局限性硬皮病患者血清中可溶性白介素-2受体、肿瘤坏死因子-α及T淋巴细胞的表达

目的观察局限性硬皮病患者血清对T淋巴细胞增殖的影响和患者血清中可溶性白介素-2受体的表达变化。方法应用免疫学方法对39例局限性硬皮病患者血清中的sIL-2R、肿瘤坏死因子(TNF)-α表达和淋巴细胞增殖率进行检测,并与对照组比较。结果局限性硬皮病患者血清可明显降低T淋巴细胞增殖率;局限性硬皮病患者外周血中sIL-2R、TNF-α含量增高,其中活动期增高更加明显;差异均有统计学意义(P<0.05)。结论 T淋巴细胞增殖率的降低和血清中sIL-2R、TNF-α水平表达异常,这些免疫相关细胞和细胞因子可能参与了局限性硬皮病的发生和发展。     

Elevated serum BAFF levels in patients with localized scleroderma in contrast to other organ-specific autoimmune diseases

Serum levels of B-cell activating factor belonging to the tumor necrosis factor family (BAFF), a potent B-cell survival factor, are elevated in patients with systemic autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis and systemic sclerosis (SSc). The objective of this study was to determine serum BAFF levels and relate the results to the clinical features in patients with organ-specific autoimmune diseases of the skin, such as localized scleroderma and autoimmune bullous diseases. Serum BAFF levels were examined by enzyme-linked immunosorbent assay in 44 patients with localized scleroderma, 20 with pemphigus vulgaris/pemphigus foliaceus, 20 with bullous pemphigoid and 30 healthy controls. Twenty patients with SSc and 20 with SLE were also examined as disease controls. Serum BAFF levels were elevated in localized scleroderma patients compared with healthy controls. Concerning localized scleroderma subgroups, patients with generalized morphea, the severest form of localized scleroderma, had higher serum BAFF levels than linear scleroderma or morphea patients. The BAFF levels of generalized morphea were comparable with those of SSc or SLE. Furthermore, serum BAFF levels correlated positively with antihistone antibody levels and the severity of skin lesion as well as the number of skin lesions. By contrast, serum BAFF levels were not significantly elevated in patients with pemphigus or pemphigoid. These results suggest that BAFF may be contributing to autoimmunity and disease development in localized scleroderma.     

Demonstration of interleukin-2, interleukin-4 and interleukin-6 in sera from patients with localized scleroderma

Localized scleroderma has been reported to be accompanied by immunological abnormalities related to B cells, but little is known about T-cell activation in this disease. In this study, serum levels of interleukin-2 (IL-2), interleukin-4 (IL-4) and interleukin-6 (IL-6), which are known to be released by activated T cells, were determined using a sensitive enzyme-linked immunosorbent assay in 48 patients with localized scleroderma and 20 with systemic sclerosis, and in 20 healthy control subjects. IL-2, IL-4 and IL-6 were detected in serum from patients with localized scleroderma but not in that from healthy controls. The presence of antihistone antibodies correlated significantly with elevated IL-4 and IL-6 levels. Decreased serum levels of IL-2, IL-4 and IL-6 paralleled improvement in cutaneous sclerosis. Frequent detection of these lymphokines in serum from patients with localized scleroderma reflects T-cell activation in this disorder.     

Alopecia areata and interleukin-2 receptor.

Interleukin-2 (IL-2) is a lymphokine produced by activated T cells and its receptor (IL-2R) is expressed on T cells; one of the IL-2R components can be measured as a soluble serum protein (sIL-2R). Levels of sIL-2R were measured as a sign of T cell activation in serum of 12 patients suffering from alopecia areata (totalis or universalis) and in a group of healthy control subjects. An enzyme-linked immunosorbent assay was used to determine the levels of sIL-2R in blood samples drawn during both the active and resting phase of the disease. In patients with alopecia areata in active phase the sIL-2R concentrations were significantly higher than in stable phase and in controls. The biologic role of sIL-2R is still unknown, but one could speculate that T lymphocyte activation with subsequent secretion of IL-2 and IL-2R expression may contribute to the immune inflammatory mechanism of alopecia areata.     

Serum levels of tenascin‐C in collagen diseases

Tenascins are a family of large multimetric extracellular matrix (ECM) proteins. Among them, large molecular weight variant tenascin‐C is known to be specifically expressed in pathological conditions. However, no link between tenascin‐C and collagen diseases has been established. The aim of our study was to determine the serum tenascin‐C levels in patients with various collagen diseases, and to evaluate the possibility that serum levels of tenascin‐C can be a useful marker for collagen diseases, correlating with the pathogenesis. Serum tenascin‐C levels of 33 patients with scleroderma (SSc), 10 patients with scleroderma spectrum disorder (SSD), 15 patients with localized scleroderma (LSc), 12 patients with dermatomyositis (DM), 10 patients with systemic lupus erythematosus (SLE) and 15 healthy controls were measured with specific enzyme‐linked immunosorbent assays. Serum tenascin‐C levels were significantly elevated in patients with SSc, SSD and LSc than in healthy controls. Significantly higher total skin thickness score or higher incidence of pitting scars/ulcers and diffuse pigmentation were observed in SSc patients with elevated tenascin‐C levels than in those with normal levels. Our study suggests that serum tenascin‐C levels are increased in fibrotic conditions, and that tenascin‐C contributes to the pathogenesis of vascular damage as well as fibrosis in SSc patients. Clarifying the role of tenascin‐C in the pathogenesis of collagen diseases may lead to a new therapeutic approach.     

Serum levels of manganese superoxide dismutase in patients with localized scleroderma

The objective was to determine the serum levels of manganese superoxide dismutase (Mn SOD) in patients with localized scleroderma and investigate their clinical significance in this disease. Serum samples from 15 patients with localized scleroderma and 20 healthy volunteers were examined by a specific enzyme-linked immunosorbent assay. Serum levels of Mn SOD were significantly higher in patients with generalized morphea than those in healthy individuals. And the patients with elevated serum Mn SOD levels had significantly larger number of sclerotic lesions and significantly higher serum levels of soluble interleukin-2 receptor than those without it. These results suggested that the serum levels of this enzyme may be a serological marker for the disease activity and the extent of skin involvement in this disease.     

Elevated soluble CD23 levels in the sera from patients with localized scleroderma

Soluble CD23 (sCD23) is closely related to B-cell activation and elevated serum levels of sCD23 have been reported in several autoimmune disorders. This study investigated the serum levels of sCD23 and determined the correlation of sCD23 with other immunologic abnormalities and clinical features in localized scleroderma. We examined 49 serum samples by an enzyme-linked immunosorbent assay in the following three subgroups: 15 patients with generalized morphoea, 22 with linear scleroderma, and 12 with morphoea. The serum levels of sCD23 were significantly elevated in patients with localized scleroderma, compared with those in healthy individuals. Of the three subgroups of localized scleroderma, patients with generalized morphoea had the highest levels of serum sCD23. The frequency of IgM antihistone antibody (AHA) and IgM rheumatoid factor (RF), the number of linear lesions, and the frequency of muscle involvement were significantly higher in patients with elevated sCD23 levels than in those with normal levels of sCD23. A significant correlation between the serum sCD23 level and the number of involved areas of the body was observed. Our data suggest that the activation of virgin B cells, which is reflected by elevated sCD23 levels, is closely associated with the production of IgM autoantibodies in localized scleroderma and furthermore that the serum levels of sCD23 are a new serological indicator of the severity of localized scleroderma.     

Serum levels of anti‐Fcγ receptor IIB/C antibodies are increased in patients with systemic sclerosis

Systemic sclerosis (SSc) is a systemic autoimmune disorder that results in fibrosis of the skin and multiple internal organs. Although the precise mechanism is unknown, it appears to result from the overproduction of extracellular matrix proteins and aberrant immune activations. Receptors for the Fc region of immunoglobulin (Ig)G (FcγR) are members of the Ig superfamily that modulate both activation and inhibition of immune responses. FcγRIIB is the sole inhibitory member, which has an intrinsic cytoplasmic immunoreceptor tyrosine‐based inhibitory motif. The present study was undertaken to investigate the circulating concentrations of anti‐FcγRIIB/C antibodies (Ab) in patients with SSc. Serum levels of anti‐FcγRIIB/C Ab were significantly increased in patients with SSc compared to those in controls and in patients with localized scleroderma. Serum levels of anti‐FcγRIIB/C Ab in patients with limited cutaneous SSc were similar to those in patients with diffuse cutaneous SSc. Among SSc patients, serum levels of anti‐FcγRIIB/C Ab were increased in those with nail‐fold bleeding and decreased in those with diffuse pigmentation and calcinosis. These findings support the notion that increased serum anti‐FcγRIIB/C Ab levels are involved in aberrant immune responses in SSc.     

Clinical significance of serum soluble Tie1 levels in patients with systemic sclerosis

Tie1 is an endothelial cell-specific tyrosine kinase receptor, which maintains vascular integrity and regulates angiogenesis via modulating angiopoietin/Tie2 signaling. Since the altered angiogenesis is closely related to the developmental process of systemic sclerosis (SSc), we herein investigated the clinical significance of serum soluble Tie1 (sTie1) levels and the expression levels of Tie1 in dermal microvascular endothelial cells (DMECs) in patients with SSc. Although serum sTie1 levels were comparable among total SSc, diffuse cutaneous SSc (dcSSc), limited cutaneous SSc (lcSSc), and healthy controls, SSc patients with decreased serum sTie1 levels had significantly shorter disease duration than those with serum sTie1 levels not decreased. In SSc patients with disease duration of >6 years, the prevalence of clinical symptoms associated with proliferative vasculopathy, such as digital ulcers, scleroderma renal crisis, and elevated right ventricular systolic pressure, was significantly higher in patients with decreased serum sTie1 levels than in those with serum sTie1 levels not decreased. In immunohistochemistry, Tie1 expression was reduced in DMECs of SSc patients with disease duration of <3 years compared with those of healthy controls. Collectively, in SSc patients with short disease duration, decreased serum sTie1 levels may reflect the down-regulation of Tie1 in DMECs. The decrease in serum sTie1 levels may serve as a marker of proliferative vasculopathy in SSc with disease duration of >6 years.     

Levels of soluble interleukin-2 receptors correlate with the severity of atopic dermatitis

Levels of soluble interleukin-2 receptors (sIL-2R) were measured as a marker of lymphocyte activation in serum of 37 patients with atopic dermatitis (AD) and of 16 patients with psoriasis vulgaris (PV), all individuals being hospitalized in the Zurich High Mountain Clinic of Davos-Clavadel (altitude 1,600 m above sea level). Measurements were performed at admission and at discharge. The PV patients served as a control group. As a further control, 20 AD patients from the Department of Dermatology in Zurich (altitude 400 m) were also evaluated. The serum sIL-2R concentration in AD patients at admission was significantly elevated in comparison with PV patients and was highly correlated with the severity of the cutaneous involvement. Comparing the 'extrinsic' and 'intrinsic' types of AD, no significant differences of sIL-2R levels were found. The sIL-2R concentrations dropped at discharge. These results suggest that the measurement of the sIL-2R level could be a marker of disease activity.     

Soluble CD4 and CD8 in serum from patients with localized scleroderma

Localized scleroderma has been shown to be accompanied by various immunologic abnormalities. To obtain functional information on activated CD4+ or CD8+ T cells, we studied the levels of soluble CD4 (sCD4) and soluble CD8 (sCD8) in serum from patients with localized scleroderma. Serum samples were examined by enzyme-linked immunosorbent assay. The samples were obtained from 49 patients in the following three subgroups: 15 patients with generalized morphea, 22 with linear scleroderma, and 12 with morphea. The levels of sCD4 and sCD8 were significantly elevated in patients with generalized morphea. Furthermore, these patients showed significantly higher levels of sCD4 than those with systemic sclerosis (SSc). The frequency of positivity for IgG anti-single-stranded DNA (ssDNA) antibody was significantly higher in localized scleroderma patients with elevated sCD4 levels than in patients with normal sCD4 levels. The frequency of positivity for antinuclear antibodies, IgM antihistone antibodies, IgG anti-ssDNA antibody and rheumatoid factor, and elevated sCD23 levels were significantly higher in localized scleroderma patients with elevated sCD8 levels than in patients with normal sCD8 levels. Our findings suggest that both CD4+ and CD8+ T cells are activated in vivo in generalized morphea and that the immunologic events in generalized morphea are different from those in SSc.     

Circulating miR-142-3p levels in patients with systemic sclerosis

Background. Recently, increased evidence has shown that serum micro (mi)RNA levels are a useful biomarker for the diagnosis, prognosis and therapeutic value of various diseases. However, serum miRNA has not been investigated in patients with systemic sclerosis (SSc), to our knowledge. Aim. To investigate the possibility that serum levels of Homo sapiens miR‐142 stem‐loop (hsa‐miR‐142‐3p), one of the miRNAs regulating the expression of integrin αV, could be a specific disease marker for SSc. Methods. Serum samples were obtained from 61 patients with SSc and 20 healthy controls. Patients with systemic lupus erythematosus (SLE), dermatomyositis (DM) and scleroderma spectrum disorder (SSD), who did not fulfil American College of Rheumatology criteria for SSc but might develop SSc in the future, were included as disease controls in this study. miRNAs were purified from serum, and miR‐142‐3p levels were measured with a quantitative real‐time PCR assay. Results. Serum miR‐142‐3p levels in patients with SSc were significantly higher than in patients with SSD, SLE or DM, and healthy control groups. Patients with increased miR‐142‐3p levels tended to have a short sublingual frenulum. Conclusions. Our data indicate that serum levels of miR‐142‐3p may be elevated specifically in patients with SSc, correlating with the severity of this disease, and may be useful diagnostic markers for the presence of SSc and for the differentiation of SSc from SSD.     

Serum apelin levels: clinical association with vascular involvements in patients with systemic sclerosis

Background Apelin is a bioactive peptide exerting its pro‐angiogenic and pro‐fibrotic effects in a context‐dependent manner through the activation of its receptor APJ, which is ubiquitously expressed on the surface of various cell types. The activation of apelin/APJ signalling appears to be involved in the pathological process of fibrotic disorders, including liver cirrhosis. Objective As an initial step to clarify the role of apelin/APJ signalling in the pathogenesis of systemic sclerosis (SSc), we investigated serum apelin levels and their clinical association in patients with SSc. Methods Serum apelin levels were determined by a specific enzyme‐linked immunosorbent assay in 56 SSc patients and 18 healthy controls. Results Serum apelin levels were comparable among three groups, including diffuse cutaneous SSc, limited cutaneous SSc and control subjects (1.77 ± 1.48, 1.63 ± 1.51 and 1.61 ± 0.44 ng/mL, respectively). When we classified SSc patients into three groups according to disease duration, serum apelin levels were elevated in early SSc (<3 years) compared with mid‐stage SSc (3–10 years) (1.74 ± 1.26 vs. 1.02 ± 0.52 ng/mL, P < 0.05). Importantly, in late stage SSc (>10 years), the prevalence of severe vascular involvements, including intractable skin ulcers, scleroderma renal crisis and pulmonary arterial hypertension, was significantly higher in patients with elevated serum apelin levels than in those without (100% vs. 20%, P < 0.05). Conclusion Apelin may be associated with altered and activated angiogenesis prior to fibrotic responses in early SSc and with the development of proliferative vasculopathy in late stage SSc.     

Serum levels of tumor necrosis factor and interleukin-13 are elevated in patients with localized scleroderma

BACKGROUND: The enhanced production of some cytokines may be related to the pathogenesis of localized scleroderma (LSc). OBJECTIVE: To determine whether serum levels of tumor necrosis factor (TNF) and interleukin (IL)-13 are elevated, and whether they correlated with clinical or serological features in patients with LSc. METHODS: Serum levels of TNF and IL-13 were examined by ELISA in 45 patients with LSc and in 20 healthy controls. RESULTS: The frequency of serum TNF detection was significantly higher in patients with LSc (24%) compared with that in healthy controls (0%). The frequency of serum IL-13 detection was also significantly higher in patients with LSc (29%) compared with that in controls (0%). In patients with LSc, elevated TNF levels significantly correlated with the presence of IgM antihistone antibodies, anti-single-stranded DNA antibodies, elevated serum IL-6 levels, the number of linear lesions, and muscle involvement. Elevated IL-13 levels were significantly associated with the number of plaque lesions and the total number of lesions. CONCLUSIONS: These results suggest that TNF and IL-13 may be associated with the development of LSc.     

Serum concentration of the soluble interleukin-2 receptor in vitiligo patients

Serum levels of sIL-2R can be used to monitor in vivo immune activation and its elevation have been shown to be correlated with T cell mediated immune disease such as atopic dermatitis, psoriasis, lymphoma and systemic sclerosis. Vitiligo is the disease of depigmentation caused by destruction of melanocytes, and there have been extensive studies on the immune pathogenesis. If the pathogenesis of vitiligo is correlated with the activation of T lymphocytes, the change of IL-2R will be detected compared with that of normal control. Therefore we sought the change in sIL-2R to determine whether T lymphocytes from patients with vitiligo show abnormal biological behavior. The quantitation of sIL-2R was done by sandwich enzyme-linked immunosorbent assay (ELISA) from the sera of 79 vitiligo patients and 40 normal controls. The results were summarized as following. The sIL-2R level in vitiligo patients (671.91 +/- 368.59 U/ml) was significantly increased compared with that of controls (370.8 +/- 71.8 U/ml; P < 0.005). According to clinical types, sIL-2R level in focal type of vitiligo patients was significantly higher than those in other types (segmental or generalized; P < 0.05). The sIL-2R level in patients less than 1 year duration was significantly higher than in patients more than 1 year duration (P < 0.05). The sIL-2R levels were not significantly different between active and inactive group. There was no significant differences among sIL-2R levels according to sex or age of onset. Our study showed that sIL-2R level was higher in vitiligo patients compared with that of normal controls, so the activation of T lymphocytes would be an important component in the pathogenesis of vitiligo. The higher sIL-2R levels in recent onset group would suggest that sIL-2R level might be an acute immunologic marker in vitiligo patients.     

Relationship between Levels of Soluble Interleukin-2 Receptors and the Types and Activity of Vitiligo

Levels of serum-soluble interleukin-2 receptors (serum sIL-2R) are thought to indicate the activation of immunocompetent cells, mainly lymphocytes. Elevated levels of serum sIL-2R have been observed in various infectious and autoimmune diseases and also after organ transplantation. It has been hypothesized that autoimmune mechanisms are involved in the pathogenesis of vitiligo. Therefore, we studied serum sIL-2R levels in relation to disease types and activity of vitiligo. We used sera separated from venous blood samples from 12 patients with dermatomally distributed type B vitiligo, 17 patients with non-dermatomally distributed type A vitiligo during the active stage, 9 patients with type A vitiligo during the inactive stage, and 12 normal control subjects. Serum sIL-2R levels were similar in type B vitiligo patients and the controls but were significantly elevated in patients with active type A vitiligo compared with controls and inactive type A vitiligo patients. It is suggested that the immune system is activated in patients with type A vitiligo during the active stage and that autoimmune mechanisms may play a role only in type A vitiligo.     

Serum levels of soluble IL-2 receptor, soluble ICAM-1, TNF-alpha, interleukin-4 and interleukin-6 in scleroderma

Background A variety of immunological markers have been reported to be elevated in patients with systemic scleroderma (SSc). Objective The aim of this study was to determine which of the following parameters: soluble IL-2 receptor (sIL-2r). soluble ICAM-1 (sICAM-1), tumour necrosis factor (TNF-alpha), interleukin-6 (IL-6) and interleukin-4 (IL-4) reflect the clinical stage of the disease and how they correlate with each other. Methods In 31 scleroderma patients the serum levels of these markers were measured in the same blood sample using ELISA test kits. The results were correlated with clinical findings such as extent of skin disease, inflammatory disease activity and involvement of internal organs. Results SIL-2r, slCAM-1 and TNF-alpha showed significant differences in subgroups of SSc patients in contrast to IL-4and IL-6, The five parameters did not correlate with each other. Conclusion sIL-2r, sICAM-1 and TNF-alpha showed differences in subgroups of scleroderma and therefore they may be useful in further studies as markers of disease activity.     

The Levels of Plasma Interleukin-2 and Soluble Interleukin-2R in Behçet's Disease: A Marker of Disease Activity

It is well known that patients with Behçet's disease (BD) have an activated immune system, probably mediated by soluble factors in the circulation. The purpose of our study was to examine the roles of plasma interleukin-2 (IL-2) and soluble interleukin-2 receptor (sIL-2R) in the pathogenesis of BD. Thirty-two patients with BD diagnosed according to the Criteria of the International Study Group for Behçet's Disease and 20 age-matched healthy persons were included in the study. The plasma levels of cytokines were measured by ELISA. Plasma levels of IL-2 and sIL-2R were increased in BD over controls, but the differences were not statistically significant. sIL-2R levels in patients with active disease were significantly higher than in either patients with inactive disease (p<0.001) or the control group (p<0.05). Our results suggest that the level of sIL-2R in BD seems to be related to disease activity.     

Adiponectin expression is decreased in the involved skin and sera of diffuse cutaneous scleroderma patients

In this study, we determined the adiponectin expression in the serum and lesional skin of patients with scleroderma (SSc). Serum adiponectin concentrations were measured in 32 patients with SSc, 10 patients with SLE, 12 patients with dermatomyositis patients and 13 healthy subjects with specific enzyme-linked immunosorbent assays. Adiponectin mRNA was determined in skin tissues of five patients with diffuse cutaneous SSc (dcSSc), seven patients with limited cutaneous SSc (lcSSc) and seven healthy subjects with real-time polymerase chain reaction. There was a significant reduction in serum adiponectin levels in patients with dcSSc. SSc patients with decreased serum adiponectin levels had higher total skin thickness score and higher incidence of pulmonary fibrosis. Adiponectin mRNA levels in skin tissues from patients with dcSSc were also reduced. Serum adiponectin levels may be a useful biomarker for fibrotic condition in patients with SSc. Clarifying the role of adiponectin in collagen diseases may lead to further understanding of the pathogenesis and new therapeutic approach.     

Serum interleukin‐34 levels in patients with systemic sclerosis: Clinical association with interstitial lung disease

Interleukin (IL)‐34 is a hematopoietic cytokine promoting proliferation and differentiation of macrophages. Because abnormal activation of macrophages is involved in the development of systemic sclerosis (SSc), we investigated serum IL‐34 levels in patients with SSc. Serum IL‐34 levels were significantly increased in diffuse cutaneous SSc compared with limited cutaneous SSc and healthy controls, while there were no significant differences between limited cutaneous SSc and healthy controls. In addition, SSc patients with increased serum IL‐34 levels more often had interstitial lung disease (ILD) than those with normal levels. Moreover, in SSc patients, serum IL‐34 levels negatively correlated with the percentage of predicted vital capacity, while they positively correlated with ground‐glass opacity score and fibrotic score on chest computed tomography. Collectively, increased serum IL‐34 levels were associated with greater frequency and severity of ILD in SSc patients. Serum IL‐34 levels may be a useful serological marker for SSc‐associated ILD.