Serum interleukin-17 levels are associated with nephritis in childhood-onset systemic lupus erythematosus

OBJECTIVES:

To determine the serum interleukin-17 (IL-17) levels in childhood-onset systemic lupus erythematosus patients and to evaluate the association between IL-17 and clinical manifestations, disease activity, laboratory findings and treatment.

METHODS:

We included 67 consecutive childhood-onset systemic lupus erythematosus patients [61 women; median age 18 years (range 11-31)], 55 first-degree relatives [50 women; median age 40 years (range 29-52)] and 47 age- and sex-matched healthy controls [42 women; median age 19 years (range 6-30)]. The childhood-onset systemic lupus erythematosus patients were assessed for clinical and laboratory systemic lupus erythematosus manifestations, disease activity [Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)], cumulative damage [Systemic Lupus International Collaborating Clinics/American College of Rheumatology (ACR) Damage Index] and current drug use. Serum IL-17 levels were measured by an enzyme-linked immunosorbent assay using commercial kits.

RESULTS:

The median serum IL-17 level was 36.3 (range 17.36-105.92) pg/mL in childhood-onset systemic lupus erythematosus patients and 29.47 (15.16-62.17) pg/mL in healthy controls (p=0.009). We observed an association between serum IL-17 levels and active nephritis (p=0.01) and migraines (p=0.03). Serum IL-17 levels were not associated with disease activity (p=0.32), cumulative damage (p=0.34), or medication use (p=0.63).

CONCLUSION:

IL-17 is increased in childhood-onset systemic lupus erythematosus and may play a role in the pathogenesis of neuropsychiatric and renal manifestations. Longitudinal studies are necessary to determine the role of IL-17 in childhood-onset systemic lupus erythematosus.     

T helper cell dysfunction in systemic lupus erythematosus (SLE): Relation to disease activity

Patients with systemic lupus erythematosus (SLE) are known to have defects in both humoral and cellular immunity. The significance of defective T cell-mediated immunity and its relationship to disease activity have not been clearly established. We studiedin vitro T helper cell (Th) function in 150 SLE outpatients and correlated Th function with validated measures of disease activity. Interleukin 2 (IL-2) production by peripheral blood mononuclear cells (PBMC) was measured after stimulation with the recall antigens influenza A virus (FLU) and tetanus toxoid (TET), irradiated allogeneic peripheral blood mononuclear cells (ALLO), and phytohemagglutinin (PHA). We observed three patterns of Th response: (1) 76 of 150 (50%) of patients responded to the recall antigens FLU and/or TET, ALLO, and PHA; (2) 62 of 150 (42%) of patients did not respond to recall antigens but responded to ALLO and PHA; and (3) 12 of 150 (8%) of patients did not respond to either recall antigens or ALLO antigens. This diminished T cell function was correlated with higher disease activity as measured by four scales of clinical activity, such that individuals who exhibited morein vitro immune dysfunction presented with significant increases in their clinical activity indicies. The alterations in T cell function could not be accounted for by medication doses alone. Thus, SLE patients have multiple distinct defects at the level of the Th cell which are associated with clinical measures of disease activity.     

Atherosclerosis in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease that has a late mortality phase owing mainly to cardiovascular manifestations. Atherosclerosis itself is characterized by inflammatory components, fulfilling the criteria of Witebsky and Rose for an autoimmune disease. SLE patients have increased risk for cardiovascular events, and these are the result of both atherosclerosis and thromboembolic events. Risk factors for atherosclerosis in SLE include “traditional” risk factors (mainly the Framingham risk factors), as well as disease-related factors including disease duration, steroid therapy, and renal disease, and inflammatory mechanisms that specifically contribute to enhanced atherosclerosis in SLE. These include specific antibodies to β2GPI; anticardiolipin antibodies; anti-oxidized low-density lipoprotein; and antibodies to heat shock proteins, complement activation, impaired ability to activate TGF-β1, and elevated levels of CRP. These findings stress the importance of surveillance and preventive strategies to control atherosclerosis in SLE.     

系统性红斑狼疮患者血清乳铁蛋白的分析

目的 比较健康人和系统性红斑狼疮(SLE)患者血清中乳铁蛋白(LF)的水平,分析SLE患者LF降低的影响因素.方法 采用ELISA检测健康儿童(n=38)、健康成人(n=46)、SLE儿童患者(n=38)、SLE成人患者(n=46)、1～80岁不同年龄段健康人(n=80)、IgA肾病患者(n=29)及其他肾病患者(n=19)血清中LF的含量.BCA法检测血清中总蛋白的含量.非配对t检验分析不同组间LF水平的差异,Spearman's相关性分析研究血清中LF与总蛋白含量间的关系.结果 SLE儿童及成人患者血清中LF水平均显著低于年龄和性别匹配的健康儿童及成人(P＜0.001),也低于IgA肾病和其他肾病患者(P ＜0.001).51～ 80岁健康人血清LF含量低于1～50岁健康人.结论 SLE患者血清中LF水平显著降低,此降低不是由于血清中总蛋白含量变化引起的.     

New therapies for systemic lupus erythematosus

In the past 40 years, prognosis for patients with systemic lupus erythematosus (SLE) has improved, with 10-year survival now approximately 90%. This is due probably to a combination of earlier disease diagnosis and diagnosis of milder disease, due in part to availability of multiple serological tests for SLE, use of steroids and other immunosuppressive agents, and availability of renal dialysis and transplantation. Despite this, however, the potential for significant morbidity and mortality remains in the group of patients with partially responsive or treatment resistant disease. More recently, advancements in the understanding of molecular mechanisms involved in the pathogenesis of SLE have translated to the development of novel therapies, offering possible alternatives to this patient cohort. Discussion of these pharmacological options and ongoing research forms the basis of this review.     

炎性细胞因子在系统性红斑狼疮中的作用

系统性红斑狼疮是一个全身性自身免疫病，常伴多器官受累，许多炎性细胞因子参与了系统性红斑狼疮的发病与发展，该病的活动性及器官损伤程度与不同的细胞因子相关。     

MCP-1 promoter polymorphism in Spanish patients with systemic lupus erythematosus

The possible role of the functional polymorphism located in the regulatory region of the monocyte chemoattractant protein-1 (MCP-1) gene in the susceptibility to systemic lupus erythematosus (SLE) was investigated. Two hundred and seventy-six SLE patients (among them, 99 with lupus nephritis and 55 with cutaneous vasculitis) and 194 ethnically matched healthy controls were included in the study. Genotyping for -2518 (A/G) MCP-1 gene polymorphism was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. No association between -2518 (A/G) MCP-1 polymorphism and susceptibility to SLE nor to lupus nephritis was found. However, a significant increase in the frequency of genotype AG and a decrease in the frequency of genotype AA were found among patients with cutaneous vasculitis (51% of AG vs. 32% in individuals without cutaneous vasculitis; P=0.008, OR=2.2, 95% CI: 1.18-4.25; and 47% of AA vs. 64%; P=0.03, OR=0.5, 95% CI: 0.27-0.96, respectively). These results indicate an association between the presence of G at position -2518 in the MCP-1 promoter region and the presence of cutaneous vasculitis among patients with SLE. This polymorphism does not seem to influence the susceptibility to SLE nor the appearance of lupus nephritis. Further studies are necessary in order to elucidate the role of this polymorphism in the pathogenesis of other inflammatory autoimmune diseases.     

抗核小体抗体与儿童系统型红斑狼疮的相关性

目的探讨抗核小体抗体（AnuA）在诊断儿童系统型红斑狼疮（SLE）中的敏感性和特异性，了解AnuA与儿童SLE临床特征、疾病活动性的相关性。方法用Hep-2细胞提取核小体。用酶联免疫吸附方法（ELISA）测定血清中的AnuA，分析AnuA和临床表现的相关性。结果52例SLE中18例AnuA阳性。27例疾病对照组中1例AnuA阳性，30例正常对照组AnuA均为阴性。AnuA在儿童SLE中的敏感性为35％，特异性为96％。AnuA阳性组SLE患儿100％有中枢神经系统损害，AnuA阴性组为47％（x^2=14．57，P〈0．05）。AnuA阳性组SLE患儿100％有肾脏损害，AnuA阴性组为5l％（x^2=13．31，P〈0．05）。AnuA阳性和AnuA阴性的SLE患儿SLEDAI评分高于10分者分别为100％和71％（x^2=6．56，P〈0．05）。结论AnuA对儿童SLE的诊断具有较高的特异性，有助于抗dsDNA抗体、抗心磷脂抗体阴性的儿童SLE的诊断。     

New insights into the progression from cutaneous lupus to systemic lupus erythematosus

ABSTRACT

Introduction

Between 5 and 25% of patients with cutaneous lupus erythematosus (CLE) can progress to systemic lupus erythematosus (SLE) during the course of the disease. There is no clear predictive guideline for the progression of CLE to SLE.     

In vitro T-cell functions specific to an anti-DNA idiotype and serological markers in patients with systemic lupus erythematosus (SLE)

The human monoclonal autoantibody 16/6 is a common anti-DNA idiotype found to have clinical relevance in patients with systemic lupus erythematosus (SLE). Therefore the ability of peripheral blood T cells of SLE patients and healthy controls to proliferate and to produce helper T-cell factors following stimulation with this idiotype was tested. It was found that T cells of 75% of healthy donors proliferated to the 16/6 idiotype, whereas only 22% of SLE patients responded to this idiotype by proliferation. On the other hand, the capability to produce T-cell helper factors specific to the 16/6 idiotype was found in a higher percentage of SLE patients (48%) as compared to healthy controls (31%). The low frequency of proliferative responses in SLE patients might be due either to the chronic exposure to the 16/6 idiotype or to the production of antiidiotype antibodies against the 16/6 idiotype, which interfere with the response to the latter stimulator.     

系统性红斑狼疮合并胸腺瘤的临床特点分析

目的探讨系统性红斑狼疮(SLE)合并胸腺瘤的的临床特点。方法回顾性分析1984年至2015年北京协和医院收治的SLE合并胸腺瘤患者的临床资料,分析临床特点、实验室检查、治疗方式和预后,并与同期国内外报道的SLE合并胸腺瘤的病例资料进行比较。结果 SLE合并胸腺瘤住院患者共11例,占SLE患者的1.55‰,占胸腺瘤患者的1.07%。女性10例,男性1例。SLE平均起病年龄25.5岁,平均确诊年龄26.4岁,胸腺瘤的平均确诊年龄28.5岁。SLE进展至胸腺瘤的平均病程为2.1年。确诊胸腺瘤时SLEDAI均值为3.6。5例患者行胸腺切除术,1例患者放疗。4例胸腺瘤标本可用于WHO分型,A型2例,AB型1例,C型1例。8例患者随访3~92月,6例SLE稳定,1例SLE活动,1例死于肿瘤转移。与国内外文献报道资料相比,本研究中的SLE合并胸腺瘤患者年龄偏小,发现胸腺瘤后的手术切除率偏低。结论 SLE合并胸腺瘤并非偶然现象,胸腺瘤症状隐匿,可能参与SLE发病。胸腺切除可能有助于SLE的临床缓解,应引起临床医师的重视。     

Genetic polymorphisms of CYP2D6 oxidation in patients with systemic lupus erythematosus

Introduction

Systemic lupus erythematosus (SLE) is a complex, multifactor autoimmune disease. The studies on aetiopathogenesis of autoimmune diseases focus on the impact the genetically conditioned impairment of xenobiotic metabolism may exert. The knowledge of oxidation polymorphism in the course of SLE may be helpful in choosing more efficient and safer therapy. We determined whether there was an association between susceptibility to SLE and particularly to CYP2D6 genotypes.

Material and methods

The study was carried out in 60 patients with SLE and 129 healthy volunteers and all the subjects were of Polish origin. The samples were analysed for two major defective alles for CYP2D6 – CYP2D6*3 and CYP2D6*4 and one wild -type allele CYP2D6*1-by the polymerase chain reaction fragment length polymorphism (PCR-RFLP) metod with DNA extracted from peripheral blood.

Results

No statistically significant differences in the incidence of CYP2D6 genotypes between the studied groups were found (p = 0.615). Risk (OR) of SLE development was 1.03 for the carriers of CYP2D6*3 allele and 1.48 for the subjects with CYP2D6*4 allele; but it was not statistically significant.

Conclusions

Increased occurrence of mutant alleles of the CYP2D6 gene in SLE patients and the calculated OR values could suggest the effect of these mutations on increased SLE development.     

Acute cardiogenic shock in a girl with systemic lupus erythematosus

Cardiac involvement is one of the main complications substantially contributing to the morbidity and mortality of patients suffering from systemic lupus erythematous (SLE). However, clinically important myocarditis is an unusual feature in SLE. We describe the clinical characteristics, management, and outcome of a 15-year young girl with SLE who developed severe left ventricular dysfunction.     

Complement receptor 1 (CR1) on erythrocytes of patients with systemic lupus erythematosus

Ninety-five (85%) of the 112 Japanese patients with systemic lupus erythematosus (SLE) were negative for the complement receptor 1 (CR1) activities on erythrocytes, while 770 (91%) of the 847 normal subjects were positive for CR1, as determined by immune-adherence hemagglutination. Pedigree analyses of the normal population suggested that the phenotype of negative CR1 was determined by a autosomal recessive gene. Among 112 SLE patients, 73 (65%) showed persistently negative CR1 during remission for over 26 months of follow-up, although the CR1 levels did vary with the disease activity in 22 SLE patients. These results show that the relative risk for developing SLE in persons with negative CR1 is 19. CR1 activity appears to be an important genetic factor related the development of SLE.     

Increased serum levels of soluble interleukin-2 receptor in patients with systemic lupus erythematosus and rheumatoid arthritis

In this study we investigated the serum levels of a released soluble form of the interleukin-2 receptor (sIL-2R) in 42 patients with rheumatoid arthritis and in 12 cases of systemic lupus erythematosus. Data were evaluated in relationship to the clinical phase and compared with those observed in normal controls (N=56) and in osteoarthritis (N = 7). Increased levels were observed in both rheumatoid arthritis (mean ± SE, 604±49 U/ml) and systemic lupus erythematosus (1438±481 U/ml). These values were significantly higher than in control (256±15 U/ml;P<0.001) and in osteoarthritis (298±33 U/ml;P<0.001) groups. In addition, the highest values were associated with the active phases of both rheumatoid arthritis (active vs inactive, 771±78 vs 451±39 U/ml;P<0.001) and systemic lupus erythematosus (active vs inactive, 2108±489 vs 499±75 U/ml;P<0.001). Our findings suggest that the detection of sIL-2R in rheumatoid arthritis and in systemic lupus erythematosus may represent a good marker of disease activity, which indirectly indicates the ongoing activation and/or proliferation of immunoreactive cells which are involved in the pathogenetic events of these autoimmune conditions.     

Immunosuppressive therapy modulates T lymphocyte gene expression in patients with systemic lupus erythematosus

To evaluate the T-cell large-scale differential gene expression in systemic lupus erythematosus (SLE) patients presenting with glomerulonephritis we studied SLE patients before and after immunosuppressive treatment. Large-scale gene expression of peripheral blood mononuclear T cells was evaluated using cDNA microarray nylon membranes containing 5184 cDNAs. Data were analysed using the SAM and Cluster and Treeview software. When untreated patients were compared to healthy individuals, 38 genes, most of them located on chromosomes 1, 3, 6, 17 and 19, were repressed, and when untreated patients were compared to treated ones, 154 genes, located on chromosomes 1, 6, 7, 12 and 17, were induced. In terms of biological function of coded proteins, the differentially expressed genes were associated with apoptosis, cell cycle, chromosomal scaffold, cytokine/chemokine, DNA repair/replication, Golgi/mitochondrial proteins, mRNA processing, signalling molecules and tumour suppressors. Two autoantigen genes related to RNA splicing (small nuclear riboprotein 70,000 MW-U1 SNR, and splicing factor 3a, 60,000 MW), and the tetranectin-plasminogen-binding protein were repressed. The Fc fragment of immunoglobulin G low affinity IIb, apoptotic protease activating factor-1, two subunits of cytochrome c, caspase 8, complement C5a, HLA-DRA, HLA-DQB1, transforming growth factor-beta receptor II, small nuclear ribonucleoprotein polypeptide N (Sm protein N) genes, heterogeneous nuclear riboprotein-C, and argininosuccinate lyase genes, among others, were induced. A total of 10 genes were repressed in untreated patients and induced in treated ones, among them tumour necrosis factor (ligand) superfamily member 9, tumour protein p53, mannosidase alpha class IA, and CD22. Although some of these differentially expressed genes are typically expressed in B cells, CD22 and CD32 have also been reported in T cells and may provide regulatory signals to B cells. Assessment of differential gene expression may provide hybridization signatures that may identify susceptibility, diagnostic and prognostic markers of SLE.     

Complement receptor expression and activation of the complement cascade on B lymphocytes from patients with systemic lupus erythematosus (SLE).

It has previously been reported that the expression of the complement receptors, CR1 on erythrocytes and blood leucocytes and CR2 on B cells, is reduced in patients with SLE, and that the reduced expression of CR1 on erythrocytes is related to disease activity. We have earlier demonstrated that normal B cells are capable of activating the alternative pathway (AP) of complement in a CR2-dependent fashion. In this study we have investigated whether disturbances in this activity may be related to the altered phenotype of SLE B cells. Flow cytometry was used to measure expression of complement receptors and regulatory proteins on B cells from SLE patients, as well as the deposition of C3 fragments occurring in vivo or after in vitro AP activation. We have confirmed, for a proportion of the patients studied, reduced expression of CR1 and CR2 on B cells, and shown a consistency between low CR2 expression and reduced in vitro AP activation in the presence of homologous, normal serum. In addition, the B cells, like erythrocytes, bear raised levels of in vivo-deposited C3dg, but not C3b fragments, compared with normal B cells. The erythrocytes from SLE patients were unable to inhibit in vitro AP activation by B cells in homologous serum. Finally, we demonstrated an inverse relationship between SLE disease activity index (SLEDAI) and the expression of complement receptor 2 (CR2) on SLE B cells. Thus, determination of CR2 on B cells may emerge as an additional laboratory tool in the assessment of SLE activity.     

系统性红斑狼疮遗传学研究进展

系统性红斑狼疮（systemic lupus erythematosus,SLE)通常被认为是自身免疫疾病的原型，遗传因素在疾病的发生中起重要作用。对狼疮鼠模型的研究已发现约30个基因位点与疾病产生有关，不同位点影响发病的不同环节。人类基因组研究则50个左右基因位点与SLE有关，其中1q23-24,1q41-42,2q37,4p16-15.2,6p21-11及16q13为6个显著相关区域，对特定患者，多个位点不同基因的组合可导致疾病表型的多样性。近期对候选基因的研究进一步证实，遗传因素在决定疾病易感性及临床表型时起作用，不同群体中所涉及的基因或其表达强度均有差异。     

Placental pathology in systemic lupus erythematosus with antiphospholipid antibodies

Systemic lupus erythematosus (SLE) is associated with a poor pregnancy outcome. Antiphospholipid antibodies (APL), which include lupus anticoagulant (LAC) and anticardiolipin antibodies (aCL), are frequently found in patients with SLE, and their presence has been associated with fetal loss. To examine placental pathologic features of SLE patients with APL, we performed a pathologic study on 47 placental tissue samples from 47 pregnant SLE patients with APL (15 patients; four LAC single-positive patients, seven aCL single-positive patients, four LAC and aCL double-positive patients) and without APL (32 LAC and aCL double-negative patients). The incidence of extensive infarction, decidual vasculopathy, decidual thrombosis and perivillous fibrinoid change, which have been thought to be characteristic lesions of APL placenta, was significantly higher in the LAC and aCL double-positive patients than in the patients without APL. Conversely, the above-mentioned lesions between the LAC or aCL single-positive patients and the APL negative patients did not differ significantly. Among the 15 patients with APL, two of the three patients with both decidual vasculopathy and thrombosis had extensive infarction associated with fetal death. Moreover, the patients having fetal death showed LAC and aCL double-positivity. In conclusion, this study indicated that the LAC and aCL double-positivity is an important factor for extensive infarction resulting from decidual vasculopathy and decidual thrombosis in the SLE placenta. Moreover, it was indicated that LAC and aCL double-positivity is an important risk factor for fetal death in the SLE patient.     

Belimumab and antipneumococcal vaccination in patients with systemic lupus erythematosus

In systemic lupus erythematosus (SLE), flares can be caused by infections. In particular, Streptococcus pneumoniae infection can be severe or even potentially lethal in absence of previous immunization or in case of ‘aggressive’ systemic antibiotic therapy. Immunization efficacy, however, can be reduced in such patients with the use of the various immunosuppressive therapeutic regimens. In particular, the use of novel monoclonal antibodies against B lymphocytes raises concerns over the potential interference with antipneumococcal vaccination. Previous studies demonstrated that belimumab therapy did not significantly reduce the efficacy of antipneumococcal vaccination, when received after the initiation of belimumab therapy. The study being evaluated in this article investigated the efficacy of vaccination in relationship to initiation of belimumab therapy in SLE patients.