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PubMed2000

[Systemic lupus erythematosus].

Systemic lupus erythematosus (SLE) is a multisystemic inflammatory rheumatic disease of unknown etiology. It is understood that immune complexes have dominant role in the pathogenesis of the disease with vasculitis being the basis of many clinical manifestations. SLE is considered to be the autoimmune disease because of many autoantibodies, some of them with the known pathogenetic role. Characteristic features of the disease are skin manifestations, arthritis, serositis as well as various tissue and organ lesions, particularly that of the kidney and nervous system. On the basis of disease activity and organ involvement the decision on the institution of immunosuppressive therapy is made.

Humans↗

PubMed2003

Is macrophage migration inhibitory factor a therapeutic target in systemic lupus erythematosus?

Systemic lupus erythematosus (SLE) is the prototype of a cluster of diseases that are characterized by a loss of self tolerance and chronic inflammation in organs including skin, kidney, brain and joints. Researchers have long debated the varying contributions of the components of the immune system to the pathogenesis of SLE, but the emigration of leucocytes from the microcirculation, and the subsequent tissue inflammation mediated by these inflammatory cells, are key features of chronic inflammation seen in SLE. Macrophage migration inhibitory factor (MIF) is a broad-spectrum pro-inflammatory cytokine. We hypothesize that MIF is an important inflammatory mediator in the perpetuation of immune activation in SLE, via its effects on activation of T and B cells, and endothelial and effector cells. As MIF exerts anti-apoptotic effects, it may also play a role in promoting abnormal survival of autoreactive lymphocytes, thus perpetuating autoimmune reactivity. In addition, MIF has a unique relationship with glucocorticoids, in that MIF can override the effects of glucocorticoids and may be important in steroid resistance. By virtue of its pluripotent functions, we propose that MIF may be a critical mediator of inflammation and damage in SLE, and that targeting of MIF may offer therapeutic benefits in this disease.

Apoptosis↗

PubMed2006

Type-I interferons and systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by the production of autoantibodies directed against nuclear antigens and chronic inflammation affecting multiple tissues. Complex genetic disorders are at the origin of the disease in humans and in SLE-prone mice, leading to the escape of auto-reactive B-lymphocytes from central and peripheral control checkpoints that operate normally in healthy organisms. Although necessary, autoimmune B-cells are not sufficient and additional mechanisms such as T-cell help are clearly needed for the disease to occur. The role of type-I interferons (type-I IFNs), and in particular IFNalpha, as prominent cofactors for SLE was suggested years ago. Leading observations in patients and recent data in SLE-prone mice have now established IFNalpha as a major actor in SLE. Several systemic clinical symptoms and laboratory findings can indeed be interpreted as downstream effects of a high IFNalpha production, and point to this cytokine as a link between the expansion of autoimmune B-cells and the stimulation of other components of the immune system. Consequently, a vicious circle is established with overt immune-cell activation and inflammatory infiltrates culminating in the selective destruction of tissue targets, notably the kidney. These notions can now be transplanted to the clinic and designate IFNalpha as a new promising therapeutic target.

Animals↗

PubMed1992

[An update on the clinical and pathogenetic value of a lymphocyte subpopulation study in systemic lupus erythematosus].

Systemic lupus erythematosus (SLE) is an entity with multiple clinical signs due to a basic immunoregulation disorder with an unbalance between humoral and cellular components of the immunological response. Its course of evolution is characterized by frequent exacerbations and remissions and the search for new activity markers of the disease is an ongoing activity. During the past years, phenotypical studies of the immunological system cells have been incorporated to the effort of establishing clinical-immunological correlations and obtaining objective parameters useful for the clinical and therapeutical management of a disease as variable as the SLE. Several disorders among lymphocitary populations have been described in the SLE; however, the published data are sometimes controversial, given the clinical and serological heterogenicity of the disease.

B-Lymphocytes↗

PubMed1994

The bcl-2 proto-oncogene is overexpressed in systemic lupus erythematosus.

Systemic Lupus Erythematosus (SLE) is a disease in which lymphoid hyper-reactivity occurs. Whether this is primary or secondary is not always clear. SLE occurs on a well defined genetic background including genes associated with the major histocompatibility complex (MHC) although family studies demonstrate that other genes must be involved as well. Other potential genes include those involved in intrinsic lymphoid hyper-reactivity, for example by preventing programmed cell death. Such examples exist in murine models of SLE, and in this study we provide evidence that one such controlling protein, bcl-2, is expressed in an increased proportion of both B and T cells in SLE patients. The increased expression was not readily related to disease activity measured by the SIS, nor by routine serological markers. This raises the possibility that the increased expression of bcl-2 seen in lymphoid cells from SLE patients may be of intrinsic genetic origin rather than being secondary to the auto-reactive process. Such increased expression could be expected to interfere with programmed cell death, to produce lymphoid hyper-reactivity and to contribute to the induction and maintenance of this prototypic systemic autoimmune disease.

Adolescent↗

PubMed2005

[Diagnostic problems and evaluation of disease activity in systemic lupus erythematosus].

Systemic lupus erythematosus (SLE) is a chronic multisystem inflammatory disorder characterised by autoantibodies production. The diagnosis of disease requires evidence of 4 out of 11 clinical and/or laboratory symptoms proposed by American College of Rheumatology. For many years attention has been drawn to the problem of finding a valid and sensitive tool for measuring SLE activity and more than 60 different methods have been proposed. Unfortunately none of them has been generally accepted. Amongst the most frequently used are SLEDAI scale and its modifications, BILAG and SLAM. The systems have been validated in prospective studies, and their reproducibility, validity and sensitivity have been compared. At present they are widely used in clinical practice. In this review currently accepted methods of SLE activity evaluation are presented.

Diagnosis, Differential↗

PubMed1982

Studies of immune abnormalities in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) in humans and in mice appears to be a syndrome with different cellular bases. In individuals, the illness is influenced by a variety of factors, including genetic, hormonal, immune, and environmental. In mice, SLE can be induced with polyclonal B-cell activators and thymectomy. Retardation of disease occurs with the gene xid on an NZB background. Tolerance studies indicate that tolerance depends upon a normal thymus. In addition, females can be nontolerant with a single immune defect, whereas males can become tolerant with only one defect; they become nontolerant with two immune defects. These studied may help to explain the prevalence of SLE in females and the protective effects of androgens. Human SLE is characterized by excessive B cell activity and impaired T cell activity, especially in active disease. A scheme by which the disease becomes activated is put forth. The details of cell-cell dialogue are becoming clearer with study of the autologous mixed lymphocyte reaction. T 4+ cells provide helper signals for T 8+ cells. Macrophages and T cells combine to regulate the AMLR. The AMLR itself gives rise to a variety of functional cells and serves as an amplification system. This system is defective in active SLE. Preliminary attempts have been made to separate human SLE into subgroups on the basis of the ratio of helper to suppressor cells (RT). A low RT is associated with renal disease, whereas a high RT characterizes patients with a multisystem illness with less important kidney involvement.

Androgens↗

PubMed2002

Identification of autoantibodies associated with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the presence of antinuclear antibodies. We performed serological analysis of cDNA expression library (SEREX) to identify autoantibodies associated with SLE. The screening of three different cDNA expression libraries with pooled sera of patients with SLE yielded 11 independent clones that reacted with pooled sera of patients with SLE. In this screening, autoantibodies to poly(ADP-ribose) polymerase (PARP), U1snRNP, and galectin-3 were prevalent in the sera of patients with SLE (26/68, 25/68, 12/63, respectively). The frequency of autoantibody to PARP was significantly higher in SLE than that of healthy donors (0/76) (38.2% vs 0%, p<0.00001). The autoantibody to PARP was infrequently detected in the serum of patients with RA (1/50). However, autoantibody to PARP was not found in the sera of patients with other rheumatic diseases including Sjogren's syndrome (0/19), systemic sclerosis (0/18), and polymyositis/myositis (0/37). The frequency of autoantibody to human galectin-3 (12/63) was significantly higher in SLE than that of healthy donors (0/56) (19% vs 0%, p=0.0006). Autoantibody to galectin-3 was not found in the sera of patients with rheumatoid arthritis (0/50), Sjogren's syndrome (0/18), and systemic sclerosis (0/19). Interestingly, autoantibody to galectin-3 was also prevalent in the sera of patients with polymyositis/dermatomyositis (16/37, 43.2%). Further functional characterization of these autoantibodies would be necessary to determine their value as diagnostic markers or to define clinical subsets of patients with SLE. Statistical analysis revealed that the presence of autoantibody to PARP was inversely related with pleurisy, and the presence of autoantibody to galectin-3 related with renal disease.

Adult↗

PubMed1989

[Acute massive mediastinal hemorrhage three weeks after mitral valve replacement in a patient with systemic lupus erythematosus].

Systemic lupus erythematosus (SLE) is one of the most common autoimmune diseases and patients suffering from this disease often died of massive hemorrhage. We report the case of a patient who died of acute massive hemorrhage three weeks after mitral valve replacement. The patient, a 42 year-old woman, had been diagnosed as having valvular heart disease at the age of 10. She underwent mitral commissurotomy at the ages of 18 and 32. SLE was diagnosed 8 years previously and corticosteroid therapy was initiated. The patient was experiencing exertional dyspnea again 1 year ago and mitral valve replacement was performed for recurrent stenosis. The postoperative course seemed to be uneventful, but on the 21st postoperative day, acute massive mediastinal hemorrhage occurred, and the patient eventually died of septicemia. Massive hemorrhage in SLE patients usually occur in the central nervous system or alimentary tract. However, bleeding can occur anywhere, so great care must be taken in regulating anticoagulant therapy.

Adult↗

PubMed1991

Antibodies to vascular heparan sulfate proteoglycan in patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease which involves the basement membranes of blood vessels in multiple organs. An important component of the microvasculature is vascular heparan sulfate proteoglycan (HSPG). In this study, we investigated the presence in SLE and other immune disease sera of autoantibodies to purified vascular HSPG. Our data demonstrate that antibody to HSPG is found primarily in SLE sera, and not in sera from controls or patients with other immune diseases. The titer of antibody to HSPG correlated with complement depletion in SLE sera. Antibody to HSPG was frequently found in high titer in SLE patients with renal and neurologic involvement. These studies indicate that our assay for antibody to vascular HSPG detects a pathologically relevant autoantibody in SLE sera. The implications of our findings for pathogenesis of vascular autoimmunity are discussed, including the relationship of anti-vascular HSPG antibody to anti-DNA and antiphospholipid antibodies.

Administration, Topical↗

PubMed1988

Neuropsychological correlates of serum lymphocytotoxic antibodies in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by frequent neuropsychiatric (NP) manifestations. At least two different pathogenetic mechanisms have been proposed for NP-SLE, including vasculitis and antibodies against neuronal antigens, the latter as expressed by the presence of brain cross-reactive lymphocyte antibodies. We have previously reported a high prevalence of cognitive dysfunction in SLE which can remain subclinical and which cannot be accounted for on the basis of disease activity, general distress, or steroid medication. In the present study, we undertook the same extensive, standardized neuropsychological testing in 98 consecutive female SLE patients in order to evaluate central nervous system functioning in relation to serum lymphocyte antibodies which were measured at the time of neuropsychological testing by a microcytotoxicity test. A significant association was observed between the presence of serum lymphocytotoxic antibodies (LCA) and cognitive impairment in patients with SLE. The pattern of impairment which predominated in the LCA-positive patients involved deficits in anteriorly associated, primarily visuospatial functions. These findings support the hypothesis of localization of a particular antigen-antibody interaction in the brain in SLE, suggesting the existence of immunological control mechanisms for normal brain functioning.

Antilymphocyte Serum↗

PubMedDate not supplied

Drug-induced systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) induced by drugs, primarily hydralazine and procainamide, is reviewed and compared with idiopathic SLE, and the use of these drugs in patients with idiopathic SLE is discussed. The etiology of SLE is unclear, but genetic predisposition is an important factor. Although more than 25 drugs have been suggested as causes of SLE, the majority of confirmed cases of drug-induced SLE involve hydralazine or procainamide. Parts of these chemical compounds apparently interact with nucleoproteins, causing stimulation of antinuclear antibody (ANA) production. The average age of patients with drug-induced SLE is nearly twice that of patients with idiopathic SLE. Approximately half the patients with drug-induced SLE are women, compared with 92% of patients with idiopathic SLE. For SLE induced by hydralazine or procainamide, musculoskeletal symptoms (especially arthritis in the hands and wrists) are the most common clinical manifestation. In patients with SLE induced by these drugs, ANAs and LE cells are present, erythrocyte sedimentation rate is often elevated, and a false-positive serologic test for syphilis is seen more frequently than in idiopathic SLE. Baseline ANA status should be determined before therapy with these drugs, and patients should be observed carefully for signs and symptoms of SLE. Hydralazine-induced SLE may be dose related; limiting the daily dose to 200 mg is recommended. Some drugs have been shown to exacerbate idiopathic SLE; these include estrogen-containing oral contraceptives and ibuprofen. Hydralazine and procainamide are probably safe for use in patients with idiopathic SLE, but alternative therapy should be considered. The clinical and laboratory manifestations of drug-induced SLE are similar to those of idiopathic SLE, but central nervous system and renal involvement are rare in drug-induced SLE.

Adrenergic beta-Antagonists↗

PubMed2006

The role of toll-like receptors in systemic lupus erythematosus.

Systemic lupus erythematosus is an autoimmune disease characterized by the production of autoantibodies against a relatively limited range of nuclear antigens. These autoantibodies result in the formation of immune complexes that deposit in tissues and induce inflammation, thereby contributing to disease pathology. Growing evidence suggests that recognition of nucleic acid motifs by Toll-like receptors may play a role in both the activation of antinuclear B cells and in the subsequent disease progression after immune complex formation. The endosomal localization of the nucleic acid-sensing Toll-like receptors (TLRs), TLR3, 7, and 9, is believed to contribute to the distinction between endogenous nucleic acids and those of foreign origin. In this article we review recent work that suggests a role for the B-cell receptor and Fcgamma receptors in delivering nuclear antigens to intracellular compartments allowing TLR activation by endogenous nucleic acids. A number of in vitro studies have presented evidence supporting a role for TLRs in SLE pathology. However, recent studies that have examined the contributions of individual TLRs to SLE by using TLR-deficient mice suggest that the situation is far more complicated in vivo. These studies show that under different circumstances TLR signaling may either exacerbate or protect against SLE-associated pathology. Further understanding of the role of TLRs in pathological autoreactivity of the adaptive immune system will likely lead to important insights into the etiopathogenesis of SLE and potential targets for novel therapies.

Animals↗

PubMed2001

Presence of cutaneous interferon-alpha producing cells in patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) patients have increased levels of interferon-alfa (IFN-alpha) in the circulation but a reduced number of functionally intact natural IFN-alpha producing cells (IPC) in peripheral blood. In search for tissue localisation of activated IPC, we investigated skin biopsies from SLE patients for the occurrence of such cells. Eleven SLE patients with inflammatory skin lesions and six healthy controls were biopsied. An immunohistochemical technique (IH) and in situ hybridisation (ISH) were used to detect intracellular IFN-alpha protein and IFN-alpha mRNA, respectively. In all 11 biopsies from SLE lesions, a high number of IPC were detected by IH. In the nonlesional SLE biopsies we could also demonstrate IPC in 10/11 patients. In 6/11 SLE patients, IFN-alpha mRNA containing cells could be detected in the specimens. A low number of IPC were detected in 1/6 healthy controls by IH, but no ISH positive cells were seen. Our results demonstrate that SLE patients have active IPC in both dermal lesions and in noninflammatory skin. A recruitment of IPC from blood to peripheral tissues may explain the low number of circulating natural IPC in SLE patients. Because the type I IFN system is involved in the SLE disease process, these results are of interest for the understanding of the pathogenesis in SLE.

Adult↗

PubMed2007

The inflammation and coagulation cross-talk in patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic inflammatory disorder with a high prevalence of cardiovascular disease due to accelerated atherosclerosis, as well as an increased risk of venous thromboembolism. Many of these clinical features have been attributed to the high prevalence of autoantibodies that are directed against phospholipid-bound antigens and that induce prothrombotic effects and disturb endothelial cell function. We conducted a case-control study in a cohort of female patients with SLE and in age-matched and sex-matched normal individuals. Patients had significantly higher levels of plasma inflammatory markers, but their overall coagulation status assessed by prothrombin fragment 1 + 2 and D-dimer plasma levels was not different from controls. Resistance against activated protein C (APC), assessed by a thrombin generation-based as well as an activated partial thromboplastin time-based method, however, was increased in patients. This defect was neither due to factor V Leiden carriership or to the use of oral contraceptives. This acquired form of APC resistance was due to proinflammatory changes associated with lower plasma levels of free protein S. In conclusion, acquired APC resistance may be an important determinant of the risk of thrombosis in patients with SLE, probably due to an active cross-talk between inflammation and coagulation systems.

Activated Protein C Resistance↗

PubMed2006

Clinical, serologic, and genetic profiles of patients with associated Sjögren's syndrome and systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS) can coexist in patients. The aim of this study was to investigate the clinical, laboratory, and serologic features of the association of the two diseases. Data from 56 patients having both SS and SLE were analyzed, with special emphasis on their clinical, laboratory, and serologic features. Data from 50 patients with SLE and 50 patients with SS served as control subjects. The mean age in SS-SLE group was lower than in patients with SS but higher than patients with SLE. When SLE and SS were associated, presence of rheumatoid factor was less frequent, whereas anti-Ro/SS-A, anti-La/SS-B, antinuclear, anti-DNA, and antiphospholipid autoantibodies appeared more often. Antiphospholipid syndrome, anemia, leucopenia, and lymphopenia were more frequent in the associated disease than in patients with SS alone. In SS-SLE patients, pulmonary, renal, skin, central nervous system involvement, and serositis occurred more often than in patients with SS alone. Thyroiditis, autoantibodies to Ro/SS-A, La/SS-B and ds-DNA was more frequent in the SS-SLE group than in patients with SLE. Genetic background of the patients did not differ significantly. In conclusion, characteristic clinical, laboratory and serologic features distinguish between the association of SS and SLE and the primary forms of these two diseases.

Adult↗

PubMed2003

Mycobacteria, an environmental enhancer of lupus nephritis in a mouse model of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by the production of antibodies directed against self antigens. Immune complex glomerulonephritis (GN) is one of the most serious complications of this disorder and can lead to potentially fatal renal failure. The aetiology of SLE is complex and multifactorial, characterized by interacting environmental and genetic factors. Here we examine the nature of the renal pathology in mycobacteria-treated non-obese diabetic (NOD) mice, in order to assess its suitability as a model for studying the aetiopathogenesis of, and possible treatment options for, lupus nephritis (LN) in humans. Both global and segmental proliferative lesions, characterized by increased mesangial matrix and cellularity, were demonstrated on light microscopy, and lesions varied in severity from very mild mesangiopathic GN through to obliteration of capillary lumina and glomerular sclerosis. Mixed isotype immune complexes (IC) consisting of immunoglobulin G (IgG), IgM, IgA and complement C3c were detected using direct immunofluorescence. They were deposited in multiple sites within the glomeruli, as confirmed by electron microscopy. The GN seen in mycobacteria-treated NOD mice therefore strongly resembles the pathology seen in human LN, including mesangiopathic, mesangiocapillary and membranous subclasses of LN. The development of spontaneous mixed isotype IC in the glomeruli of some senescent NOD mice suggests that mycobacterial exposure is accelerating, rather than inducing, the development of GN in this model.

Animals↗

PubMed2005

Removal of dying cells and systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a very heterogeneous systemic autoimmune disease, in which autoantibody synthesis against nuclear constituents is the main immunological characteristic. These autoantibodies underwent affinity maturation and isotype switching. Additionally, T-cell tolerance against nuclear autoantigens should be affected in these autoimmune patients. Nuclear material derived from apoptotic and/or necrotic cells may serve as an important source of autoantigens. However, dead and dying cells as well as cellular debris are rapidly removed from tissues by phagocytes without eliciting inflammation or immune responses under healthy conditions. During apoptosis nuclear components are strongly modified through enzymatic reactions. If these cells are not timely cleared, those autoantigens may be released, taken up, and presented by dendritic cells in tissues or presented by follicular dendritic cells in lymph nodes to T and B cells, respectively. This could be a mechanism for breaking the peripheral self-tolerance. In this article we focus on the deficient clearance of apoptotic cells in SLE patients and its importance in development of this autoimmune disease.

Journal Article↗