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PubMed2004

Apolipoprotein E polymorphism in patients with neuropsychiatric SLE.

The aim of this study was to investigate a relationship between neuropsychiatric SLE (NPSLE), characterized by many different neurological and psychiatric disorders, and the polymorphism of apoE as a neurobiologically important molecule conferring increased risk and a worse prognosis of a variety of CNS diseases. One hundred and forty-six SLE patients and 93 healthy controls were studied. Out of the SLE cohort, 48 patients (32.8%) were diagnosed with NPSLE and further classified according to criteria of onset, extent, relapsing tendency and type of neuropsychiatric impairment. Apolipoprotein E (apoE) polymorphism was determined by PCR-RFLP and confirmed by isoelectrofocusing. The frequency of the epsilon4 allele was significantly higher in the NPSLE group than in the non-NPSLE group (17.7% vs. 3.1%, chi(2)=19.05, p<0.0001). Distribution of apoE genotypes was significantly different between NPSLE and non-NPSLE groups (chi(2)=80.95, p<0.0001). Both epsilon4 allele frequency (17.7% vs 8.6%, chi(2)=5.082, p<0.024) and genotype distribution (chi(2)=7.202, p<0.027) were significantly different between NPSLE group and the controls. The allele epsilon4 was also associated with earlier disease onset (Fisher's test, p<0.036) and peripheral nervous system involvement (chi(2)=8.242, p<0.0041), but not with relapse frequency ( p<0.37) or major/minor subtype of the disease ( p<0.90). The epsilon4 allele carriers did not develop significantly more neuropsychiatric syndromes than non- carriers (1.75+/-0.23 sy (mean +/- SD) in epsilon4 vs 1.85+/-0.19 sy (mean +/- SD) in non-epsilon4 carriers, Mann-Whitney test, p<0.78). In conclusion, the data suggest an association between apoE polymorphism and NPSLE.

Adult↗

PubMed2004

Survival of patients with SLE admitted to an intensive care unit-a retrospective study.

We examined the demography, reasons for admission and cause of death in systemic lupus erythematosus (SLE) patients admitted to a medical intensive care unit (ICU) over a 7-year period. Fourteen patients were admitted during this period-all were female, 13 were of mixed ethnic ancestry and one a black South African. Of the 14 patients, 12 were admitted as a result of lupus activity, 2 had sepsis as the major cause of admission, although 5 other patients developed infection during their admission. Five patients had a generalised flare of their disease or progressive renal failure. Seven patients were admitted with a variety of lupus-related pathologies. In general the precise cause of death was difficult to determine. Of the 14 patients, 9 had impaired renal function on admission including 1 with sepsis and 1 of the survivors. Three patients (21%) survived, one with respiratory failure due to shrinking lung, a second with an acute flare of SLE and a third with pulmonary emboli. This study demonstrates that lupus in our community may produce life-threatening flares. Although cause of death was not always definitely identified, admission to the ICU was primarily due to active SLE and not sepsis or iatrogenic disease.

Adolescent↗

PubMed1980

Relationship of renal histopathology in SLE nephritis to immunoglobulin class of anti-DNA.

Using a newly-developed solid-phase radioimmunoassay for DNA-binding immunoglobulins, immunoglobulin M (IgM), immunoglobulin G (IgG) and immunoglobulin A (IgA) anti-DNA were measured in serums from 11 patients with active untreated systemic lupus erythematosus (SLE) with nephritis. All patients underwent renal biopsy and were classified according to standard criteria as having diffuse or focal proliferative glomerulonephritis. Although both groups had almost identical total anti-DNA (13.1 versus 13.9 micrograms/ml, respectively), the IgM to IgG ratio was significantly higher (p less than 0.01) in the group with DPGN (7.51) than in the group with FPGN (1.10). We suggest that the switchover mechanism from IgM to IgG antibody production is more profoundly impaired in SLE with severe renal disease than in SLE with mild renal disease.

Adolescent↗

PubMed1990

The structural requirements for anti-cardiolipin antibody binding in sera from patients with syphilis and SLE.

In a search for specific binding patterns of anti-phospholipid (PL) antibody reactivity in sera from patients with systemic lupus erythematosus (SLE), a quantitative assay was used to compare binding curves with those from beef heart cardiolipin (CL) and the following CL analogues: diphosphatidyl propylene glycol (DPPG), which lacks the internal hydroxyl group on the glycerol moiety; acetyl CL (ACL), in which an acetyl group is substituted for the glycerol hydroxyl group; and dimethyl CL (DCL), in which a methyl group is positioned on each phosphate group. In syphilitic sera the plateau level of antibody binding was decreased by 15 and 41% with DPPG and ACL, respectively. Binding to DCL was dramatically suppressed to levels only slightly above baseline. Only the binding curves for CL and DPPG showed saturability, and analysis by Eadie-Scatchard plots showed that the change in binding was primarily due to a more than twofold increase in KD (decreased antibody avidity). Similar patterns were seen with sera from patients with SLE and SLE-like illness, but some uniquely shaped binding curves were observed. Compared to control CL, peak binding levels were 75-88% for DPPG, 16-20% for ACL, and only 1-4% for DCL. These data indicate that the integrity of the CL headgroup, especially at the phosphate moiety, is essential for recognition by anti-CL antibodies from some sources.

Antibodies, Monoclonal↗

PubMed1988

Clinical findings in patients with SLE whose sera contain antibodies to ribosomal ribonucleoprotein.

In a clinical and serological study performed on a large series of patients with different connective tissue diseases, anti-ribosomal ribonucleoprotein (rRNP) antibodies were detected only in a small proportion of sera with systemic lupus erythematosus (SLE). SLE patients positive for anti-rRNP autoantibodies showed a significantly higher incidence of hemolytic anemia. The reasons for this surprising association are still unclear; however, this finding suggests that rRNP precipitin might be considered as a useful marker of a particular subgroup of patients with SLE.

Anemia, Hemolytic, Autoimmune↗

PubMed1991

Specific proliferative responses following the induction of experimental SLE in mice.

We have previously reported the induction of experimental systematic lupus erythematosus (SLE) in mice by immunization with a human monoclonal antibody that expresses a common anti-DNA idiotype (16/6 Id). Following immunization, antibodies directed against various nuclear autoantigens could be detected in the sera of the mice. In the present study, we investigated the proliferative responses of lymph node cells to one particular autoantigen (DNA) following the induction of experimental SLE. Cells reactive with ssDNA could be detected following immunization of BALB/c mice with the 16/6 Id. The appearance of these DNA-reactive cells succeeded the appearance of 16/6 Id-specific cells. The activation of this subset of autoreactive cells could be achieved only by the immunization of the mice with the 16/6 Id, but not by their immunization with DNA, thus suggesting that the induction of experimental SLE is associated with the alteration of the low responsive potential of the mice to DNA.

Amino Acid Sequence↗

PubMed1989

Studies of anti-F(ab')2 antibodies and VH region distribution among SLE kindreds.

Genomic DNA samples from kindreds of patients with systemic lupus erythematosus were examined for VH region genotypes using probes representing JH and representative members of the human VH gene families (VHI-VHVI) in parallel with distribution of high levels of anti-F(ab')2 (generic anti-idiotype) in some non-affected SLE family members. Identical VH region genotypes were present in an SLE female proband and one unaffected normal male sibling. Three normal unaffected family members with elevated anti-F(ab')2 showed AB, AD, and AC (non-identical)VH genotypes. VH region genotype pattern distributions do not appear to directly correlate with production of high levels of anti-F(ab')2 in SLE families.

Autoantibodies↗

PubMed1992

Implications of modifying cardiolipin acyl composition by diet. 1. Cardiolipin acyl chain is an important determinant in the binding to antiphospholipid antibodies in SLE sera.

Antiphospholipid antibodies (aPL), prevalent in sera of patients with systemic lupus erythematosus (SLE), have been linked to thrombosis, thrombocytopenia, recurrent miscarriages, neurological disorders and ischemic heart disease. Most evidence suggests that phosphodiester-linked phosphate groups are the reactive epitope of cardiolipin (CL) in binding to aPL. Little attention has been given to the acyl moiety. To address this problem we have evaluated the ELISA binding of 12 highly positive IgG anticardiolipin antibody-positive SLE sera to: bovine CL (86.1% 18:2n-6), monolyso CL (MLCL; bovine CL minus 1 fatty acid), dilyso CL (DLCL; minus 2 fatty acids), tetraoleoyl CL (TOCL), myristoyl CL (MCL) and E. coli CL. The reductions in binding of the IgG aPL antibodies relative to bovine CL were as follows: DLCL 83%; MLCL 70.7%; MCL 58%; and TOCL 14% (P less than 0.05). These data suggest that the number of acyl chains and the unsaturation of the acyl chain of CL may be important determinants in the binding to aPL present in SLE sera. To investigate the nutritional relevance of this finding, we examined the incorporation of several dietary fatty acid classes into the CL pool of mice. Mice were fed diets containing n-6 (safflower oil), n-9 (olive oil) or n-3 fatty acids as either 18:3n-3 (linseed oil) or 20:5n-3/22:6n-3 (fish oil) for a 5 month period. The feeding of fish oil and olive oil resulted in replacement of a substantial portion of 18:2n-6 with 22:6n-3 or 18:1n-9, respectively. These results suggest that there may be therapeutic value in modifying the CL acyl composition by nutritional means with respect to binding to pathogenic aPL.

Animals↗

PubMed2005

SLE: challenges and candidates in human disease.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immunological hyperactivity and multi-system organ damage. A complex genetic trait involving multiple genes, with both genetic heterogeneity and a threshold effect for disease expression, SLE involves abnormalities of both the innate and adaptive immune systems. Recognition of an 'interferon signature' in SLE leukocytes, of the role of B cells in promoting disease activity, and of FCGR3A alleles as a biomarker of end organ damage, provide important insights into disease pathogenesis. Nonetheless, coordinated studies in humans and model systems hold promise for an even more rapid advance in understanding pathways of disease development and strategies for intervention. More effective markers of disease risk, disease activity, severity of organ damage and outcomes would facilitate earlier diagnosis and guide appropriately targeted treatment.

B-Lymphocytes↗

PubMed2004

Decreased phagocytosis of apoptotic cells in diseased SLE mice.

Antibodies against nucleosomes are a serological hallmark of systemic lupus erythematosus (SLE). Apoptotic cells are the unique source of nucleosomes, which are formed through cleavage of chromatin by nucleases. These nucleosomes and other autoantigens targeted in SLE are expressed in apoptotic blebs or at the surface of apoptotic cells. Therefore, it is conceivable that circulating antibodies can influence apoptotic cell clearance. Using an in vitro phagocytosis assay, we analysed the phagocytic efficacy for apoptotic cells of resident peritoneal macrophages from pre-morbid and diseased lupus mice. The assay was carried out in the presence of autologous serum, using autologous apoptotic thymocytes as targets. Under these conditions macrophages from diseased MRL/lpr and NZBxNZW(F1) lupus mice, and from age-matched NZB mice showed a decreased phagocytic efficacy (decrease 47%, 48% and 37%, respectively compared to measurements in pre-morbid mice). The cause of this decrease resides in the serum, and is not due to an acquired defect of macrophages. In conclusion, during disease progression in murine SLE, apoptotic cell clearance becomes impaired, which might amplify further disease progression.

Age Factors↗

PubMed2004

Immunogenicity of superoxide radical modified-DNA: studies on induced antibodies and SLE anti-DNA autoantibodies.

Superoxide anion radical (SAR) is formed in almost all aerobic cells and it is the most abundant species generated by several enzymatic and non-enzymatic pathways in mammalian tissues, leading to unfavorable alteration of biomolecules including DNA. The SAR-modified macromolecules have been implicated in several disease states including disorders of inflammation. The SAR-induced damage to DNA showed hyperchromicity, single strand breaks, decrease in melting temperature, and modification of bases. Superoxide modified-DNA in rabbits elicited high titer antibodies and showed diverse antigens binding characteristics. The induced antibodies recognized native DNA and other nucleic acid polymers. Anti-DNA IgG from SLE sera, purified on Protein-A-Sepharose matrix, exhibited increased recognition of superoxide anion radical modified-DNA than native DNA in competitive immunoassay. The visual formation of immune complex between induced antibodies and native DNA, and between SLE anti-DNA IgG and superoxide modified-DNA, is a clear indication of property sharing between SLE autoantibodies and experimentally induced antibodies against superoxide modified-DNA.

Animals↗

PubMed2005

Ascites, pleural effusion, and CA 125 elevation in an SLE patient, either a Tjalma syndrome or, due to the migrated Filshie clips, a pseudo-Meigs syndrome.

BACKGROUND: The combination ascites, pleural effusion, and elevated CA 125 are usually associated with a malignancy. CASE: A 38-year-old SLE patient consulted her physician for shortness of breath. On clinical examination, she had a tender abdomen and reduced breathing sounds. X-ray and computed tomography of the chest showed pleural effusion. An adjustment of her SLE maintenance therapy was performed. Vaginal ultrasound and computed tomography of the abdomen revealed massive ascites and an intracavitair myoma of 2 cm, but no obvious mass in the pelvis. CA 125 was 887 U/ml. A laparoscopy was performed showing ascites and 2 Filshie clips embedded in the peritoneum of the vesicouterine pouch, but no sign of malignancy. Both clips were removed. The cytology of the aspirated ascites showed sings of acute inflammation. Within 10 weeks, the pleural effusion was resolved and the CA 125 normalized. CONCLUSION: The combination of ascites, pleural effusion, CA 125 elevation, and no tumor in an SLE patient is either a Tjalma syndrome or due to the migrated Filshie clips a pseudo-Meigs syndrome.

Adult↗

PubMed1987

Heat-shock protein synthesis by human peripheral mononuclear cells from SLE patients.

Peripheral blood mononuclear cells (PBMC) from systemic lupus erythematosus (SLE) patients have heat shock protein (hsp) 70 and hsp 85 as well as the response to various temperatures of normal PBMC and are inducible for these proteins over about 5-8 levels with heat exposure in short-term culture. Synthesis of hsp 70 and hsp 85 as well as the response to various temperatures and the time course of induction were typical for mammalian cell systems. This enhancement with heat-shock treatment was blocked by actinomycin D added before heat exposure. This demonstration that hsp genes are activated in PBMC from active SLE patients without heat exposure supports the hypothesis that gene activation can serve some roles in these cells and be related to the PBMC function in SLE patients. These observations are at least correlative and consistent with a possible homeostatic function for hsps in this system.

Dactinomycin↗

PubMed1988

Immunogenetics of SLE and primary Sjögren's syndrome.

SLE is a syndrome defined by clinical criteria and by the presence of autoantibodies reactive with nucleic acids and proteins concerned with transcription and translation. Breeding experiments in mice have illustrated the enormous genetic heterogeneity of this syndrome, of which the final common pathway is a widespread immune complex disease. The causes of SLE in humans are likely to be equally multifactorial. Family studies have demonstrated that genetic factors exist, but each factor appears to be a relatively weak disease-susceptibility gene. The major exceptions to this are the very rare complete deficiencies of classical pathway complement components, which are almost invariably accompanied by the development of SLE. Observations of these patients have led to the formulation of hypotheses relating complement and its receptor, CR1, to the defective removal of immune complexes from the circulation.

Animals↗

PubMed2005

[Pathogenesis of systemic lupus erythematosus (SLE)--the central role of complement].

The traditional view of the pathogenesis of SLE is that immune complexes containing autoantigens and autoantibodies activate complement, and that this causes inflammatory injury to tissues. Although this model is biologically plausible, it cannot account for all of the clinical observations that link the complement system and SLE. In particular, the observation that complement deficiency causes lupus is hard to reconcile with the concept that complement activation products are the major cause of inflammatory injury in the disease. More recent data suggests that the role of complement in SLE is rather protective. Bindung of complement might prevent an autoimmune response by supporting the clearance of immuncomplexes and apoptotic cell debrid.

Animals↗

PubMed2004

Challenges in bringing the bench to bedside in drug development for SLE.

It is now widely accepted that the current standard of care for systemic lupus erythematosus (SLE) patients is inadequate. There has not been a new medication approved for this disease in thirty years. Attempts to develop and test new drugs have been ongoing since the mid-1990s, but have encountered formidable obstacles. Current models for lupus pathogenesis have provided a theoretical framework for understanding how heterogeneous genetic defects might combine in various ways to increase susceptibility to SLE in different individuals, and could have important implications for new drug development. With the current burst of drug discovery and increased public awareness of SLE, the impetus to overcome these obstacles has never been greater.

Animals↗

PubMed1998

Anti-endothelial cell antibodies in primary antiphospholipid syndrome and SLE: patterns of reactivity with membrane antigens on microvascular and umbilical venous cell membranes.

Although there has been recent emphasis on autoantibodies to epitopes on beta-2-glycoprotein I and prothrombin in the pathogenesis of antiphospholipid syndrome (APS), antibodies other than those directed toward epitopes on phospholipid binding proteins are present. These include those reactive with antigens on platelet membrane glycoproteins, and with vascular endothelial cell membrane. As the pathogenesis of the thrombotic manifestations of APS remains unexplained, further characterization of these antibodies may be informative. We have confirmed anti-endothelial cell binding to a range of cell membrane antigens in systemic lupus erythematosus (SLE) and primary APS. Furthermore, differences in both the pattern of antibody binding and band intensity between human umbilical vein (HUVEC) and human microvascular endothelial cells (HMEC-1) were demonstrated. Of 17 primary APS sera, antibody binding to HUVEC cell membranes was found in nine and to HMEC-1 membranes in seven. Binding at 72-79 kD was confined to HUVEC. In 32 SLE sera, binding to HUVEC and HMEC-1 membranes was detected in 17 and 22 respectively, binding at 135-155 kD being confined to HMEC-1. These results are consistent with the phenotypic variation in endothelial cells of different origins and confirm the frequent presence of autoantibodies reactive with vascular endothelium in both SLE and PAPS. Whether these antibodies could be involved in the pathogenesis of thrombosis, through induction of endothelial cell apoptosis or damage, remains to be determined.

Adult↗

PubMed1996

Fc gamma RIIa polymorphism in systemic lupus erythematosus (SLE): no association with disease.

An allotypic variant of Fc gamma RIIa, Fc gamma RIIa-HR (Fc gamma RIIa-R131), has been shown in vitro to reduce the capacity of phagocytic cells to bind and internalize IgG-containing immune complexes. Our aim was to determine whether this allotypic variant was associated with susceptibility to SLE and the development of lupus nephritis, as previous studies have suggested. Fc gamma RIIA genotype analysis was performed by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) in 215 Caucasoid, 70 Afro-Caribbean, and 46 Chinese patients with SLE, and in 259,77 and 49 ethnically matched controls, respectively. Distribution of Fc gamma RIIa genotypes between the patients and ethnically matched controls was not significantly different in the three populations studied. No association between the Fc gamma RIIa-HR allotype and nephritis was found. Our results suggest that the Fc gamma RIIa-HR allotype is not a major factor predisposing to the development of SLE, or to lupus nephritis.

Base Sequence↗