosis (SSc), which precedes tissue fibrosis
Repetitive episodes of ischemia and reperfusion (I/R) and persistent oxidative stress are responsible for progressive endothelial dysfunction, activation of vascular mesenchymal cells and leakage of growth factors leading to progressive tissue fibrosis and late organ dysfunction [6]
We investigated the association of serum levels and polymorphisms of two pattern recognition receptors (PRR) of the lectin pathway, mannose-binding lectin (MBL) and ficolin-2, with predisposition to and clinical features of SSc
Summary
Repetitive episodes of ischemia and reperfusion (I/R) are a cardinal feature of the pathogenesis of systemic sclerosis (SSc), which precedes tissue fibrosis. This study investigated whether serum levels and polymorphisms of mannose-binding lectin (MBL) and ficolin-2 (FCN2), two pattern recognition receptors of the lectin pathway, are associated with the predisposition to and clinical features of SSc. Systemic sclerosis (SSc) is a complex autoimmune disease associated with a high morbidity and mortality [1], in which vascular injury, extensive fibrosis, and autoantibodies are the cardinal pathologic features. Repetitive episodes of ischemia and reperfusion (I/R) and persistent oxidative stress are responsible for progressive endothelial dysfunction, activation of vascular mesenchymal cells and leakage of growth factors leading to progressive tissue fibrosis and late organ dysfunction [6]. Apart from the adaptive immune system, components of innate immunity have been implicated in the pathogenesis of SSc including the complement system, an ancient cascade of circulating serum proteins and proteases [8,9]
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