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PubMed1998

Defective early T and T-dependent B cell activation in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is characterized by autoantibody production of unknown origin. Since T-B cell interaction is a key event to produce antibodies, we investigated this interaction through study of CD69, CD40 ligand (CD40L) and CD23 expression (three very early activation antigens). Peripheral blood mononuclear cells (PBMC) from inactive lupus patients were studied following culture with either medium alone, anti-CD3 monoclonal antibody (mAb), recombinant interleukin-4 (rIL-4) or phorbol myristate acetate (PMA)+/-ionomycin. Analysis of CD23 expression on lupus B cells in basal conditions and after anti-CD3 challenge of PBMC, a reflection of cognate interaction between T and B cells, was clearly defective. Conversely, CD23 expression on lupus B cells following non-cognate T cell signals (rIL-4) was preserved. CD69 and CD40L expression was also impaired in lupus T cells following anti-CD3 challenge. Nonetheless, activation by means of PMA and/or ionomycin was preserved both in T cells (CD69 and CD40L expression) and in B cells (CD23 expression). These results indicate that B cells from inactive lupus patients display a normal early response to direct B-cell stimuli. Conversely, T-dependent B-cell stimuli are clearly defective in SLE patients in remission. These results indicate that T-B cognate interaction related to defective T cell activation located between surface membrane and protein kinase C (PKC)/ionomycin function is an intrinsic characteristic of these patients.

B-Lymphocytes↗

PubMed2005

Toll-like receptor activation in the pathogenesis of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is characterized by the production of pathogenic autoantibodies to nucleoproteins and DNA. The level of anti-DNA antibodies correlates with disease severity, and the deposition of these immune complexes (ICs) in the kidneys is thought to contribute to disease pathogenesis. Recent evidence suggests that the DNA component of ICs purified from SLE patients (SLE DNA-ICs) contributes to the development of SLE pathology. SLE DNA-ICs induce proliferation of self-reactive B cells and cytokine production by plasmacytoid dendritic cells (PDCs) in a TLR9-dependent manner. One of the cytokines induced by DNA-containing ICs is interferon alpha (IFN-alpha). Elevated serum levels of IFN-alpha and overexpression of interferon-induced genes have been observed in SLE patient blood and shown to correlate with disease severity. We have recently found that the mechanism of IFN-alpha production by PDCs depends on TLR9 and FcgammaRIIa (CD32), and CD32 delivers SLE DNA-ICs to intracellular lysosomes containing TLR9. This CD32-TLR9 pathway, which is operative in PDCs, is distinct from the BCR/TLR9 pathway in B cells and may prove to be a novel target for future SLE therapies. In this article, the role of toll-like receptors, cytokines, and Fc receptors expressed by PDCs in the pathogenesis of SLE is summarized.

Animals↗

PubMed1981

Increased 16 alpha-hydroxylation of estradiol in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is one of many chronic diseases with a predilection for the human female. The reasons for the high female to male (9:1) incidence remain unknown. The total extent of hydroxylation estradiol at either C-16 to more estrogenic metabolites or at C-2 to the catechol estrogens was determined by a radiometric method in the human. Comparing 23 SLE patients to 44 normal controls, an increase in the extent of hydroxylation toward the 16 alpha-metabolites was found in SLE (SLE 15.2 +/- 4.3%, range 8.8-30%; normal 9.1 +/- 2.3%, range 5.3-14.4%; P less than 0.001). Increased 16 alpha-hydroxylation was found in both males (SLE 13.2 +/- 3.0%, normal 8.3 +/- 2.1%) and females (SLE 15.7 +/- 5%, normal 9.9 +/- 2.2%) with disease when compared to normal subjects. In addition, studies of several other chronic diseases by the same method did not indicate a similar alteration in 16 hydroxylation. No change in hydroxylation at C-2 was found in male patients, but a decrease was found in female patients. These data suggest that increased hydroxylation of estradiol at C-16 occurs in SLE. The 16 alpha-metabolites have been shown to be potent estrogens, and these data might give some insight into the pathogenesis of the disease.

Adolescent↗

PubMed2002

Systemic lupus erythematosus.

Systemic lupus erythematosus is a pleomorphic, autoimmune disorder of unknown cause that can afflict all parts of the body. New insights into its pathogenesis, the employment of preventive measures and combinations of immunosuppressive therapy, as well as the introduction of biologics, are beginning to alter the prognosis and improve the quality of life for individuals with this serious disease.

Animals↗

PubMed2003

The epidemiology of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is the most diverse of the autoimmune diseases because it may affect any organ of the body and display a broad spectrum of clinical and immunological manifestations. Although previously considered a rare disease, SLE now appears to be relatively common in certain groups of the population. This is probably due to the development of several immunological tests that have allowed the description of many atypical or benign cases that otherwise might not be diagnosed. Furthermore, with the introduction since 1982 of a set of more sensitive criteria for SLE classification, more cases can nowadays be detected. In the present article, we review the most important data regarding the incidence and prevalence of this disease in the general population, the epidemiologic information on the patterns of disease expression in specific subsets and the studies on mortality in SLE. An important amount of information comes from the data obtained from the "Euro-Lupus Cohort," a series of 1000 patients with SLE from several European countries that have been followed prospectively since 1991.

Europe↗

PubMed2004

Immunoglobulin E and systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by intense polyclonal production of autoantibodies and circulating immune complexes. Some reports have associated SLE with a Th2 immune response and allergy. In the present study 21 female patients with SLE were investigated for total IgE and IgE antibodies to dust house aeroallergens by an automated enzyme-linked fluorescent assay, and were also evaluated for antinuclear IgE autoantibodies by a modified indirect immunofluorescence test using HEp-2 cells as antigen substrate. Additionally, immunocapture ELISA was used to investigate serum anti-IgE IgG autoantibodies. Serum IgE above 150 IU/ml, ranging from 152 to 609 IU/ml (median = 394 IU IgE/ml), was observed in 7 of 21 SLE patients (33%), 5 of them presenting proteinuria, urinary cellular casts and augmented production of anti-dsDNA antibodies. While only 2 of 21 SLE patients (9.5%) were positive for IgE antibodies to aeroallergens, all 10 patients with respiratory allergy (100%) from the atopic control group (3 males and 7 females), had these immunoglobulins. SLE patients and healthy controls presented similar anti-IgE IgG autoantibody titers (X = 0.37 +/- 0.20 and 0.34 +/- 0.18, respectively), differing from atopic controls (0.94 +/- 0.26). Antinuclear IgE autoantibodies were detected in 17 of 21 (81%) sera from SLE patients, predominating the fine speckled pattern of fluorescence, that was also observed in IgG-ANA. Concluding, SLE patients can present increased IgE levels and antinuclear IgE autoantibodies without specific clinical signs of allergy or production of antiallergen IgE antibodies, excluding a possible association between SLE and allergy.

Adolescent↗

PubMed2002

Treatment options for juvenile-onset systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an inflammatory chronic disease characterized by the presence of activated helper T-cells that induce a B-cell response, resulting in the secretion of pathogenic autoantibodies and the formation of immune complexes. SLE in children is a disease of low prevalence with a wide range of clinical manifestations, which means that the number of randomized controlled studies are few and usually involve a small number of patients. In recent years, new therapeutic agents have appeared and the role of older treatments has been clarified. Many of these treatments are designed to reduce inflammation. The spectrum is broad and ranges from traditional nonsteroidal anti-inflammatory drugs (NSAIDs) to cytotoxic agents that have anti-inflammatory effects. The current treatment of children or adults depends on the clinical expression of the disease. Minor manifestations usually respond to the administration of NSAIDs, low doses of corticosteroids, hydroxychloroquine, or methotrexate. Thalidomide could be used for refractory skin lesions. Major manifestations can endanger the patient's life and require early, aggressive treatment. Kidney disease and other manifestations have been related to the formation or deposit of tissular immune complexes. Therefore, for years the main aim of treatment has been to suppress the immune response. The immunosuppressant treatments used in children with SLE include high doses of corticosteroids, azathioprine, methotrexate, cyclosporine, and cyclophosphamide. Several combinations of medications have been used to obtain a rapid remission or to reduce the risk of toxicity of prolonged administration of cytotoxic agents. Intravenous gamma-globulin has been successfully used in the treatment of lupus nephritis, vasculitis, and acute thrombocytopenia. In spite of numerous published studies, the use of these drugs is still controversial. The immunosuppression achieved with these treatments is nonspecific, not always effective, and associated with significant toxicities; the most significant being growth retardation, accelerated atherosclerosis and severe infectious complications. The purpose of new biological therapies is to achieve specific immunosuppression, which makes it possible to design more effective and less toxic therapeutic strategies. Mycophenolate mofetil is a promising alternative in patients who do not respond to high doses of cyclophosphamide or azathioprine. Some recently developed monoclonal antibodies such as anti-CD40L or anti-IL-10, or other molecules such as LJP394 may prove useful in the near future. Finally, stem cell transplantation may be proposed in patients with severe juvenile-onset SLE who do not respond to any treatment.

Adrenal Cortex Hormones↗

PubMed2002

Genome screening for susceptibility loci in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex, multigenic autoimmune disease with a wide spectrum of clinical manifestations. Much of the pathology is attributed to deposition to various tissues of immune complexes continuously formed with autoantibodies; thus, the pathogenesis is related to dysregulation of self-reactive B cells. Recent family linkage studies and allele-sharing linkage analyses of affected sibling pairs have advanced genome screening for susceptibility loci in SLE, and a considerable number of chromosomal intervals with significant or suggestive linkage to SLE have been identified. However, there are still several inherent difficulties in precisely identifying loci and genes, as the complexity of polygenic inheritance of SLE phenotypes is considerable. One must note that each specific aspect of diverse SLE phenotypes (clinical manifestations and immunological abnormalities) is mostly controlled separately by a different set of susceptibility loci. Involvement of positive and negative epistatic gene interactions often puzzles genetic analyses. Studies on SLE using murine lupus models are ongoing to solve some of these difficulties. Comparative studies have identified several syntenic chromosomal intervals with susceptibility loci in both mouse models and humans. Thus, combining knowledge derived from both human and murine studies is vital. The ultimate identification of susceptibility genes and their functions will probably depend largely on studies using genetically manipulated mutant mice, including those with homologous recombination of potent polymorphic target genes. The up-coming completion of genomic sequences in mice and humans is predicted to limit the numbers of potent candidate genes in particular genomic intervals and accelerates this line of studies. Such knowledge will lead to elucidation of genetic and cellular mechanisms involved in the dysregulation of self-reactive lymphocytes in the pathogenesis of SLE. Prophylactic and therapeutic clinical approaches can then be better designed.

Animals↗

PubMed1983

Radiologic findings in late-onset systemic lupus erythematosus.

Systemic lupus erythematosus in the elderly has a different clinical and serologic course from that in young patients. Radiographic findings in patients in whom the diagnosis was made after age 50 were compared with findings in younger patients to see if the radiologic patterns are also different. The only significant radiographic difference between the two groups was that the older group had a greater incidence of soft-tissue swelling of the hands and wrists (p less than 0.001). There was no significant difference in osteopenia, erosion, soft-tissue calcification, alignment abnormalities, or intrathoracic findings. Of 24 patients over age 50, two developed lymphoma and another developed multiple myeloma. The data agree with clinical observations that there is a higher incidence of arthritis in late-onset lupus, but clinical findings of increased incidence of pleuropericardial disease are not confirmed radiographically. The coincidence of hematologic malignancy with late-onset lupus in this series is noteworthy.

Adolescent↗

PubMed1995

Effect of histone and histone-RNA complexes on the disease process of murine systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is characterised by the production of a variety of autoantibodies against cell surface, nuclear and cytoplasmic antigens. The antigen or antigens responsible for the induction of this disease is/are unknown. We have analysed the antigenicity and pathogenicity of free histones and histones complexed with RNA in Balb/c, B10 Br, C57BL/6 and MRL-lpr/lpr mice by giving 1 microgram and 25 micrograms of each antigen intraperitoneally in complete and incomplete Freund's adjuvant. The same number of control animals were injected with either adjuvant or PBS. In the initial experiment we gave three doses of antigen at three weekly intervals. B10 Brown and C57BL/6 mice had no response to the antigens. Balb/c mice developed a mild transient antibody response against H1 histone, branched peptide of ubiquitinated H2A (peptide T4) and also against ssDNA. However in repeated experiments when the histone-RNA complex was injected into young MRL-lpr/lpr animals at two weekly intervals, a significantly increased antibody response was detected against H1, peptide T4 and some histone peptide residues (204-218 of H1, 1-20 and 65-85 of H2A, 1-25 of H2B, 1-21 of H3 and 1-29 of H4) compared to the control groups. Moreover, this group also showed elevated serum anti-DNA antibody levels and early impairment of renal function assessed by the urine protein levels. These experiments have demonstrated that there is a genetic variation in antibody responses against histones and histone-RNA complexes and that histone-RNA complexes exaggerate the disease in young MRL-lpr/lpr mice by inducing antibodies to basic regions of histones and other autoantigens.

Animals↗

PubMed1987

Prothymosin alpha restores the depressed autologous and allogeneic mixed lymphocyte responses in patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is characterized by a variety of profound T-cell abnormalities among which are decreased autologous and allogeneic mixed lymphocyte reactions (auto-MLR and allo-MLR, respectively). In a group of 10 patients with SLE, the mean auto-MLR and allo-MLR responses, tested by tritiated thymidine incorporation, were significantly decreased. If optimal doses of highly purified prothymosin alpha (ProT alpha) were present during the auto- of allo-MLR, the T-cell proliferative responses of SLE patients were increased to normal levels. ProT alpha had more pronounced enhancing effect in patients than in normal individuals. Among patients, ProT alpha was more effective in those who had active disease and low proliferative responses. These results demonstrate that ProT alpha can fully restore the deficient T-cell proliferative responses in auto- and allo-MLR in patients with SLE. ProT alpha, or a certain peptidic fragment of it, could prove potentially useful in the treatment of SLE.

Adjuvants, Immunologic↗

PubMed2001

Molecular basis of deficient IL-2 production in T cells from patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease characterized by diverse cellular and biochemical aberrations, including decreased production of IL-2. Here we show that nuclear extracts from unstimulated SLE T cells, unlike extracts from normal T cells, express increased amounts of phosphorylated cAMP-responsive element modulator (p-CREM) that binds the -180 site of the IL-2 promoter. Nuclear extracts from stimulated normal T cells display increased binding of phosphorylated cAMP-responsive element binding protein (p-CREB) to the -180 site of the IL-2 promoter, whereas nuclear extracts from stimulated SLE T cells display primarily p-CREM and decreased p-CREB binding. In SLE T cells, p-CREM bound to the transcriptional coactivators, CREB binding protein and p300. Increased expression of p-CREM correlated with decreased production of IL-2. The transcription of a reporter gene driven by the -180 site was enhanced in normal T cells, but was suppressed in SLE T cells. These experiments demonstrate that transcriptional repression is responsible for the decreased production of IL-2 by SLE T cells.

5' Untranslated Regions↗

PubMed2002

Defective production of functional 98-kDa form of Elf-1 is responsible for the decreased expression of TCR zeta-chain in patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE), the prototypic autoimmune disease, is characterized by defective expression of TCR zeta-chain. Elf-1 (E-74-like factor) is a member of the Ets (E-26-specific) family and is crucial for the basal transcription of TCR zeta-chain in Jurkat cells. We previously demonstrated that Elf-1 exists in the cytoplasm mainly as 80-kDa form and after phosphorylation and O-glycosylation it moves to the nucleus as a 98-kDa which binds DNA. We now demonstrate that Elf-1 is crucial for the transactivation of TCR zeta-chain promoter in normal and SLE T cells. Defective expression of TCR zeta-chain in SLE T cells is associated with two distinct molecular defects in the generation of the 98-kDa DNA binding Elf-1 form. In the first, the levels of the 98-kDa form were either decreased or absent. In the second, the apparent levels of the nuclear Elf-1 form were normal but included only two of the three bands into which the nuclear Elf-1 form separated in isoelectric focusing gels. Because both the transcription and the translation processes of Elf-1 gene are normal in SLE T cells, our data demonstrate that abnormal posttranslational mechanisms of the Elf-1 protein result in defective expression of functional Elf-1, and consequently, the transcriptional defect of TCR zeta-chain in patients of SLE.

Adult↗

PubMed2001

Natural medicine and nutritional therapy as an alternative treatment in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder without a known cure. Conventional medicine typically approaches the disease with a treatment plan that includes the use of corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), antimalarial drugs, and chemotherapeutic agents. The results vary and safety is questionable. Conservative treatment methods, such as the use of vitamins, minerals, and fatty acids, have been shown to have an impact on the activity of the disease. Alternative medicine treatments, including the use of dehydroepiandrosterone (DHEA) and Chinese medicines, such as Tripterygium wilfordii Hook F (TwHF), have gained a growing interest recently and may prove to be viable treatment options in the future. The elimination of possible associated factors, such as food allergens and SLE-symptom eliciting foods like alfalfa seeds, have also been shown to affect disease activity. Conservative alternative medicine approaches have been shown to provide some benefit in SLE studies; however, the evidence is limited, and the overall effectiveness and long-term safety have not been established. More research must be conducted in this area to further establish firm treatment protocols which provide maximum therapeutic benefit and minimum treatment-related side effects.

Adjuvants, Immunologic↗

PubMed2002

Emerging concepts in the molecular pathogenesis of systemic lupus erythematosus.

Systemic lupus erythematosus is a prototypic autoimmune disease that afflicts predominantly women during their child-bearing age. The disease is characterized by the production of autoantibodies and immune complexes in association with a diverse array of clinical manifestations. Investigation into the etiopathogenesis has been directed at identifying the genes that provide susceptibility to the disease, the complex cellular and cytokine aberrations and the biochemical abnormalities that are responsible for them. Understanding the immune cell signaling and gene transcription abnormalities will help us tailor new strategies for efficient biotherapy of the disease.

Animals↗

PubMed1998

Oxidants, anti-oxidants, essential fatty acids, eicosanoids, cytokines, gene/oncogene expression and apoptosis in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an auto-immune disease in which free radicals, eicosanoids, cytokines and nitric oxide seem to play a major role. An increase in the generation of superoxide anion and excess of interleukin-2 (IL-2), tumour necrosis factor (TNF) and pro-inflammatory eicosanoids and a fall in the production of nitric oxide and anti-oxidants such as superoxide dismutase and glutathione peroxidase seems to occur during the active phase of the disease. Thus, an imbalance in the pro-and anti-inflammatory molecules and a change in the delicate balance between the oxidants and anti-oxidants seems to have a vital role in the pathophysiology of SLE. In addition, a defect in the apoptosis of pro-inflammatory T cells may perpetuate the chronic inflammatory process in SLE. Thus, methods designed to suppress the generation of free radicals. IL-1, IL-2 and TNF and of eicosanoids and augment the concentrations of nitric oxide and anti-oxidants and enhance the apoptotic death of the pro-inflammatory T cells may be benefit in the management of SLE. Recent studies suggest that essential fatty acids and their metabolites, whose levels were found to be low in SLE, may restore the balance between pro- and anti-inflammatory molecules, oxidants and anti-oxidants and induce apoptosis of T cell.

Animals↗

PubMed2002

[B-cell anomalies in systemic lupus erythematosus].

Systemic lupus erythematosus is a non-organ-specific autoimmune disease characterized biologically by B lymphocyte hyperactivity and the production of autoantibodies directed against various cellular components, in particular nuclear antigens. Different strains of mice spontaneously develop a lupus-like disease and constitute a guidelight for human SLE. Both polyclonal B cell stimulation and clonal expansion induced by self-antigens participate in B cell hyperactivity observed in human and mouse SLE. B cells are hyperactive to various stimuli, in particular those delivered by T cells through surface molecules or cytokines. The consequences are an increased production of immunoglobulins and the development of autoantibodies thought to induce the major part of tissue lesions. B cells also participate in the pathological process as antigen-presenting and cytokine-secreting cells. An intrinsic defect of B cells is suspected to be responsible for B cell anomalies as illustrated by certain spontaneous murine models of SLE (motheaten mice) and by lupus-like syndromes observed in mice rendered deficient for genes controlling the B-cell receptor (BCR) signaling pathway. Genome wide scan analysis of various lupus strains allowed to identify several loci predisposing to lupus among which certain are associated with B cell hyperactivity suggesting that the intrinsic defect is inherited.

Animals↗

PubMed2002

Optic neuritis and retinal vasculitis as primary manifestations of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a common multisystem disorder. However, retinal vasculitis as a primary manifestation of SLE is uncommon, accounting for only 4% of causes of retinal vasculitis. The postulated mechanism appeared to be vaso-occlusion of the retinal arterioles by thrombosis, with resultant ischaemia. Optic neuropathy in SLE is also rare, with a prevalence of 1%. This is a case report of a young lady who presented to us with retinal vasculitis as her initial presentation of SLE. Interestingly, the pathologic mechanism appeared to be inflammatory and not vaso-occlusive.

Adult↗