In Vitro Effects of Thymosin on T-Cell Subsets in Systemic Lupus Erythematosus

The possible immunomodulatory influence of thymosin on lymphocytes from patients with active systemic lupus erythematosus (SLE) has been evaluated. Such patients have decreased numbers of T-suppressor (Tγ) cells and normal numbers of T-helper (Tμ) cells, resulting in an abnormally low Tγ/Tμ ratio. In vitro incubation of lymphocytes from active SLE patients with thymosin resulted in a normalization of the Tγ/Tμ ratio. This occurred because of a decrease in Ty cells rather than an increase in Tγ cells. The normalization of Tγ/Tμ ratios in vitro in the presence of thymosin is compatible with possible in vivo immunomodulatory effects of these peptides.     

Direct Demonstration of Immunoregulatory T-Cell Defects in Patients with Systemic Lupus Erythematosus

The present study was undertaken to determine directly whether immunoregulatory T cells have a defective suppressor function in patients with systemic lupus erythematosus (SLE), and whether anti-T-cell antibodies are essential for immunoregulatory T-cell defects. Peripheral blood T cells and T-cell subsets were determined in 52 SLE patients. The ratio of T4 to T8 cells was distributed over a wider range in patients with SLE than in the controls. Patients with SLE were divided into three groups (low, normal and high) by the T4/T8 ratio. Lymphocytes from 12 SLE patients (7 with low and 5 with high T4/T8 ratios) were studied extensively. Their disease was inactive or in remission. Anti-T-cell antibodies were not detected, and yet the patients had immunological abnormalities characterized by the presence of antinuclear antibodies and hypergammaglobulinaemia. The SLE patients with high T4/T8 ratios had a decreased number of T8 cells, and defective suppressor-effector cells. In contrast, patients with low T4/T8 ratios had decreased T4 cells and/or increased T8 cells, and defective suppressor-inducer cells. Two patients with low T4/T8 ratios had both suppressor-effector and suppressor-inducer cell defects. These results indicate that immunoregulatory circuits in SLE patients are heterogeneous and that immunoregulatory defects exist even when the disease is inactive or in remission. Anti-T-cell antibodies were not essential for such immunoregulatory defects. Thus, immunoregulatory T-cell defects and the development of SLE may be independent conditions due to other unknown causes.     

In Vitro TNP-Specific Antibody Formation by Peripheral Lymphocytes from Patients with Systemic Lupus Erythematosus

Immunological reactivity in patients with systemic lupus erythermatosus (SLE) was assessed by investigating in vitro trinitrophenyl (TNP)-specific antibody formation by peripheral lymphocytes. Peripheral lymphocytes from 16 patients with SLE were cultured with TNP conjugated with horse erythrocytes (TNP-HRBC) in the presence of 2-mercaptoethanol. The hemolytic plaque assay was used to detect hapten (TNP)-specific antibody-forming cells. Peripheral lymphocytes from normal individuals failed to produce antibody to TNP, whereas SLE lymphocytes produced a significant number of plaque-forming cells. Co-culture experiments with SLE and normal lymphocytes suggested that patients with SLE have a defect in T lymphocytes, leading to abnormal antibody production.     

Lithium In Vitro Enhances Interleukin-2 Production by T Cells from Patients with Systemic Lupus Erythematosus

Cellular immunity is impaired in patients with systemic lupus erythematosus (SLE). A decreased production of interleukin-2 by T cells isolated from blood of patients with SLE was found. the decrease correlated with severity of the disease. It was shown that incubation in vitro of T cells with 5 mM of lithium chloride augmented interleukin-2 production. the increase in cultures of T cells from patients with SLE was higher that than in healthy individuals. It is belived that lithium increases the cytosol inositol triphosphate level and subsequently augmented impaired itra-cellular signal transduction in the T cells from patients with SLE.     

Lithium In Vitro Enhances Interleukin-2 Production by T Cells from Patients with Systemic Lupus Erythematosus

Abstract

Cellular immunity is impaired in patients with systemic lupus erythematosus (SLE). A decreased production of interleukin-2 by T cells isolated from blood of patients with SLE was found. the decrease correlated with severity of the disease. It was shown that incubation in vitro of T cells with 5 mM of lithium chloride augmented interleukin-2 production. the increase in cultures of T cells from patients with SLE was higher that than in healthy individuals. It is belived that lithium increases the cytosol inositol triphosphate level and subsequently augmented impaired itra-cellular signal transduction in the T cells from patients with SLE.     

Dendritic Cells in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) persists as a chronic inflammatory autoimmune disease and is characterized by the production of autoantibodies and immune complexes that affect multiple organs. The underlying mechanism that triggers and sustains disease are complex and involve certain susceptibility genes and environmental factors. There have been several immune mediators linked to SLE including cytokines and chemokines that have been reviewed elsewhere []. A number of articles have reviewed the role of B cells and T cells in SLE []. Here, we focus on the role of dendritic cells (DC) and innate immune factors that may regulate autoreactive B cells.     

细胞因子和系统性红斑狼疮系统性红斑狼疮(SLE)

SLE是一种主要影响育龄妇女的自身免疫性风湿性疾病.SLE的流行在各种族人群中是不同的,在黑人妇女中的发病率大约是1∶250,在中国妇女中大约是1∶1000,在白人妇女中大约是1∶4300.超过80%的SLE 病例影响关节、皮肤和血液,30%～50%的病例会影响肾脏、中枢神经系统和心肺系统.10%～ 30%的病例中存在与动静脉血栓形成有关的抗心肌磷脂抗体.大多数病例有明显的全身表现, 包括疲劳不适、发热、纳差、恶心和体重减轻.     

Belimumab Therapy in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a complex heterogeneous disease, posing challenges to clinical trials. As in other autoimmune diseases, B-lymphocytes play a central role in lupus pathogenesis. The finding that selection and survival of B cells are controlled by a variety of signals, including those provided by the longevity factor BAFF (B-cell activating factor), also called BLyS (B-lymphocyte stimulator), led to preclinical trials that revealed that BAFF represents a promising therapeutic target for human lupus. Belimumab is a fully human monoclonal antibody directed against BAFF. Lessons learned from early clinical trials led to improved methods and success of phase III trials, with recruitment of patients with both clinically and serologically active disease, development and use of a novel SLE Responder Index, and progressive and special restrictions on immunosuppressive and corticosteroid use. These studies offer an attractive blueprint to conduct future clinical trials in SLE. The overall steroid-sparing ability and benefits of belimumab on musculoskeletal and mucocutaneous organ systems suggest that it has an impact on the clinical management of SLE patients. Future directions include studies to determine the role of belimumab in early SLE, as well as in renal or CNS involvement.     

Distributions of HLA Class II Alleles in Autoantibody Subsets Among Norwegian Patients with Systemic Lupus Erythematosus

In order to find potential correlations between HLA class II alleles and anti-SS-A, -SS-B, -Sm and anti-snRNP responses among Norwegian patients with systemic lupus erythematosus (SLE), HLA-DRB1, -DRB3*0101, -DQA1 and -DQB1 alleles were determined by DNA typing 50 patients and 108 controls. HLA distributions were analysed in the following autoantibody subgroups: anti-SS-A with -SS-B, anti-SS-A without -SS-B, anti-snRNP without -Sm, anti-SS-A without -snRNP and anti-snRNP without -SS-A. The autoantibodies were detected by EIA (enzyme immunuassay). Patients with anti-SS-A and -SS-B had significantly increased frequencies of DRB1*03, DRB3*0101, DQA1*0501, DQB 1*0201 (in linkage disequilibrium) versus controls and versus patients without anti-SS-A and -SS-B. No differences in HLA distribution were found when the group with anti-SS-A alone was compared to the group with anti-SS-A and concomitant -SS-B. Comparing the groups with and without anti-SS-A and -SS-B, the highest RR were found for the alleles DRB1*03, DRB3*0101, DQB1*0501, DQB1*0201 (in linkage disequilibrium) with RR: 16.8, 5.0, 19.6, 10.3, respectively, P<0.05). RR for DQw2/DQw6 heterozygotes was 3.5 (Ns.), and RR for cases having DQa molecules with glutamine in position 34 and DQ/3 molecules with leucine in position 26 on both chains was 6.3 (P <0.05). No HLA associations were observed in the group with anti-snRNP without concomitant -Sm or without concomitant -SS-A. These results show that production of anti-SS-A and -SS-B is associated to the HLA alleles DRB1*03, DRB3*0101, DQA1*0501, DQB1*0201, and that this haplotype shows stronger correlation to these responses than DQw2/DQw6 heterozygosity or HLA molecules having glutamine in position 34 (DQa) and leucine in position 26 (DQ/3). The failure to observe any correlation with DRB1*15, 16 (DR2) in the group with anti-SS-A alone may demonstrate ethnic differences concerning this response. The failure to identify any HLA associations for the anti-snRNP response may reflect the heterogeneity of the molecules that constitute this antigen.     

Systemic Lupus Erythematosus and Related Diseases

NZB (H-2^d) mice are well known for the production of IgM autoantibodies to ssDNA. However, an FI cross between NZB and either NZW or SWR mice is required to produce IgG nephritogenic antibodies to dsDNA and glomerulonephritis. The contribution of parental class II loci in the hybrid mice is clearly important to the development of anti-dsDNA antibodies, In contrast, NZB mice congenic with the la^bm12 mutation develop IgG autoantibodies to dsDNA despite being homozygous for Ia. As a part of our effort to examine the mechanisms of disease development in NZB.H-2^bm12 mice, we have generated a panel of monoclonal antibodies against nucleic acids. A subgroup of these antibodies exhibited strong electrostatic interaction with nucleic acids as evidenced by inhibition of their binding by a moderate increase in ionic strength. Interestingly, the effect of salt was either all or none; e.g., antibodies were either markedly inhibited or virtually unaffected. The importance of this ionic interaction was highlighted by analysis of DNA binding of antibodies from serum and nephritic kidneys of NZB.H-2^bm12 mice. Antibodies specific for ssDNA, which are common in NZB mice and not associated with nephritic lupus, are largely unaffected by salt. However, serum and kidney eluted IgG antibodies specific for dsDNA were markedly inhibited by salt. We postulate that B cell clones whose antibodies exhibit electrostatic interaction with DNA are preferentially expanded during the course of lupus in NZB.H-2^bm12 mice and that such antibodies contribute significantly to glomerulonephritis.     

B-Cell-Targeted Therapy for Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a classic autoimmune disease characterized by a myriad of immune system aberrations, most likely resulting from pathogenic autoantibody production, immune complex deposition, and subsequent end-organ damage. B cells play a key role in the pathogenesis; therefore, B-cell-targeted therapies, including B-cell depletion and blockage of B-cell survival factors such as B-lymphocyte stimulator (BLyS), are potential therapeutic targets for SLE. In uncontrolled clinical trials from approximately 20 studies, rituximab--a mouse-human chimeric anti-CD20 monoclonal antibody that effectively depletes B cells--has been demonstrated to reduce disease activity and decrease serum autoantibodies, with a clinical response of 86% in a case series of approximately 400 SLE patients with refractory disease, with or without concomitant use of cyclophosphamide. Epratuzumab, a humanized anti-CD22 monoclonal antibody that partially depletes B cells, has also been shown to reduce disease activity but not to decrease autoantibody levels in patients with moderately active SLE. Randomized controlled phase I/II trials in patients with active SLE have documented that belimumab, a humanized anti-BLyS monoclonal antibody, reduces B-cell numbers, inhibits disease activity and decreases anti-double-stranded DNA autoantibody in SLE patients. All these therapies are well tolerated, but accompanying infectious complications have been observed. Other B-cell-targeted therapies such as 'humanized' monoclonal antibodies to CD20 (e.g. ocrelizumab) and agents that interrupt B-cell/T-cell interactions also have potential, and the efficacy of these, along with rituximab, belimumab and epratuzumab, needs to be determined by randomized controlled trials.     

B-Cell Targeted Therapies in Systemic Lupus Erythematosus

Systemic lupus erythematosus is a multisystem autoimmune disease characterized by the formation of autoantibodies that target a variety of self antigens. B cells are fundamental to the development of these antibodies and are a target for intervention in the disease. This review discusses four therapies that target B cells by inducing B-cell depletion, reduction in B-cell proliferation and differentiation, or modulation of B-cell function. Rituximab is an anti-CD20 chimeric monoclonal antibody that depletes B cells but not plasma cells. Systematic reviews of open label studies, particularly in lupus patients refractory to conventional therapy, have suggested that rituximab can be an effective treatment for non-renal lupus and lupus nephritis. However, randomized, double-blind, controlled trials comparing rituximab with placebo in addition to standard of care therapy for non-renal lupus and lupus nephritis over 12 months failed to demonstrate efficacy using the planned primary endpoints, although there were some post-hoc analyses suggesting that rituximab may have beneficial effects that would be worthy of further study as no significant toxicity has been demonstrated. Treatment with belimumab, a humanized monoclonal antibody targeted against B lymphocyte stimulator (BLys), was more efficacious than placebo and had no significant increase in adverse events in two non-renal, phase III lupus trials when given in addition to standard of care therapy for 52 weeks. Belimumab is licensed for the management of lupus in the US and in Europe. Atacicept is a humanized fusion protein that binds BLys and APRIL (a proliferation-inducing ligand) that might be more effective than belimumab in the management of lupus. Unfortunately a phase II/III trial of atacicept in lupus nephritis had to be stopped due to the development of low immunoglobulin levels and pneumonias in some patients. However, in retrospect these complications may have been due to concomitant treatment with mycophenolate mofetil and results of a 52-week, non-renal, phase III trial with atacicept are awaited. Epratuzumab is a humanized monoclonal antibody that targets CD22 on B cells and results in modulation of B-cell function and migration, as CD22 regulates adhesion and inhibits B-cell receptor (BCR) signalling. Epratuzumab at a cumulative dose of 2,400 mg over 4 weeks has been shown to improve lupus disease activity compared with placebo 12 weeks after initiation of therapy in a phase II study, and a 12-month phase III study is on-going. B-cell targeted therapies are an attractive prospect for treating lupus disease and the results of current phase III trials are eagerly awaited. Finding the most appropriate trial design to demonstrate efficacy in lupus trials has been a challenge. The SRI (SLE response index) used in the belimumab studies and the BICLA (British Isles Lupus Assessment Group-based Composite Lupus Assessment) used in the epratuzumab studies are currently the promising trial designs for non-renal studies. For lupus nephritis it is important that trials are of adequate duration to be able to demonstrate benefit of new therapies over conventional therapy.