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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↗

PubMed2006

A case of interface perianal dermatitis in a dog: is this an unusual manifestation of lupus erythematosus?

Discoid lupus erythematosus (DLE) is a well-known autoimmune disorder described in dogs and humans. In dogs, DLE is considered the second most common immune-mediated dermatitis and is usually localized to the nasal planum. DLE does not evolve to generalized disease, however lesions may spread to the bridge of the nose and less commonly may extend to periocular region, pinnae, distal limbs, and mucocutaneous junctions (lips, oral cavity, and genital region). A 4-year-old male Bavarian Mountain Scenthound developed a chronic, erosive, cutaneous lesion located exclusively in the perianal region without facial skin involvement. Clinical signs included erythema, depigmentation, severe alopecia, crusting, and ulceration. Histologically, the hallmarks of the changes were an interface dermatitis consisting of plasma cells, lymphocytes, neutrophils, and macrophages, hydropic degeneration of basal cells, few apoptotic cells in the basal layer, pigmentary incontinence, and a focal thickening of the basement membrane, which was characterized by linear deposition of IgG. Despite the unusual localization the lesion was diagnosed as DLE based on the characteristic histologic and immunohistologic features. Following diagnosis, corticosteroid therapy resulted in a complete resolution of perianal lesions.

Anal Canal↗

PubMed1993

Pathophysiology and pharmacology of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is the classical example of an immune complex (IC) associated systemic autoimmune disease. Although an important part of SLE etiopathogenesis has yet to be discovered, it is generally accepted that genetic factors, sex hormones, alternations in T- and B-lymphocyte activity and defects in RES-function contribute to the development of SLE. In an SLE patient, symptoms and severity of the disease are linked to the pattern of autoantibodies expressed, referring to some pathophysiological importance of antibodies found in SLE. In addition, the interindividually variable expression of antibodies to ds-DNA, Ro or anticardiolipin, for example, permit a subtyping of SLE and indicate SLE as collective concept of heterogeneous systemic connective tissue diseases with overlapping, e.g. to dermatomyositis, progressive systemic sclerosis or Sjögren's syndrome. In view of the variable, heterogeneous disease manifestations, it is obvious that the strategy in SLE therapy is to treat manifestations and not just SLE per se. Using this concept together with pathophysiologically related control parameters and standard clinical investigations, 90 to 95% of SLE patients are adequately treated with NSAID, steroids, antimalarials and immunosuppressiva. Only 5-10% need experimental therapy, and this kind of treatment should be strictly limited to this group.

Autoantibodies↗

PubMed1989

The role of the idiotypic network in the induction of experimental systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) has been induced in C3H.SW mice by their immunization with a human monoclonal anti-DNA antibody that bears a common idiotype-16/6 Id. Following immunization, high levels of murine anti-16/6 and anti-anti-16/6 antibodies were detected in the sera of the immunized mice. Elevated titers of autoantibodies reacting with ssDNA, dsDNA, poly(I), poly(G), RNP, Ro, and La were also observed. The serological findings were associated with significant proteinuria, leukopenia, and elevated erythrocyte sedimentation rate. Immune complex deposition in the glomerular mesangium and sclerosis of the glomeruli were demonstrated. To study whether or not anti-idiotype antibodies are involved in the induction of the disease, a murine monoclonal antibody against the 16/6 Id was prepared and injected into C3H.SW mice. The anti-16/6 Id antibody induced experimental SLE similarly to the 16/6 Id with an accelerated kidney pathology. A study performed on different mouse strains indicated that the susceptibility to the induction of SLE by the 16/6 Id is strain dependent and directly correlates to their ability to produce anti-16/6 Id specific antibodies.

Animals↗

PubMed2004

Aortic aneurysm in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is frequently associated with cardiovascular manifestations, but rarely complicated with aortic disease. We report a 28-year-old female patient with a 14-year history of SLE and a 3-year history of hypertension. She had suffered from palpitation and chest tightness for 1 month before admission. Heart echo showed thoracic to low abdominal level with low flow. A computed tomography (CT) scan confirmed aneurysms of the descending thoracic and upper abdominal aorta, down to the renal level. Diagnosis of aortic aneurysm should be considered in patients with SLE, especially those who have a history of hypertension, prolonged steroid use, palpitation and chest pain. Current imaging modalities, such as cardiac echo, CT and magnetic resonance angiography may provide earlier detection of subclinical disease, which may aid in preventing these fatal complications. It is important to control hypertension aggressively in patients with SLE. In addition to decreasing steroid doses, early use of immunosuppressive agents and accurate noninvasive image modalities may allow us to prevent severe damage to the aorta and avoid the fatal complications.

Adrenal Cortex Hormones↗

PubMedDate not supplied

High levels of TH2 cytokine gene expression in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease with a clear imbalance in the network made up of different cytokines. However this statement has been derived from studies which have focused on the analysis of some specific cytokines and few have simultaneously analyzed those cytokines that could be involved in the pathogenesis of SLE. Therefore, we decided to analyze interleukin IL-1b, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor-a (TNF-a) and gamma interferon (IFN-g) gene expression in peripheral blood mononuclear cells from 17 women with SLE and 10 normal females by a coupled reverse transcriptase-polymerase chain reaction technique. High gene expression of IL-4, IL-6, IL-10 and TNF-a was found in SLE patients as compared to normal subjects. The expression of IL-1b, IL-2 and IFN-g genes was low or undetectable. The resulting high level of cytokines with strong effect on proliferation and differentiation of B lymphocytes in SLE could be responsible for the characteristic B cell hyperactivity and autoantibody production seen in SLE.

Adolescent↗

PubMed1997

Lymphocyte subsets in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterised by increased B cell activity and depressed T cell function. However, the contribution of the immunoregulatory system to its pathogenesis is still unclear. The recent development in the production of monoclonal antibodies and the availability of bench-top flow cytometers have allowed rapid quantitation of peripheral blood lymphocyte subsets. We analysed the distribution of the lymphocyte subsets in 24 patients with active SLE and 18 with inactive SLE. The distribution of immunoregulatory cells in 72 normal volunteers was used as control. Statistical analysis showed that there were significant differences between both the SLE groups and the normal controls, for total lymphocytes, T cells, B cells, T helper cells, T suppressor cells, T helper/suppressor ratio and natural killer cells. There was a significant difference for T helper cells between active and inactive SLE. T helper cells levels were found to be low in inactive SLE and lower in active SLE. It appears that treatment-induced remissions did not restore the levels of immunoregulatory cells to normal. Thus, T helper cell levels reflect disease activity and longitudinal assays of T helper cells may serve as an indicator of disease reactivation.

Adult↗

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↗

PubMed1991

Anticardiolipin antibodies in patients from Malaysia with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is highly prevalent in Malaysia, which has a mixed population of Malays, Chinese, and Indians. A quantitative enzyme linked immunosorbent assay (ELISA) was used to determine anticardiolipin antibody (aCL) levels (total immunoglobulin, IgG, and IgM) in 200 patients with SLE (164 Chinese, 26 Malay, and 10 Indian) attending the University Hospital of Kuala Lumpur, Malaysia, and 103 matched controls. Only 33 (16.5%) of the patients had raised aCL levels; 26 had raised IgG aCL, five IgM aCL, and two both IgG and IgM aCL. There was a low prevalence of raised levels of aCL in the population studied, which was seen in conjunction with a rare occurrence of thrombosis. The classical association of high aCL levels with thrombocytopenia and recurrent abortions was noted, though not with cerebral disease. The low prevalence of aCL in this study population of mixed racial origin contrasts with findings in European patients with SLE and lends support to the influence of local factors, be they genetic or environmental, on the clinical manifestations of this disease.

Abortion, Habitual↗

PubMedDate not supplied

Animal models of human systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a human autoimmune disease of unknown etiology. Clinical, serologic, immunologic, and pathologic findings are highly variable in different patients and at different times in the same patient. Murine and canine animal models of SLE have been found with clinicopathologic abnormalities resembling those observed in humans. Each animal model has unique characteristics; taken together they reflect the spectrum of disease in human SLE.Investigations in the animals have suggested that genetic, hormonal, immunologic, viral, and other environmental factors contribute to and modify the expression of disease. Where analogous studies are available for humans, the same factors have been found to modify disease expression in a similar fashion. Together, these studies have helped to clarify the multifactorial basis for SLE.The best characterized abnormalities are immunologic. These include excessive B cell function with the formation of large amounts of autoantibodies, and T cell abnormalities which include defects in T cell regulatory function as well as certain T cell effector functions.The animal models of SLE also serve as convenient test subjects for newer therapeutic modalities. It is hoped that further study of the animal models will provide a more rational approach to therapeutic modulation of disease in humans with SLE.

Animals↗

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↗

PubMed2000

Impairment of genomic DNA binding to a putative dysfunctional receptor on erythrocytes independent of complement and antibodies in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is characterized by a variety of autoantibodies and other immune abnormalities indicative of an immunological hyperactivity. Antibodies against native DNA, however, are a disease-specific marker and play a major role in the pathogenesis of systemic or organ-specific disease manifestations. Nevertheless, the mechanisms causing the appearance of autoantibodies and immune complexes in SLE are not yet understood. Here, we report that chromosomal DNA and other forms of nucleic acids are usually cleared from circulation by binding to a yet unidentified receptor-like protein on the surface membrane of erythrocytes, independently from complement or antibodies. The binding kinetics of DNA and other nucleic acids to erythrocytes are significantly altered in SLE patients, showing an overall reduced binding capability and presaturated binding kinetics. Significant amounts of chromosomal DNA can be isolated from erythrocytes of SLE patients but not from normal controls. Electron microscopy shows electron-dense particles on the surface of SLE erythrocytes (approximate size 20-40 nm). Comparative genomic hybridization reveals that the nucleic acid isolated from erythrocytes of SLE patients is of genomic and random origin, leading to an accumulation of "free" nucleic acids in the periphery, which eventually induces a B-cell immune response.

Antibodies↗

PubMed2006

Immunoglobulin GM and KM genotypes in Korean patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune complex deposition. We genotyped immunoglobulin allotypes of G1M (f,z), G2M (n+,n-), G3M (b,g) and KM (1,3) in 142 Korean patients with SLE and 200 healthy controls to investigate the role of the allotypes in SLE. The allele frequency of G1M (z) was significantly higher in patients with SLE as compared to the healthy controls (94.6% vs. 84.3%, corrected P = 0.0004, OR 3.30, 95% CI 1.71-6.88). The frequency of G2M (n-) allele was also higher in patients with SLE (95.3% vs. 88.3%, corrected P = 0.008, OR = 2.71, 95% CI 1.38-5.72). Distribution of the tested allele frequencies for G3M and KM were not different between the patients and controls. In the respect of antibody production, there was increased genotype frequency of G1M (z/z) in anti-Sm(-) SLE (P = 0.023 vs. control, P = 0.042 vs. anti-Sm (+) SLE). In conclusion, particular genotypes at G1M (f,z) and G2M (n+,n-) loci are significantly associated with SLE. These immunoglobulin genes may contribute to the etiology of SLE and production of autoantibodies.

Adult↗

PubMed2006

Increased aortic pulse wave velocity in middle aged women with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a connective tissue disease where inflammatory activity affects several organ systems. An increased risk of cardiovascular disease has been identified in these patients, even after correction for traditional risk factors. The aim of the present study was to evaluate arterial stiffness and central hemodynamics in women with SLE in comparison to controls. Arterial tonometry was used to measure aortic (carotid-femoral) and arm (carotid-radial) pulse wave velocity (PWV), reflected pressure waves, and aortic augmentation index (AIx) in 27 women with SLE (52 to 68 years) and 27 controls. Aortic PWV was higher in women with SLE than controls, 9.8 m/s versus 8.2 m/s (P < 0.01), after correction for mean arterial pressure and body mass index, 9.5 m/s versus 8.5 m/s (P < 0.05). Other parameters were similar, arm PWV, 8.4 versus 8.5 m/s, AIx 34 versus 33% and calculated central aortic pulse pressure 48 versus 43 mmHg, in SLE and controls, respectively (NS). Aortic PWV was positively associated to C-reactive protein (CRP) and complement factor 3 (C3). Women with SLE have increased stiffness of their elastic central arteries. This may be one factor contributing to the increased cardiovascular risk seen in this cohort.

Aorta↗

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↗

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↗

PubMed2004

Subcutaneous panniculitis-like T-cell lymphoma with vacuolar interface dermatitis resembling lupus erythematosus panniculitis.

Lupus erythematosus (LE) panniculitis (LEP) is a form of chronic cutaneous LE most often characterized by erythematous subcutaneous nodules. The histopathology of LEP may be distinctive, allowing a diagnosis even in the absence of any other LE features. Lymphocytic infiltration of the panniculus is termed lymphocytic lobular panniculitis. This entity has been reported in both LEP and subcutaneous panniculitis-like T-cell lymphoma. We describe a 67-year-old woman who presented with multiple dermal and subcutaneous nodules on her legs and hips. Biopsy specimens of roughly 15 lesions were interpreted as being diagnostic of LEP, however, with each subsequent biopsy specimen more atypical cells were observed. The patient responded only to moderate doses of oral prednisone, and failed intralesional triamcinolone acetonide, oral immunosuppressive agents, oral antimalarial agents, and oral thalidomide. Three years after the onset of her disease, ulcerated plaques and nodules developed. At this time a T-cell receptor gene rearrangement was present and subcutaneous panniculitis-like T-cell lymphoma was diagnosed. Despite multiple doses of chemotherapy she died approximately 1 year after diagnosis. Patients with apparent LEP that have atypical lymphocytes in their biopsy specimens should be followed up closely for the development of T-cell malignancy.

Aged↗

PubMed2006

A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by activation of the type I interferon (IFN) pathway. Here we convincingly replicate association of the IFN regulatory factor 5 (IRF5) rs2004640 T allele with SLE in four independent case-control cohorts (P = 4.4 x 10(-16)) and by family-based transmission disequilibrium test analysis (P = 0.0006). The rs2004640 T allele creates a 5' donor splice site in an alternate exon 1 of IRF5, allowing expression of several unique IRF5 isoforms. We also identify an independent cis-acting variant associated with elevated expression of IRF5 and linked to the exon 1B splice site. Haplotypes carrying the variant associated with elevated expression and lacking the exon 1B donor site do not confer risk of SLE. Thus, a common IRF5 haplotype driving elevated expression of multiple unique isoforms of IRF5 is an important genetic risk factor for SLE, establishing a causal role for type I IFN pathway genes in human autoimmunity.

Case-Control Studies↗