Quantitation of autoantibody-secreting B cells in systemic lupus erythematosus

An ELISA spot assay was used to quantitate the number of autoantibody-secreting B cells in the peripheral blood of patients with systemic lupus erythematosus. Patients with active disease had 20 fold more anti-DNA, 4 fold more anti-actin and 3 fold more anti-myosin secreting lymphocytes than controls but normal numbers of anti-cardiolipin and anti-transferrin secreting B cells. 60% of SLE patients had increased numbers of B cells reactive with multiple autoantigens. These data suggest that B cell activation in SLE may be influenced by both antigen-specific and antigen-independent factors.     

B细胞活化因子与系统性红斑狼疮

B细胞活化因子(BAFF)是近年来发现的对B细胞生存分化具有重要作用的因子,通过结合于三种不同受体发挥促B细胞分化成熟、类别转换、促进体液免疫应答及参与T细胞活化等功能。BAFF过表达时可在小鼠模型引发严重的自身免疫疾病,使用BAFF拮抗剂可使动物模型的自身免疫病得到一定程度的缓解。部分系统性红斑狼疮(SLE)患者中BAFF的水平有不同程度增高,并与抗dsDNA抗体滴度相关。抗BAFF单克隆抗体治疗SLE临床研究初步结果显示安全性好,疾病活动度下降。BAFF拮抗剂有望成为有效的治疗SLE的新型药物。     

Belimumab for the treatment of systemic lupus erythematosus

Given their pivotal role in autoantibody production, B-cells have become an attractive therapeutic target in systemic lupus erythematosus (SLE). Belimumab, a fully human monoclonal antibody against B lymphocyte stimulator (BLyS), a B-cell survival factor, was licensed in 2011 for the treatment of autoantibody-positive SLE. The BLISS-52 and BLISS-76 Phase III trials successfully demonstrated that belimumab (10 mg/kg) with standard therapy significantly decreased disease activity in SLE patients compared to placebo with standard therapy. Overall, belimumab has been found to be safe and well tolerated. While the BLISS-52 and BLISS-76 studies are the largest clinical trials in SLE to date, they mainly focused on musculoskeletal, mucocutaneous, hematologic and general constitutional features of the disease. Patients with severe lupus nephritis and severe central nervous system disease were excluded from these trials. Studies of belimumab in lupus nephritis are ongoing that may clarify the role of this agent in the clinical management 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.     

Case report and review of lupus erythematosus cells in cytology fluids

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease typically diagnosed by a combination of physical findings and clinical laboratory testing. Several decades ago, the diagnosis of lupus included the lupus erythematosus (LE) cell assay. Autoimmune serology techniques such as anti-nuclear antibody staining have replaced the LE cell assay. However, as presented in this report and review of the literature, the in vivo finding of LE cells by cytopathology remains an important finding consistent with the diagnosis of SLE.     

Cytokine-independent progression of immunoglobulin production in vitro by B lymphocytes from patients with systemic lupus erythematosus.

B lymphocytes from patients with systemic lupus erythematosus (SLE) secreted high levels of immunoglobulin spontaneously when cultured in vitro. Addition of the cytokines interleukin-2, interleukin-4 and interleukin-6 either alone or in combination failed to augment spontaneous immunoglobulin synthesis. Percoll-separated low-density SLE B lymphocytes matured into immunoglobulin-secreting cells also independent of exogenous interleukins. During maturation these cells became enlarged and less dense, and began to express CD23. This was in contrast to normal B cells, which did not secrete immunoglobulin spontaneously but synthesized IgM after interleukin stimulation. These results indicate that in vitro immunoglobulin synthesis by SLE B cells is already initiated in these cells and progresses independently of further stimulatory manoeuvres.     

Autoantibody-dependent and autoantibody-independent roles for B cells in systemic lupus erythematosus: Past,present, and future

It has long been known that B cells produce autoantibodies and, thereby, contribute to the pathogenesis of many autoimmune diseases. Systemic lupus erythematosus (SLE), a prototypic systemic autoimmune disorder, is characterized by high-circulating autoantibody titers and immune-complex deposition that can trigger inflammatory damage in multiple organs/organ systems. Although the interest in B cells in SLE has historically focused on their autoantibody production, we now appreciate that B cells have multiple autoantibody-independent roles in SLE as well. B cells can efficiently present antigen and activate T cells, they can augment T cell activation through co-stimulatory interactions, and they can produce numerous cytokines which affect inflammation, lymphogenesis, and immune regulation. Not surprisingly, B cells have become attractive therapeutic targets in SLE. With these points in mind, this review will focus on the autoantibody-dependent and autoantibody-independent roles for B cells in SLE and on therapeutic approaches that target B cells.     

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.     

Associations of B cell‐activating factor (BAFF) and anti‐BAFF autoantibodies with disease activity in multi‐ethnic Asian systemic lupus erythematosus patients in Singapore

To measure the levels of B cell‐activating factor (BAFF) and endogenous anti‐BAFF autoantibodies in a cohort of multi‐ethnic Asian systemic lupus erythematosus (SLE) patients in Singapore, to determine their correlation with disease activity. Serum samples from 121 SLE patients and 24 age‐ and sex‐matched healthy controls were assayed for BAFF and anti‐BAFF immunoglobulin (Ig)G antibody levels by enzyme‐linked immunosorbent assay (ELISA). The lowest reliable detection limit for anti‐BAFF‐IgG antibody levels was defined as 2 standard deviations (s.d.) from blank. Correlation of serum BAFF and anti‐BAFF IgG levels with disease activity [scored by SLE Activity Measure revised (SLAM‐R)], and disease manifestations were determined in these 121 patients. SLE patients had elevated BAFF levels compared to controls; mean 820 ± 40 pg/ml and 152 pg ± 45/ml, respectively [mean ± standard error of the mean (s.e.m.), P < 0·01], which were correlated positively with anti‐dsDNA antibody levels (r = 0·253, P < 0·03), and SLAM‐R scores (r = 0·627, P < 0·01). In addition, SLE patients had significantly higher levels of anti‐BAFF IgG, which were correlated negatively with disease activity (r = –0·436, P < 0·01), levels of anti‐dsDNA antibody (r = –0·347, P < 0·02) and BAFF (r = –0·459, P < 0·01). The majority of patients in this multi‐ethnic Asian SLE cohort had elevated levels of BAFF and anti‐BAFF antibodies. Anti‐BAFF autoantibody levels correlated negatively with clinical disease activity, anti‐dsDNA and BAFF levels, suggesting that they may be disease‐modifying. Our results provide further information about the complexity of BAFF pathophysiology in different SLE disease populations and phenotypes, and suggest that studies of the influence of anti‐cytokine antibodies in different SLE populations will be required when selecting patients for trials using targeted anti‐cytokine therapies.     

Accelerated atherosclerosis in systemic lupus erythematosus and other connective tissue diseases

Connective tissue diseases are associated with increased morbidity and mortality related to a higher rate of cardiovascular events and higher prevalence of subclinical atherosclerosis. Atherosclerosis is now considered a multifactorial process where autoimmunity and chronic inflammation play an important pathogenic role. In systemic autoimmune rheumatic diseases in general, and in systemic lupus erythematosus in particular, atherosclerosis cannot be explained by traditional cardiovascular risk factors alone. Cellular and humoral mechanisms, together with specific factors associated with the disease itself and/or its treatments, have been advocated to explain the acceleration of arterial wall organic damage in these patients. Endothelial dysfunction, carotid intima-media thickness and plaque evaluations provide accurate detection of atherosclerotic process at a preclinical stage, before appearance of clinical disease, allowing preventive measure introduction with the aim to modify the cardiovascular risk in subjects with systemic autoimmune rheumatic diseases.     

Subcutaneous and intravenous belimumab in the treatment of systemic lupus erythematosus: a review of data on subcutaneous and intravenous administration

Introduction: Loss of B cell tolerance is a hallmark feature of the pathogenesis of Systemic Lupus Erythematosus (SLE). Recent advances in B cell therapy have focused on targeted therapy aimed at inhibiting B cell activation and reducing B cell survival. Belimumab, a human monoclonal antibody against B cell activating factor (BAFF) was licensed in 2011 for the treatment of SLE.

Areas covered: We review the data on the intravenous and subcutaneous formulations of belimumab in the management of patients with SLE. BLISS-52 and BLISS-76 demonstrated the efficacy of intravenous belimumab (10mg/kg) as an add-on therapy in SLE patients with active disease. A recent phase III trial of intravenous belimumab reported similar results in North East Asian patients. Subcutaneous belimumab (200mg/weekly) has demonstrated similar efficacy, safety and tolerability and was approved by the FDA in 2017 for the treatment of active autoantibody positive SLE patients receiving standard therapy.

Expert commentary: Belimumab is generally safe and well tolerated. The most common clinical manifestations of SLE in the clinical trials were arthritis, mucocutaneous disease and serositis. Patients with severe lupus nephritis and central nervous system disease were excluded from these clinical trials.     

Endometriosis and systemic lupus erythematosus: a comparative evaluation of clinical manifestations and serological autoimmune phenomena

PROBLEM: In view of evidences suggesting association between endometriosis (EM) and systemic lupus erythematosus (SLE), we have performed a comparative evaluation of clinical and humoral immunologic abnormalities in both diseases. METHOD OF STUDY: Forty-five women (18-40 years) with histologically confirmed pelvic EM, 21 healthy-women and 15 female SLE-patients (18-40 years) without surgically confirmed EM were prospectively evaluated. Immunologic investigations were performed by blinded researchers. RESULTS: None of the EM-patients fulfilled criteria for SLE. However, EM-patients presented higher frequencies of arthralgia (62%) and generalized myalgia (18%) superior than normal-controls (24%, P = 0.004/0%, P = 0.048) but comparable with SLE-patients (33%, P = 0.052/27%, P = 0.5). Similarly to SLE (7%), 9% of EM-patients presented fibromyalgia. Antinuclear antibodies (ANA) were detected in 18% of EM-sera, as compared with healthy-women (0%, P = 0.014) and SLE-patients (93%, P = 0.0005). In contrast with SLE, antibodies to dsDNA, Sm and U1RNP were negative in EM-sera. Anti-Ro and anticardiolipin antibodies were more often in SLE (40%, 33%) than in EM-patients (2%, P < 0.001/9%, P = 0.04). Elevated immune-complexes and low total complement were more frequent in SLE (40%, 13%) compared with EM-sera (7%, P = 0.005/0%, P = 0.01). CONCLUSIONS: Our data indicate differences of ANA antigenic specificity and complement consumption between EM and SLE. The high prevalence of generalized musculoskeletal complaints in EM justifies a multidisciplinary approach.     

Abnormalities of B cell subsets in patients with systemic lupus erythematosus

The prototypic autoimmune disease, SLE, is known to be associated with polyclonal B cell hyperreactivity. Developing an understanding of the complex nature of human B cell differentiation, largely through the application of multiparameter flow cytometry to an analysis of circulating B cells has permitted an assessment of whether specific stages of B cell maturation are affected by the tendency for polyclonal B cell activation. Moreover, the analysis of perturbations of the specific stages of B cell maturation has generated new information on whether abnormalities in B cell differentiation are primarily involved in autoimmune disease immunopathology or, rather, are secondary to the inflammatory environment characteristic of subjects with this autoimmune disease. Multivariant analysis has begun to document abnormalities in B cell maturation that are primarily associated with lupus, or, alternatively related to disease duration, disease activity and concomitant medication. Together, these analyses have provided new insights on the role of B cell over-reactivity in SLE.     

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。     

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.     

Hepatitis B antigen and systemic lupus erythematosus

Summary Sera from 22 patients with systemic lupus erythematosus (SLE) were examined for the presence of hepatitis B antigen (HBsAg) by a complement fixation (CF) test, by an immunoelectrophoretic method (counterelectrophoresis-CEP), and by radioimmunoassay (RIA). The sera from 8 patients gave positive results using CF. However, the same sera and sera from 28 additional SLE patients, when tested with CEP and RIA, were not shown to contain HBsAg.Additional studies were carried out in order to characterize the factor responsible for the false positive CF of the 8 SLE sera. It was shown that the sera also fixed complement in presence of normal serum previously submitted to freezing and thawing or heating at 65°C. The complement fixing factor was readily absorbed by aggregated IgG but not by insolubilized HBsAg. Complement fixation was strongly diminished by 2-mercaptoethanol treatment of SLE serum. It thus appears that the false positive reactions for the presence of HBsAg obtained by CF are due to the occurrence of anti-antibodies reacting with aggregated IgG. There is no increased incidence of HBsAg in the serum of SLE patients.This work was supported by the Dubois-Ferrière Dinu Lipatti Foundation and the Swiss National Fund (grant no. SR 3260-0.74).     

Peroxisome proliferator‐activated receptor gamma agonists in the prevention and treatment of murine systemic lupus erythematosus

Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are known to have many immunomodulatory effects. We have previously shown that the PPARγ agonist rosiglitazone is beneficial when used early in prevention of disease in murine models of systemic lupus erythematosus (SLE) and SLE-related atherosclerosis. In this report, we demonstrate that another PPARγ agonist, pioglitazone is also beneficial as a treatment for early murine lupus, indicating that this is a class effect and not agent-specific. We further attempt to define the ability of PPARγ agonists to ameliorate established or severe autoimmune disease using two mouse models: the MRL.lpr SLE model and the gld.apoE^−/− model of accelerated atherosclerosis and SLE. We demonstrate that, in contrast to the marked amelioration of disease seen when PPARγ agonist treatment was started before disease onset, treatment with rosiglitazone after disease onset in MRL.lpr or gld.apoE^−/− mice had minimal beneficial effect on the development of the autoimmune phenotype; however, rosiglitazone treatment remained highly effective at reducing lupus-associated atherosclerosis in gld.apoE^−/− mice after disease onset or when mice were maintained on a high cholesterol Western diet. These results suggest that beneficial effects of PPARγ agonists on the development of autoimmunity might be limited to the early stages of disease, but that atherosclerosis, a major cause of death in SLE patients, may be ameliorated even in established or severe disease.     

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.     

系统性红斑狼疮患者外周血内皮祖细胞的实验研究

目的探讨系统性红斑狼疮患者外周血内皮祖细胞（EPC）数量、功能是否改变。方法连续选入33例系统性红斑狼疮（SLE）患者做为SLE组,33名门诊健康体检者为对照组。流式细胞分析计量外周血CD34和KDR双阳性细胞,同时原代培养EPC,培养7 d后MTT法检测增殖能力,改良boydon小室法检测迁移能力。结果SLE组外周血EPC数量较对照组显著减少,P〈0.01;SLE组的增殖、迁移能力均较对照组减弱,P〈0.01。结论系统性红斑狼疮患者外周血EPC数量减少,增殖、迁移功能降低,可能是SLE促动脉粥样硬化发生的机制之一。