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PubMed2005

Infections and SLE.

Viral and bacterial infections may serve as an environmental trigger for the development or exacerbation of systemic lupus erythematosus (SLE) in the genetically predetermined individual. In addition, SLE patients are more prone to develop common (pneumonia, urinary tract infection, cellulitis, sepsis), chronic (tuberculosis), and opportunistic infections possibly due to inherit genetic and immunologic defects (complement deficiencies, mannose-binding lectin [MBL] polymorphisms, elevated Fcgamma III and GM-CSF levels, osteopontion polymorphism), but also due to the broad spectrum immunosuppressive agents that are part of therapy for severe manifestations of the disease. Hence, SLE patients are considered a high-risk population, where identification and treatment of chronic infections such as tuberculosis, hepatitis B or human immunodeficiency virus, are important prior to the institution of immunosuppression so as to prevent reactivation or exacerbation of the infection. Infections in SLE patients remain a source of morbidity and mortality. A caveat often encountered is to distinguish between a lupus flare and an acute infection; in such cases parameters including elevated CRP (and adhesion molecules) may aid in the diagnosis of infection. Recent research has provided convincing evidence that EBV infection may play a major role not only in molecular mimicry but also in aberrations of B cells and apoptosis leading to a state of perpetual heightened immune response in SLE.

Animals↗

PubMed1999

Cytogenetic study and FISH analysis in lymphocytes of systemic lupus erythematosus (SLE) and systemic sclerosis (SS) patients.

Systemic lupus erythematosus (SLE) and systemic sclerosis (SS) are autoimmune diseases characterized by the presence of antibodies against ubiquitous self antigens. The presence of clastogenic factors (CF) capable of inducing chromosome breakage has also been reported in the plasma of some patients. We aimed to assess basal frequency of cytogenetic damage in lymphocytes and presence of CF in the plasma of two groups of SLE and SS patients displaying a different antibody status (ACA-/Scl70+ or ACA+/Scl70-), using the micronucleus (MN) assay and FISH analysis with a pancentromeric DNA probe. As compared with controls, we found significantly higher MN frequencies in SS patients, but not in SLE patients. In addition, our data showed a significant prevalence of C-MN in SLE and ACA-/Scl70+ patients and of C + MN in ACA+/Scl70- patients. We observed a positive response in three out of the five CF experiments performed on plasma of SS patients. The three patients whose plasma caused MN induction were subtyped as ACA-/Scl70+, whereas the other subjects had ACAs. The same tests on six SLE patients gave negative results.

Adult↗

PubMed1979

Significance of levels of specific immunoglobulins to DNA in SLE patients' sera detected by solid phase radioimmunoassay.

A solid phase radioimmunoassay was developed for detecting the quantity of double-stranded and single-stranded DNA antibodies in patients with systemic lupus erythematosus and other connective tissue diseases. The assay system employs a solid support 96-well, flex-vinyl microtiter plate to which bovine methyl albumin is layered, followed by denatured or native calf thymus DNA. A 1:80 dilution of patients' sera was added to respective wells followed by tritiated high affinity anti-IgG, -IgA, or IgM. Denatured DNA (single-stranded DNA) bound to methylated bovine serum albumin had less than 5% reannealment to the double-stranded form and provided a better substrate for Ab binding than double-stranded DNA, producing a linear binding curve. Of 58 patients diagnosed as having systemic lupus erythematosus (SLE), only 11 having active SLE had IgG antibody levels of greater than 5.0 microgram/ml to single-strand DNA. Renal involvement of some degree was found in all 11 with the high concentrations of IgG antibodies to DNA correlating with severe involvement. Patients with IgM antibodies to DNA alone had more benign types of SLE with little renal involvement. No abnormal levels of IgA Ab to either single-strand DNA or double-strand DNA were found in SLE patients' sera. Corticosteroid and/or immunosuppressant treatment caused a marked drop in the IgM Ab level to DNA within 10 days while IgG Ab to DNA remained high for up to 30 days. Quantitation of IgG and IgM Ab to single-strand DNA provides a useful method for diagnosing severe SLE with possible renal involvement and monitoring the course of the disease during therapy.

Antibody Specificity↗

PubMed2001

Crossreactivity of SLE autoantibodies with 70 kDa heat shock proteins of Mycobacterium tuberculosis.

Heat shock proteins (hsp) may be involved in the initiation and perpetuation of autoimmune diseases. In order to investigate the possible role of hsp and other intracellular proteins of Mycobacterium tuberculosis in the autoantibody production in SLE, the immuno-crossreactivity of SLE autoantibodies with Mycobacterium tuberculosis sonic extract and hsp-70 kDa was investigated. These proteins showed significant binding with Protein A-Sepharose isolated SLE IgG. Western blotting of hsp-70 with SLE IgG showed strong recognition, suggesting possible involvement of hsp and other intracellular proteins of Mycobacterium tuberculosis in the autoantibody induction in SLE.

Animals↗

PubMed1990

The effect of the immunomodulator agent AS101 on interleukin-2 production in systemic lupus erythematosus (SLE) induced in mice by a pathogenic anti-DNA antibody.

The role of the synthetic immunomodulator AS101 on the production of interleukin-2 (IL-2) by spleen cells of mice with SLE was investigated. BALB/c female mice, in which SLE was induced by immunization with the pathogenic idiotype of anti-DNA antibody 16/6 Id were treated with AS101 for 7 weeks 2 and 4 months after induction of the disease. The ability of the splenocytes of the mice with SLE to produce IL-2 was restored after administration of AS101. This effect was particularly impressive when the 7-week AS101 treatment was initiated 4 months after immunization. Despite its beneficial effect on IL-2 production, AS101 exerted no influence on the titres of autoantibodies in the sera of the mice. It also had no effect on clinical parameters of SLE, such as the increased sedimentation rate, proteinuria and low white blood cell counts. Our data indicate that defective IL-2 production in SLE is probably secondary to other disease processes and is not necessarily associated with the production of autoantibodies in this disorder.

Adjuvants, Immunologic↗

PubMed1991

A study of immune responses to myelin and cardiolipin in patients with systemic lupus erythematosus (SLE).

Sera from 39 patients with SLE, 20 patients with cerebrovascular disease with no evidence of SLE, and 20 normal controls were tested for antibodies to cardiolipin (CL), brain total upper (UPG) and lower phase (LPG) glycolipids, myelin basic protein (MBP), myelin, and single strand DNA (ssDNA) by ELISA. Binding to the glycolipids and MBP was negative or negligible in all the groups, but significant binding was observed against CL, myelin and ssDNA in some of the SLE patients. Many sera from SLE patients with cerebral disorders and high CL binding also demonstrated high binding to myelin. These sera also labelled cell surface antigens on neonatal mouse neurons and astrocytes by immunofluorescence in tissue culture. A correlation was found to exist between anti-CL and antimyelin antibodies in SLE patients with cerebral lesions, but not between anti-ssDNA and anti-CL antibodies. As much as 80-90% of the specific activity of these antibodies could be absorbed out by the relevant antigens but only partially by the other antigens. In the control groups binding was low and no specific absorption could be demonstrated.

Absorption↗

PubMed1993

Higher anti-heparan sulphate reactivity during systemic lupus erythematosus (SLE) disease exacerbations with renal manifestations; a long term prospective analysis.

Cross-reactive antibodies against heparan sulphate (HS) have been suggested to play a role in initiating renal disease in SLE. Recently, we found that HS-reactivity is mediated by anti-DNA antibodies complexed with DNA and histones. To evaluate the clinical significance of anti-HS reactivity, we studied prospectively a cohort of 72 consecutive SLE patients, of whom 22 experienced 40 exacerbations. In 20 of these exacerbations renal symptoms were present. In these 20 exacerbations significantly higher anti-DNA (median 1:160) and anti-HS (median 1:30) titres were detected compared with exacerbations without renal manifestations (median 1:60 for anti-DNA and negative for anti-HS). There were no correlations with other symptoms of SLE. Anti-HS titres showed a significant correlation with anti-DNA antibody titres (rs = 0.57, P < 0.05). Anti-HS without anti-DNA reactivity was never detected. Some SLE patients showed a high anti-DNA titre without anti-HS reactivity, suggesting that not all anti-DNA antibodies are able to bind to histone/DNA complexes and thus to exhibit anti-HS reactivity. Our findings indicate that anti-HS reactivity is correlated with renal disease in SLE.

Antibodies, Antinuclear↗

PubMed1994

Precursor frequencies for DNA-specific B lymphocytes in patients with systemic lupus erythematosus (SLE).

Precursor frequencies for anti-DNA-secreting B cells were estimated in six healthy donors and 18 SLE patients with active and inactive disease. Precursors for IgG anti-dsDNA-secreting B cells were exclusively detected in SLE patients (73% of active patients and one inactive patient, 0.01-0.99% of IgG-producing B cells). These frequencies were in the same order of magnitude as frequencies of precursors for IgG anti-tetanus toxoid, which were detectable in three healthy volunteers after booster vaccination (0.07-0.8% of IgG-producing B cells), but not before (< 0.01%). Precursors for IgG anti-ss-DNA secreting B cells were observed in 33% of healthy donors and in 78% of SLE patients (0.01-0.32% of IgG-producing B cells). Only patient-derived IgG anti-DNA clones cross-reacted with (33%) or were monoreactive to dsDNA (12%). Precursors for IgM anti-DNA-secreting B cells were observed in healthy donors and SLE patients in comparable frequencies and with similar reactivities with ssDNA and dsDNA. Segregation analyses and sorting experiments showed that > 94% of clones secreting IgG anti-DNA were derived from in vivo sIgG+ B cells. sIgM+ B cells were induced to switch in vitro; however, only twice were cultures containing IgM and IgG anti-DNA antibodies observed under clonal conditions. In conclusion, our results indicate that precursor B cells for IgG anti-dsDNA in SLE patients are similarly selected and expanded as are precursor B cells specific for foreign antigens such as tetanus toxoid.

Adult↗

PubMed2004

Amelioration of lupus manifestations by a peptide based on the complementarity determining region 1 of an autoantibody in severe combined immunodeficient (SCID) mice engrafted with peripheral blood lymphocytes of systemic lupus erythematosus (SLE) patients.

A peptide based on the complementarity determining region (CDR)1 of a human monoclonal anti-DNA autoantibody (hCDR1) was shown to either prevent or treat an already established murine lupus in systemic lupus erythematosus (SLE)-prone mice or in mice with induced experimental SLE. The present study was undertaken to determine the therapeutic potential of hCDR1 in a model of lupus in severe combined immunodeficient (SCID) mice engrafted with peripheral blood lymphocytes (PBL) of patients with SLE. To this end, PBL obtained from lupus patients were injected intraperitoneally into two equal groups of SCID mice that were treated either with the hCDR1 (50 micro g/mouse) once a week for 8 weeks, or with a control peptide. Mice were tested for human IgG levels, anti-dsDNA autoantibodies, anti-tetanus toxoid antibodies and proteinuria. At sacrifice, the kidneys of the successfully engrafted mice were assessed for human IgG and murine complement C3 deposits. Of the 58 mice transplanted with PBL of SLE patients, 38 (66%) were engrafted successfully. The mice that were treated with the control peptide developed human dsDNA-specific antibodies. Treatment with hCDR1 down-regulated the latter significantly. No significant effect of the treatment on the levels of anti-tetanus toxoid antibodies could be observed. Treatment with hCDR1 resulted in a significant amelioration of the clinical features manifested by proteinuria, human IgG complex deposits as well as deposits of murine complement C3. Thus, the hCDR1 peptide is a potential candidate for a novel specific treatment of SLE patients.

Adoptive Transfer↗

PubMed1990

The importance of the pathogenic 16/6 idiotype in the induction of SLE in naive mice.

We have previously demonstrated the pathogenicity of the common anti-DNA idiotype designated 16/6 Id. Immunization of naive mice with the 16/6 Id induced SLE-like disease characterized by serological (e.g. anti-dsDNA and anti-Sm auto-antibodies), clinical (increased ESR, leucopenia and proteinuria), and pathological (16/6 Id deposition in kidneys) parameters. To elucidate further the role of the 16/6 Id in SLE induction the following studies were carried out: BALB/c mice were immunized with SA-1, a human anti-DNA monoclonal antibody carrying the 16/6 Id; TB-68, a mouse monoclonal anti-tuberculosis (TB) glycolipid, which binds dsDNA and carries the 16/6 Id; TB-72, a mouse monoclonal anti-TB glycolipid that binds DNA and does not harbour the 16/6 Id; and 4B4, a human anti-Sm antibody that carries the 16/6 Id. SLE was induced in BALB/c mice only when immunized with SA-1, TB-68, and 4B4, namely antibodies with diverse binding capacities albeit having the 16/6 Id. Our studies further support previous evidence on the pathogenic role attributed to the 16/6 Id in SLE, and suggest that SLE is most probably an idiotype-induced disease.

Animals↗

PubMed1998

Pregnancy outcome in systemic lupus erythematosus (SLE): a review of 54 cases.

AIM: To compare the pregnancy outcome, in particular gestational age and birth weight in women with systemic lupus erythematosus (SLE) diagnosed before and after pregnancy, and to review data on presence or absence of the antiphospholipid (aPL) antibody and flares of disease activity. METHOD: Case histories were reviewed of women with a diagnosis of SLE and an obstetric event attending Monash Medical Centre (MMC) over an eight year period (1988-96). Fifty-four pregnancies in 28 women were studied, with 44 occurring after the diagnosis of SLE (Group 1) and ten prior to the diagnosis of SLE (Group 2). RESULTS: In Group 1 there were 25 live births (63%) with 16 full term and nine premature deliveries, 12 spontaneous abortions, three foetal deaths in utero and four elective terminations. In Group 2 there were seven live births (70%), two spontaneous abortions and one foetal death in utero. The mean gestational age of live births was 35.8 weeks and 39.2 weeks respectively (p < 0.001). The mean birth weight of live births was 2448 g and 3030 g respectively (p < 0.023). a PL antibodies were positive in eight of 26 women tested with three live births and were negative in 18 of 26 women with 12 live births. Flares of disease activity occurred in 17 of 28 pregnancies. CONCLUSION: Pregnancy in women with a predisposition to SLE have a high risk of an adverse outcome. Clinical disease confers an additional risk. The mean gestational age and birth weight were significantly less in women with established disease. Mild flares in disease activity resulted in a favourable outcome while renal flares had a worse outcome.

Adult↗

PubMed2006

Association of a common interferon regulatory factor 5 (IRF5) variant with increased risk of systemic lupus erythematosus (SLE).

Interferon regulatory factor 5 (IRF5) belongs to a family of transcription factors that control the transactivation of type I interferon system-related genes, as well as the expression of several other genes involved in immune response, cell signalling, cell cycle control and apoptosis. Two recent studies reported a significant association between the IRF5/rs2004640 T allele and systemic lupus erythematosus (SLE). The purpose of this study was to determine whether the reported rs2004640 T allele association could be replicated in our independent SLE case-control sample. We genotyped DNA samples from 370 white SLE-affected female subjects and 462 white healthy female controls using the TaqMan Assay-on-Demand for rs2004640, and performed a case-control genetic association analysis. Frequency of the rs2004640 T allele was significantly higher in cases than in controls (56.5% vs. 50%; P= 0.008). The odds ratio for T allele carriers was 1.68 (95% CI: 1.20 - 2.34; P= 0.003). Our results in an independent case-control sample confirm the robust association of the IRF5/rs2004640 T allele with SLE risk, and further support the relevance of the type I interferon system in the pathogenesis of SLE and autoimmunity.

Adolescent↗

PubMed1984

B-cell-tropic interleukins in murine systemic lupus erythematosus (SLE) 1.

Functional in vitro studies of B cells from 3 murine strains which develop severe early onset SLE-like disease with marked polyclonal B cell hyperactivity lead to the following conclusions: 1.) B cell proliferation and differentiation in lupus mice remains dependent on accessory signals of either macrophage or T cell origin; 2.) B cells from BXSB, NZB/W and MRL/1 mice appear to require the same number and type of signals as normal B cells to undergo polyclonal or antigen-directed responses. B cells of BXSB and NZB/W, but not MRL/1, origin differ from normal B cells by their higher sensitivity (or degree of response) to the signals they receive; 3.) Proliferating T cells in enlarged nodes and spleens of older MRL/1 mice, in the absence of mitogens, secrete in vitro abnormally high levels of a factor (L-BCDF) inducing terminal differentiation of activated B cells to Ig secreting cells. Based on these findings, murine SLE can be divided into 2 main types which may, nevertheless, share some characteristics: Type 1 murine SLE, characterized by primary B cell hyperresponsiveness to activating signals and lymphokines promoting B cell growth and differentiation (NZ and BXSB strains); and, Type 2 murine SLE, characterized by T helper cell hyperactivity and overproduction by proliferating T cells of one or more B cell differentiation factors (MRL/1 strain). In both types of murine SLE, abnormal responses to accessory signals or overproduction of differentiation-inducing signals ultimately leads to polyclonal and auto-antigen specific B cell expansion, hypergammaglobulinemia and auto-antibody production, and Ig gene rearrangement (IgM to IgG switching), resulting in the production of pathogenic IgG type auto-antibodies and disease.

Animals↗

PubMed1990

Immune complex binding to erythrocyte-CR1 (CD 35), CR1 expression and levels of erythrocyte-fixed C3 fragments in SLE outpatients.

Erythrocytes (E) from a cross-sectional group of 22 outpatients with systemic lupus erythematosus (SLE) and/or mixed connective tissue disease (MCTD), the majority without active disease (n = 14), were analyzed for CR1 antigen expression and capacity to bind complement opsonized, radiolabelled immune complexes (IC). Furthermore, E-bound C3 fragments and the plasma C3d concentration were determined. E-bound C3b/iC3b fragments were not elevated in patients with SLE, whereas E from 11 out of 22 SLE patients had increased C3d levels which correlated with the plasma C3d concentration (Rs 0.73, p less than 0.001). E-fixed C3d fragments did not affect the binding of Mab or preopsonized IC to E-CR1 and were not correlated with disease activity or medical treatment. Antigen expression of E-CR1 measured by ELISA or agglutination showed positive correlation with the IC binding capacity of E-CR1 (Rs 0.92 and 0.72 respectively, p less than 001). The IC binding capacity of E-CR1 from SLE patients was significantly reduced (p less than 0.005), whereas the antigen expression of CR1 (ELISA) on E from the patients did not differ from that of E from healthy donors (p greater than 0.1). E-CR1 antigen was measured by Mab reacting with an epitope outside the IC-binding site of E-CR1. E-CR1 antigen expression or IC binding showed no correlation either with disease activity or prednisolone treatment. However, 4 og 5 patients with MCTD and 4 of 5 patients receiving Imurel were found to have low E-CR1 expression and capacity to bind IC. Thus, measurement of antigenic E-CR1 in a cross-sectional group of SLE outpatients by use of Mab reacting with an epitope outside the ligand-binding region of CR1 did not reveal a significantly reduced CR1 expression. However, an assay for CR1-mediated IC binding showed a clearly reduced E-CR1 function.

Antigen-Antibody Complex↗

PubMed1993

DNA typing for HLA-DPB1-alleles in German patients with systemic lupus erythematosus using the polymerase chain reaction and DIG-ddUTP-labelled oligonucleotide probes. Members of SLE Study Group.

Genomic DNA of 178 German Caucasian patients with systemic lupus erythematosus are studied for HLA-DP locus by using PCR and DIG-ddUTP-labelled oligonucleotide probes. A significant increase of DPB1*0101 is observed in SLE patients compared with healthy controls (chi 2 = 15.27, p.c. < 0.004). DPB1*0501 and *0901 are also slightly increased (chi 2 = 5.85, P < 0.05, p.c. = NS; chi 2 = 5.64, P < 0.05, p.c. = NS). There is no significant difference in frequency of DP alleles between male and female patients. Since a linkage disequilibrium between HLA-B, DR and DP loci is found in our SLE patients, an analysis is performed assessing the relative importance of these HLA-markers to SLE. The results show that the increase of DPB1*0101 in SLE patients is associated with the HLA-B8, DR3 haplotype and it suggests a more important role for HLA-B8, DR3 or genes within this haplotype than for DPB1*0101 in the genetic predisposition for SLE.

Alleles↗

PubMed2003

Co-stimulatory blockade in the treatment of murine systemic lupus erythematosus (SLE).

Although the life span of patients with systemic lupus erythematosus (SLE) has improved considerably over the last several decades, the toxicities of chronic immunosuppressive therapy are major causes of morbidity and mortality. Safer and more effective therapies for SLE are clearly needed. SLE is characterized by excessive activation of both B and T lymphocytes. Activation of these cells requires both antigen engagement and co-stimulatory signals from interacting lymphocytes (Carreno, B.M. M. Collins, 2002, Annu. Rev. Immunol. 20: 29-53; Grewal, I.S. R.A. Flavell, 1998, Annu. Rev. Immunol. 16: 111-135). Thus, blockade of co-stimulatory signals offers a new therapeutic approach to SLE. Our short-term goal has been to understand the effect of co-stimulatory blocking reagents on the development, selection, and activation of pathogenic anti-dsDNA antibody producing B cells in mice genetically pre-determined to develop SLE and showing signs of either early or advanced disease activity. Our long-term goal is to use the knowledge we gain to design therapeutic regimens for humans that avoid the complications of long-term immunosuppression. As new co-stimulatory molecules are discovered, studying their mechanism of action in animal models and their clinical utility in human autoimmune disease should lead both to a new understanding of disease pathogenesis and also to safer and more effective therapies.

Abatacept↗

PubMed2001

[A case of diffuse panbronchiolitis with SLE complicated by fungal infection].

We report a patient who developed SLE during the course of diffuse panbronchiolitis (DPB) and had candidiasis later. The patient fulfilled the criteria for diagnosis of SLE after appearance of fever and general peripheral arthritis. Regarding serum virus antibody values at the time of SLE diagnosis, IgG and IgM of human Parvovirus B19 (B19) were positive by the EIA test and also by the serum PCR test. For continuously Pseudomonas aeruginozae in sputum cultures because of existing DPB, immunosuppressasnt therapy with prednisolone and mizoribine was given while suppressing proliferation of bacterial infections with antibiotics. As a result, the intensity of SLE decreased smoothly. About 1 month after beginning of the treatment, the chest X-ray revealed infiltrative densities in the lingual area of the left lobule and in S3 of the right lobule. Judging from the clinical course and various examination findings, concurrence of candidiasis was suspected. Fungal infection in this patient was progressive, so various antifungal agents were used concurrently. Furthermore, immunoglobulin therapy was supplemented while determining serum immunoglobulin levels, and doses of prednisolone and mizoribine were reduced rapidly. Afterward the patient followed a satisfactory clinical course. About 2 years later SLE recurred, aspergillosis developed concurrently and the disease progressed rapidly to its termination. DPB itself is difficult to control and often complicated with various diseases. Therefore, immunosuppresant therapy for complications is sometimes used in addition to the treatment of DPB. More careful observations on the clinical course are necessary in dealing with this disease.

Adult↗

PubMed1977

Frequency and clinical significance of antibodies to ribonucleoprotein in SLE and other connective tissue disease subgroups.

Antibodies to the ribonucleoprotein (RNP) component of extractable nuclear antigen were measured in patients with systemic lupus erythematosus (SLE) and other connective tissue subgroups by counterimmunoelectrophoresis. Antibodies to RNP were found in the sera of 32% of patients with a primary diagnosis of SLE, 29% of patients with features of SLE and erosive joint disease, none of 9 scleroderma patients, and in 75% of 8 patients with features of SLE and scleroderma. In the SLE patients overall there was an increased frequency of sclerodactyly and severe Raynaud's phenomenon in the patients with antibodies to RNP but no association of antibodies to RNP was found with the presence of erosive joint disease, Sjögren's syndrome, or the absence of renal disease in these patients.

Adolescent↗