Implication of plasma gelsolin in systemic lupus erythematosus patients

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder with more than one organ involvement. Kidney is the foremost commonly affected one. Gelsolin is a protein that induces depolymerization of actin filaments thus preventing downstream stimulation of inflammatory reactions. The aim of this work was to detect the relation of plasma gelsolin to SLE disease activity and severity indices in order to find out if plasma gelsolin could be used as a biomarker of the disease. This study was conducted on 50 SLE female patients and 30 matched control. SLE disease activity Index (SLEDAI) and SLE damage index (SDI) were assessed. All lupus nephritis (LN) patients were subjected to an ultrasound-guided kidney biopsy. Plasma gelsolin level was measured. The mean age of the patients was 38.5 ± 6.3 years (26–51 years) with median disease duration of 5 (3–9.3) years. Eighteen patients had LN, 11 had cardiac manifestations and 12 had chest manifestations. The mean SLEDAI was 13.1 ± 4.5 (4–22) and the median SDI was 2 (1–3). Plasma gelsolin level was significantly lower in SLE patients (74.9 mg/l; 57.5–98.8 mg/l) compared to control (801.5 mg/l; 225–1008.3 mg/l) (p < 0.001). There were significant negative correlations of gelsolin levels with anti-ds DNA (r = − 0.63, p < 0.001), SLEDAI (r = − 0.79, p < 0.001), and SDI (r = − 0.74, p = 0.001). Plasma gelsolin level was significantly lower in SLE patients with high/very high activity grades compared to those with low and moderate (p = 0.007 and p < 0.001 respectively). A gelsolin level of ≤ 78.95 mg/l significantly predicted renal affection (p < 0.001), with a sensitivity of 100%, specificity 71.9%, and a positive predictive value 66.7%. A decreased gelsolin level is associated with disease activity in SLE patients. Plasma gelsolin was well related to disease activity and severity with a high predictive value for renal affection comparable to anti-ds DNA titre. Plasma gelsolin is a potentially important predictive biomarker for SLE and LN.


Background
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder with more than one organ involvement, when becomes hyperactive forming antibodies attacking ordinary organs like the skin, kidneys, brain, joints, heart, lungs, and blood [1,2]. Renal involvement is common in SLE with the kidney being the foremost commonly affected organ, and it is a significant cause of morbidity and mortality [3]. Lupus nephritis (LN) evolves whenever autoantibodies target the kidneys, which filter waste. This leads to renal inflammation which may result in blood or protein in the urine, elevated blood pressure, impaired kidney function, or finally kidney failure [4][5][6]. A lot of research is focusing at the discovery of the latest biomarkers for the early detection and tracking of SLE and LN [7].
Gelsolin is a multifunctional protein that has actin filament severing, capping, and nucleating functions [8][9][10]. This protein has two different isoforms: a cytoplasmic and a circulating isoform. Gelsolin induces the depolymerization of actin filaments; this would prevent the

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Egyptian Rheumatology and Rehabilitation downstream stimulation of inflammatory reactions by these actin filaments [11,12]. In conditions of acute damage or inflammation, gelsolin levels tend to decrease [13,14]. Gelsolin is involved in the immune response and considered an anti-inflammatory modulator. Gelsolin depletion is additionally linked to the release of inflammatory mediators [15,16].

Methods
Plasma samples and clinical data were collected from 50 female SLE patients attending the Rheumatology outpatient clinic and department inpatient of Benha University Hospitals diagnosed according to the European League against Rheumatism (EULAR)/American College of Rheumatology (ACR) SLE classification criteria [17]. Pregnant patients and cases with other immunological disorders or liver diseases were excluded. Thirty apparently healthy individuals represented the control group with a comparable age, sex, and social level.
All LN patients (n = 18) were subjected to an ultrasound-guided kidney biopsy and samples evaluated according to the international society of nephrology/ renal pathology society (ISN/RPS) classification [20].
The plasma gelsolin level was measured by a sandwich ELISA kit (Cat n o : E1233HU, Shanghai Crystal Day Biotech Co., Ltd., China) according to manufacturing instructions.
Statistical analysis: data were analyzed using the statistical package for the social sciences (SPSS) software, version 22.0 (IBM, Armonk, NY, USA). Categorical data were presented as numbers and percentages, mean ± SD (range) or median with interquartile range (IQR). Chisquare (χ2) and Fisher's exact tests were used for comparisons. Linear association between variables was assessed by Spearman's correlation coefficients. Receiver operating characteristics (ROC) curves were constructed to assess the ability of gelsolin to predict the activity and severity of SLE. Univariable and multivariable logistic regression analysis was run to detect the predictors of renal affection. A p value < 0.05 was considered significant.
The median plasma gelsolin level was significantly lower in patients with musculoskeletal manifestations (69.4 mg/l; 46.5-83.2 mg/l) than in cases without (94 mg/l; 70.1-482.1 mg/l) (p = 0.003). Plasma gelsolin values were comparable between those with and without skin, cardiac, or pulmonary manifestations (p = 0.07, p = 0.79, and p = 0.36 respectively). The median plasma gelsolin level was significantly lower in patients with high and very high activity compared to those with a low/ moderate grades (p = 0.007 and p < 0.001 respectively).
Plasma gelsolin level (≤ 81.1 mg/l) had a significant predictive value in the differentiation of high/very high disease activity grade from low/moderate grades (p < 0.001) with sensitivity 78.1% and specificity 77.8%. At a  Fig. 3).

Discussion
SLE is a chronic autoimmune inflammatory disease associated with various immunological events, characterized by a wide range of clinical manifestations with unpredictable flares and remissions that usually end by permanent injury [21]. In Egypt, SLE had a wide variety of clinical and immunological manifestations comparable to other nations and disparity across the country [22]. Assessment of renal function in SLE patients is imperative because early detection and management of renal involvement can essentially improve renal outcome [23]. The discovery, development, and validation of novel biomarkers which can expect clinical outcomes is a significant mission, particularly in SLE patients who develop heterogeneous clinical manifestations and must begin aggressive therapies [24]. Plasma gelsolin is one of the most important actinbinding proteins in the actin-clearing system that plays important roles in body protection and internal environment balance. Plasma gelsolin has been pronounced to play vital roles in serious situations, such as acute inflammation, trauma, burns, and sepsis [25]. The depletion of gelsolin during the rapid increase of globular and filamentous actin in the clearance cycle is a possible mechanism for the reduction of plasma gelsolin levels in severe diseases [26]. In addition, decreased plasma gelsolin  levels in the circulation have been reported in chronic inflammatory diseases [27]. In this study, the plasma gelsolin was significantly lower in patients compared to control and this result coincided with the study of Parra et al. [28] and Mitto et al. [29]. In addition, Hu et al. [26] demonstrated that plasma gelsolin levels in patients with SLE and RA were significantly decreased compared to controls. This was also observed in the study of Osborn et al. [30] who observed that the mean circulating plasma gelsolin levels were significantly lower in patients with RA. Esawy et al. [30] demonstrated that plasma gelsolin levels were decreased in psoriatic arthritis (PsA) patients compared to the controls, while Haung et al. [31] found that the expression level of gelsolin in both serum and whole blood cells was decreased in primary Sjogren's syndrome patients.
In this work, the median plasma gelsolin level was significantly lower in patients with renal and with musculoskeletal manifestations than in those without. There were no significant differences according to the presence and absence of skin, cardiac, or pulmonary manifestations. Also, there was an insignificant relation of plasma gelsolin levels with the patients' ages, disease duration, and other laboratory parameters.
There were significant negative correlations of plasma gelsolin level with anti-dsDNA antibodies titers, SLEDAI  and SDI. In agreement, Parra et al. [28] demonstrated that plasma gelsolin decreased in SLE patients when they developed a clinical flare. Hu et al. [26], showed a significant negative correlation between plasma gelsolin levels and SLEDAI. Meanwhile, they found no correlation between plasma gelsolin levels and RA disease activity. Also, Osborn et al. [32] documented the lack of a correlation between plasma gelsolin levels and disease activity in RA. This suggested the potential clinical application of plasma gelsolin in SLE diagnosis and disease activity evaluation. Esawy et al. [30] notified that a significant negative correlation between plasma gelsolin and PsA activity was detected. The median of plasma gelsolin level was significantly lower in SLE patients with a high/ very high activity compared to those with low /moderate grade. At a level of ≤ 81.1 mg/l, there was a significant predictive value differentiating high/very high disease activity from low/moderate. In the present study, there is a significant negative correlation between plasma gelsolin level and urinary protein/24 h in SLE patients. The median plasma gelsolin level was significantly lower in LN patients with class II, III, and IV in comparison to non-renal patients. Meanwhile, differences of plasma gelsolin levels among these histopathological classes were non-significant. The optimal cut-off point of plasma gelsolin in this study associated with the SLE disease was ≤ 152.6 mg/l with a validated sensitivity of 88% and 90% specificity. Dimitrijevic et al. [33] demonstrated that plasma gelsolin deposits were detected and varied in samples with significant association between these deposits and LN morphologic classifications indicating their potential biological marker value in LN severity and glomerular injury.
In the current work, it was found that plasma gelsolin and anti-ds DNA antibodies were good predictors of renal affection. Plasma gelsolin level (≤ 78.95 mg/l) significantly predicted renal affection with 100% sensitivity and 71.9% specificity, while anti-dsDNA titer (≥ 54 IU/ml) would predict with 88.9% sensitivity and 59.4% specificity. Misra et al. [34] declared that plasma gelsolin may be better used as a severity biomarker for the evaluation of glomerulonephritis than anti-dsDNA. The general existence of plasma gelsolin deposits in patients with LN morphologic classification I to V indicated that plasma gelsolin should be better used as a biomarker for LN disease activity rather than a specific diagnosis index. All these pieces of evidence indicate that plasma gelsolin might be used as an inflammatory marker.
Among the study limitations is the lack of full information about the anti-phospholipid status and medications received by the patients. Further larger-scale longitudinal studies are warranted to explain role of gelsolin in SLE pathogenesis and treatment outcomes. Additional work can consider gelsolin deposits in renal tissue in parallel with plasma. More studies can focus on the reversal of plasma gelsolin reduction which may be a new therapeutic target for SLE patients.

Conclusion
A decreased plasma gelsolin level was associated with clinical disease activity in SLE patients. It was well related to SLE disease activity and severity. Plasma gelsolin had a high sensitivity and specificity associated with SLE disease as well as a high predictive value for renal affection. Gelsolin level was comparable to antids DNA titre as predictors of renal affection. Plasma gelsolin might be used as a biological marker for SLE and predictive biological marker for lupus nephritis.