Plasma cytokine profiles in systemic sclerosis: associations with autoantibody subsets and clinical manifestations

Abstract

IntroductionSystemic sclerosis (SSc) (scleroderma) is a complex autoimmune disease that clinically manifests as progressive fibrosis of the skin and internal organs. Anti-centromere antibodies (ACAs), anti-topoisomerase antibodies (ATAs), and anti-RNA polymerase III antibodies (ARAs) are three mutually exclusive SSc-associated autoantibodies that correlate with distinct clinical subsets characterized by extent of cutaneous involvement and pattern of organ involvement. The current report sought to determine whether plasma cytokine profiles differ in SSc patients grouped according to these SSc-associated autoantibody subsets.MethodsPlasma from 444 SSc patients and 216 healthy controls was obtained from the Scleroderma Family Registry and University of Texas Rheumatology Division. Patients were classified according to the presence of ACAs, ATAs, ARAs, or none of the above (antibody-negative). Levels of 13 cytokines were determined using multiplex assays.ResultsCompared with females, healthy control males had higher plasma levels of IL-2 (P = 0.008), IL-5 (P = 0.01) and IL-8 (P = 0.01). In addition, in controls, IL-6 (P = 0.02) and IL-17 (P = 0.01) levels increased with advancing age. After adjusting for age and gender, SSc patients had higher circulating levels of TNFα (P < 0.0001), IL-6 (P < 0.0001), and IFNγ (P = 0.05) and lower IL-17 (P = 0.0005) and IL-23 (P = 0.014). Additional analyses demonstrated that disease duration also influenced these cytokine profiles. IL-6 was elevated in ATA-positive and ARA-positive patients, but not in ACA-positive patients. IL-8 was uniquely increased in the ATA-positive subset while both ATA-positive and ACA-positive subsets had elevated IFNγ and IL-10. IL-5 was only significantly increased in the ACA-positive subset. Lastly, patients with interstitial lung disease had elevated IL-6 and patients with pulmonary hypertension had elevated IL-6 and IL-13.ConclusionsPlasma cytokine profiles differ in SSc patients based on the presence of SSc-associated autoantibodies. Plasma cytokine profiles in SSc patients may also be affected by disease duration and the pattern of internal organ involvement.

Comparison of Serum IL-23 and IL-17 Levels in Patients with Systemic Sclerosis and Healthy Subjects

“…We found no statistically significant difference between serum IL-17 and IL-23 levels in dcSSc and lcSSc groups (p= 0.066 and p= 0.652, respectively), supporting the findings of Murata et al [12], as they could not find any difference between IL-17 levels of dcSSc and lcSSc [12]. In SSc pathogenesis, immune system dysregulation is thought to take part especially during the earlier stages [15]. In our study, no statistically significant difference was detected between disease duration and IL-17 and IL-23 levels in the non-parametric correlation analysis (p= 0.071and p= 0.257, respectively).…”

“…These results are similar to Murata et al, regarding IL17 levels [12]. On the other hand, Gourh et al, showed that as the disease progresses, IL-17 levels decrease, and IL-23 levels increase in the second decade after diagnosis [15]. Kurusawa et al also stated that IL-17 had an important role in SSc pathogenesis [11].…”

“…In contrast to our study, in a study by Radstake et al, along with increased IL-17 levels in the patient group, had also found IL-23 level and IL-23 receptor expression on CD4+ cells to be higher comparing to the control group was shown in a study by Radstake et al, [14]. In contrast, in a study by Gourh et al on 444 SSc and 216 healthy controls, IL17 and IL23 levels were found to be lower while IL-6, IL-13 ve TNF alpha levels were higher in the SSc group [15]. We found no statistically significant difference between serum IL-17 and IL-23 levels in dcSSc and lcSSc groups (p= 0.066 and p= 0.652, respectively), supporting the findings of Murata et al [12], as they could not find any difference between IL-17 levels of dcSSc and lcSSc [12].…”

“…Autoimmunity, and uncontrolled fibroblast activation causing vascular damage and tissue fibrosis are thought to be responsible for the pathogenesis. SSc is generally assumed to be a Th2 cytokine disease [15]. [21].…”

“…In another study by Radstake TR et al, found both higher IL-17 and IL-23 levels in SSc patients [14]. However, IL-17 and IL-23 levels were determined higher in healthy controls compared to SSc patients in some studies [15]. Also, there have been studies addressing the possible relationship between IL-17, IL-23 and organ involvement, disease duration, autoantibody positivity.…”