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PubMed2006

Association of a non-synonymous single-nucleotide polymorphism of DNASEI with SLE susceptibility.

OBJECTIVES: To investigate the association of a non-synonymous single-nucleotide polymorphism (SNP) in DNASEI with susceptibility to systemic lupus erythematosus (SLE) and the production of autoantibodies to nuclear antigens. METHODS: The Gln244Arg (rs1053874) SNP was studied in 276 SLE patients and in 368 healthy controls of Spanish ancestry. Its relationship with SLE susceptibility, serum DNase I activity, anti-ribonucleoprotein (RNP), anti-double-stranded DNA (dsDNA), anti-nucleosome and anti-single-stranded DNA (ssDNA) antibodies was determined. RESULTS: An association of the Gln244Arg SNP with SLE susceptibility that followed a recessive genetic model (P=0.002) was found. The GG genotype was more common in SLE patients (59.8%) than in controls (47.3%). However, the Gln244Arg genotype did not correlate with DNase I activity in sera from SLE patients or from controls. In addition, the Gln244Arg SNP did not influence autoantibody titres significantly. CONCLUSION: The association of the Gln244Arg SNP with SLE susceptibility indicates that common polymorphisms in DNASEI play a role in the genetics of SLE. However, the lack of effect of the Gln244Arg SNP on serum DNase I activity calls into question the direct involvement of this specific SNP.

Antibodies, Antinuclear↗

PubMed2006

The systemic and SmD183-119-autoantigen-specific cytokine memory of Th cells in SLE patients.

OBJECTIVES: The aim of the study was to analyse the cytokine memory of T-cells derived from systemic lupus erythematosus (SLE) patients and healthy donors enriched for autoantigen-specific T-cells by in vitro stimulation with SmD1(83-119), a common autoantigen in SLE. METHODS: Autoreactive CD3+ T-cells derived from 37 SLE patients and 14 healthy donors were enriched by repetitive ex vivo stimulation of peripheral blood mononuclear cells (PBMCs) with SmD1(83-119). For control, PBMCs were stimulated only with interleukin-2 (IL-2). After two rounds of antigenic stimulation, cultures were stimulated with PMA/ionomycin to probe the cytokine memory by intracellular cytokine staining. Frequencies of cytokine-expressing T-cells were analysed and, in SLE patients, compared with disease activities and autoantibody levels. RESULTS: Comparing the cytokine memory in the cultures, SLE patients displayed higher frequencies of tumour necrosis factor-alpha (TNF-alpha)+ T-cells than healthy donors and the frequencies correlated with disease activity. Frequencies of SmD1(83-119)-specific TNF-alpha+ T-cells and of memory T-cells expressing interferon-gamma (IFN-gamma) correlated with serum anti-dsDNA antibody levels. The frequencies of IL-10 expressing SmD1(83-119)-specific T-cells were lower among PBMCs of SLE patients. Relatively higher frequencies of IL-10+ T-cells in SLE patients correlated with low disease activities, and low anti-dsDNA and anti-SmD1(83-119) antibody concentrations in culture supernatants. CONCLUSIONS: The memory of autoreactive SmD1(83-119)-specific and unspecific stimulated peripheral Th cells for re-expression of cytokines is shifted towards more cells expressing TNF-alpha and less IL-10+ cells, when compared SLE patients with normal donors. This shift towards proinflammatory memory effector Th cells correlates with disease severity and humoral autoimmunity.

Antibodies, Antinuclear↗

PubMed1990

Pathogenic idiotypes of autoantibodies in autoimmunity: lessons from new experimental models of SLE.

Systemic lupus erythematosus (SLE) is considered a classical autoimmune disease that involves many biological systems. Similar to other autoimmune conditions, its etiology is multifactorial entailing genetic, environmental, hormonal, and immunologic factors. In this review we demonstrate that by using a pathogenic idiotype of anti-DNA autoantibodies, it is possible to explain some of the pathogenesis and diversity of clinical and serological manifestations reported by SLE patients. The 16/6 idiotype (Id) is a representative pathogenic idiotype of anti-DNA autoantibodies. The serum titers of 16/6 Id in SLE patients correlate with clinical activity of the disease, and are deposited in afflicted tissues in SLE patients. SLE was experimentally induced in naive mice after immunization with 1 microgram of the Id. The disease is characterized clinically (proteinuria), serologically (e.g., anti-dsDNA, anti-Sm antibodies), and by pathological findings (e.g., deposition of 16/6 Id in the kidneys). The condition can be induced by other human and mouse antibodies carrying the 16/6 Id, as well as by mouse antimonoclonal-16/6 Id and by T cell lines and clones specifically reactive with 16/6 Id. There are strain-dependent differences in susceptibility to the induction of systemic lupus erythematosus (SLE). Induction of SLE is directly correlated with the ability to respond to the 16/6 idiotype (or 16/6 Id)2 by anti-Id antibody production. It is easier to induce the disease in females, and it can be modulated by manipulation of sex hormones. Being able to identify the pathogenic idiotype allowed us to generate T suppressor (Ts) cells specific for the 16/6 Id. Treatment of mice with these T cells abrogated the disease. Our studies point to the importance of pathogenic idiotypes of autoantibodies in autoimmunity, which suggests that SLE may represent a dysregulation of a functional network of idiotypes-anti-idiotypes interactions among autoreactive B cells, T helper cells, and T suppressor cells.

Animals↗

PubMed2000

Comparison of lung perfusion scintigraphic findings in pulmonary thromboembolism in systemic lupus erythematosus, SLE plus antiphospholipid syndrome, and primary antiphospholipid syndrome.

In this study, we compared and reviewed the findings on lung perfusion scans performed in patients with systemic lupus erythematosus (SLE), systemic lupus erythematosus with associated antiphospholipid syndrome (SLE + APS), and primary antiphospholipid syndrome (PAPS), to evaluate the prevalence of pulmonary embolism in restricted samples of the patient groups. Lung perfusion scintigraphy with 99Tc(m)-macroaggregated albumin was performed in 31 patients (SLE = 7; SLE + APS = 14; PAPS = 10). The seven patients with SLE alone and the 10 patients with PAPS had normal perfusion lung scans. Six of the 14 SLE + APS patients showed a segmental uptake defect on multi-view perfusion scans. Thus, the SLE + APS patients were found to have a higher risk of pulmonary thromboembolism than the SLE alone and primary APS patients (P<0.05). The results of our study suggest that lung perfusion scintigraphy should be performed routinely in these patients, even in the absence of pulmonary clinical manifestations, to obtain baseline data for disease outcome and management.

Adult↗

PubMed1995

Up-regulated expression of Fas antigen (CD95) by peripheral naive and memory T cell subsets in patients with systemic lupus erythematosus (SLE): a possible mechanism for lymphopenia.

Fas antigen (CD95) is a membrane-associated molecule that mediates apoptotic cell death and may play a role in the induction and maintenance of T cell tolerance. To elucidate the involvement of Fas antigen in human autoimmune diseases, we analysed Fas antigen expression by peripheral T cells from patients with SLE and rheumatoid arthritis (RA), using three-colour flow cytometry. Both CD4+ and CD8+ T cells from SLE patients expressed Fas antigen in a higher density than did these cells from healthy donors and from RA patients. Enhancement of Fas antigen density was noted in Fas+CD45RO+ memory T cells from SLE patients. More remarkably, a significant expression of Fas antigen was observed in CD45RO- naive T cells from SLE patients. CD4+CD45RO- T cells from SLE patients co-expressed Fas antigen and early to intermediate activation antigens such as CD25 and CD71, and late activation antigen HLA-DR in only FashiCD4+ naive T cells. Such up-regulation of Fas antigen expression in SLE patients seems to be clinically meaningful, because mean fluorescence intensity (MFI) of Fas antigen on CD4+ T cell subsets inversely correlates with the absolute size of CD4+ T cell subsets in peripheral blood of SLE patients. These results suggest that T cells with increased Fas antigen expression may be highly susceptible to apoptotic cell death, in vivo. A putative mechanism for lymphopenia in SLE patients is discussed.

Adult↗

PubMed2005

Cross-recognition between histones and La/SSB may account for anti-DNA reactivity in SLE patients.

Antibodies to La/SSB are detected in sera of patients with primary Sjogren's syndrome (pSS) and systemic lupus erythematosus (SLE). The vast majority of anti-La/SSB positive sera contain antibodies directed towards a linear B-cell epitope of La/SSB spanning the sequence 349-364aa (pep349-364). The aim of this study was to evaluate the fluctuation of antibody levels to major B-cell epitopes of La/SSB over time and investigate for their possible crossreactions. Sequential sera from 15 SLE and 15 pSS patients, followed from 3 to 10 years were obtained. All patients with SLE were positive for anti-Ro/SSA, anti-La/SSB and anti-dsDNA antibodies and patients with pSS were positive for anti-Ro/SSA and anti-La/SSB antibodies. Sera from 30 patients with SLE without anti-La/SSB antibodies and 30 healthy individuals served as disease and negative control respectivelly. All sera tested for the presence of anti-pep349-364 antibodies, using a specific ELISA. Specific anti-pep349-364 IgG was purified from sera of SLE patients and evaluated for cross reactivity against dsDNA and histones. In all SLE sera the levels of anti-pep349-364 antibodies varied in time and fluctuated in parallel with anti dsDNA antibodies. Anti-pep349-364 IgG purified from 7 SLE patients. Five out of 7 were found to react with calf thymus DNA in ELISA. All purified (7/7) anti-pep349-364 IgG preparations reacted with histone H1 and failed to produce a positive immunofluorescence pattern in Crithidia luciliae anti-dsDNA assay which lacks histones. Competative inhibition experiments demonstrated that histone H1 could inhibit completely the binding of anti-pep349-364 IgG to pep349-364 while pep349-364 inhibited by 70% the binding of anti-pep349-364 IgG to histone H1. These findings indicate that a subgroup of SLE patients possess cross-reacting anti-histone H1 antibodies and anti-pep349-364 antibodies, which can be faulty considered as anti-dsDNA reactivity in regular ELISA techniques.

Animals↗

PubMed1982

In vitro immune response of SLE lymphocytes. The mechanism involved in B-cell activation.

Peripheral blood lymphocytes from 26 patients with systemic lupus erythematosus (SLE) and six normal individuals were tested for IgG synthesis in the presence or absence of PWM. Lymphocytes from patients with active SLE synthesized increased amounts of IgG in the absence of PWM and reduced amounts of IgG in the presence of PWM. Serum from patients with active SLE had an enhancing effect on the in vitro IgG synthesis of normal lymphocytes. The IgG or F(ab')2 fractions of SLE serum retained the enhancing effect on in vitro IgG synthesis, and the enhancing activity was absorbed by human spleen cells. As little as 4 h of incubation with SLE serum was needed for the enhancing activity of normal lymphocytes. Treatment of B lymphocytes appeared to be of main importance for an increase in the in vitro IgG synthesis of SLE serum-treated lymphocytes. These results suggest that anti-B-lymphocyte antibodies from patients with active SLE are responsible in part for the hyperactive response of SLE B lymphocytes.

Antibody-Producing Cells↗

PubMed2002

Angiotensin-converting enzyme gene polymorphism and vascular manifestations in Korean patients with SLE.

Systemic lupus erythematosus (SLE) is an inflammatory multisystem disease of unknown etiology with immunologic aberrations. Many studies have shown that genetic and environmental factors are implicated in the development of SLE. Angiotensin-converting enzyme (ACE) affects various immune phenomena through the renin-angiotensin and kallikrein-kininogen systems by creating angiotensin II and inactivating bradykinin. We investigated the correlation between insertion/ deletion polymorphism of the ACE gene and the clinical manifestations of SLE, especially vascular involvement and lupus nephritis. Two-hundred and eleven Korean patients fulfilling the ACR criteria and 114 healthy subjects were enrolled. The ACE genotype was determined by polymerase chain reaction using genomic DNA from peripheral blood. The nephritis patients were classified by the WHO classification. In addition, the activity and chronicity index were used to assess the severity of renal involvement. We evaluated vascular involvement by the presence or absence of hypertension, Raynaud's phenomenon, livedo reticularis, antineutrophil cytoplasmic antibody and the SLICC/ACR Damage Index. The gene frequency of ACE gene polymorphism was as follows: II 39 vs 34%, ID 41 vs 50%, DD 20 vs 16% in SLE patients and controls, respectively. There was no difference in genotype frequency between both groups. There were no significant differences between the distribution of ACE gene genotypes and lupus nephritis and its related parameters, including WHO classification, activity index, chronicity index, renal dysfunction and amount of 24 h urinary protein. The ACE genotypes and alleles did not affect the presence of vascular manifestations evaluated, but the frequency of DD genotype was significantly low in SLE patients with Raynaud's phenomenon compared to those without Raynaud's phenomenon (P = 0.002 for ACE ID vs DD and II, OR 2.7, 95% CI 1.43-5.09; P=0.023 for ACE DD vs ID and II, OR 0.33, 95% CI 0.12-0.89). Also skewing from DD to II genotype was noted in patients with anti-Sm antibody compared to those without anti-Sm antibody (P = 0.025 for ACE DD vs ID and II, OR 0.21, 95% CI 0.05-0.93). The onset age of serositis was older in patients with the ID genotype than the others (ID= 34.5+/-10.8, II + DD = 25.6+/-10.2, P= 0.002). Also the onset age of malar rash was older in patients with II genotype than the others (II=26.7+/-8.4, ID+DD=21.3+/-9.0; P=0.021). The patients with I allele showed a significantly higher frequency of serositis (P = 0.022). Taken together, the I/D polymorphisms of ACE gene did not affect susceptibility of SLE, lupus nephritis and the vascular manifestations, including Raynaud's phenomenon, in Korean SLE patients, although the DD genotype was negatively associated with Raynaud's phenomenon among SLE patients. However, it would be valuable to evaluate the role of other genes potentially related to vascular events, such as endothelin, nitric oxide or angiotensin II receptor as well as ACE gene.

Adult↗

PubMed2000

Genetic aspects of inherent B-cell abnormalities associated with SLE and B-cell malignancy: lessons from New Zealand mouse models.

Genes that predispose to SLE are closely related to key events in pathogenesis of this disease. As much of the pathology can be attributed to high affinity autoantibodies and/or their immune complexes, some of the genes may exert effects in the process of emergence, escape from tolerance mechanisms, activation, clonal expansion, differentiation, class switching and affinity maturation of self-reactive B cells. A number of growth and differentiation factors and signaling molecules, including positive and negative regulators, are involved in this process. Genetic variations associated with functional deficits in some of such molecules can be involved in the susceptibility for SLE. As is the case with SLE, hereditary factors play significant roles in the pathogenesis of B cell chronic lymphocytic leukemia (B-CLL). Patients with B-CLL or their family members frequently have immunological abnormalities, including those associated with SLE. It is suggested that certain genetically determined regulatory abnormalities of B cells may be a crossroad between B-CLL and SLE. A thorough understanding of the genetic pathways in B cell abnormalities leading to either SLE or B-CLL is expected to shed light on their association. New Zealand mouse strains are pertinent laboratory models for these studies. Chromosomal locations of several major genetic loci for abnormal proliferation, differentiation and maturation of B cells and relevant candidate genes, located in close proximity to these intervals and potentially related to the SLE pathogenesis, have been identified in these mice. Further studies make for a wider knowledge and understanding of the pathogenesis of SLE and related B-cell malignancy.

Animals↗

PubMed1990

Pathogenic anti-DNA antibodies in SLE: idiotypic families and genetic origins.

We have adopted an idiotypic approach to study the double stranded DNA (dsDNA) binding antibodies of systemic lupus erythematosus (SLE). Three anti-idiotypic reagents, 8.12, 3I, and F4, identify cross reactive idiotypes that are each expressed on anti-dsDNA antibodies in the sera of many patients with SLE. These idiotypic antibodies are implicated in the pathogenesis of SLE as they are present in immune complex deposits in the kidneys of patients with SLE glomerulonephritis. The autoantibody associated idiotypes are also expressed on antibodies that do not bind DNA. We are investigating the origin of the pathogenic anti-dsDNA antibodies of SLE by comparing the autoantibodies, the antibodies to foreign antigens, and the myeloma proteins that express each SLE associated idiotype. In conjunction with serological analysis of these idiotypic systems, molecular genetic studies indicate that both the 8.12 and the 3I autoantibody associated idiotypes may be germline encoded, while the F4 idiotype is generated by somatic mutation. The data further suggest that the antigenic specificity of the pathogenic anti-DNA antibodies of SLE is acquired through somatic mutation of germline immunoglobulin genes. By studying the regulation of genes capable of encoding pathogenic autoantibodies, in both SLE patients and non-autoimmune individuals, we may be able to elucidate the pathogenesis of autoimmune disease and begin to design more effective therapeutic interventions.

Antibodies, Antinuclear↗

PubMed2003

[The variation of T-cell clonal repertoire in patients with systemic lupus erythematosus (SLE) following autologous peripheral blood hematopoietic stem cell transplantation].

OBJECTIVE: Analyze the variation of T cell receptor(beta) (TCRbeta) CDR3 gene expressing repertoire in systemic lupus erythematosus (SLE) patients before and after autologous peripheral blood hematopoietic stem cell transplantation (APBSCT), to search the pathogenesis of SLE and characteristics of T cell reconstitute immune after APBSCT. METHODS: Reverse transcriptase - polymerase chain reaction (RT-PCR) amplified 25 subfamily genes of TCRbeta prom peripheral blood lymphocytes (PBLs) of SLE patient with APBSCT and run denaturation polyacrylamide sequencing gel electrophoresis, set up a map of TCRbetaCDR3 gene expressing repertoire. The bands of TCRbeta gene repertoire in the electrophoresis gel can be used to analyze the variety of T cell clones which expanded and disappeared in cases of SLE. Cut the bands and sequencing. Compare sequences of TCRbetagenes in normal and abnormal T cell clones to understand the relationship between TCRbeta gene and autoimmune diseases. RESULTS: In the normal control group, TCRbeta gene repertoires show more than 10 bands in each of 25 TCRbetaV families, characterized as Gaussian distribution. TCRbeta gene repertoire in the 8 patients with SLE were abnormally. Four patients expressed TCRbetaV13.1 gene preferentially. Three patients had TCRbetaV8, TCRbetaV9 and TCRbetaV18 genes over expressed. These over expressive genes represented the oligoclonal expansion of T cell populations. After APBSCT the TCRbeta gene repertoires regained CDR3 polymorphism in 5 patients, some of them recovered to normal completely. The sequencing analyse show dense and strong band in map of TCRbeta gene repertoires were T cell monoclonal or oligoclonal expansion frequently. In a case of SLE an amino acid sequence of TCRbetaV8 CDR3 was same to a sequence of disease correlative T cell clone with ankylosing spondylitis that had been reported in a literature before. CONCLUSION: SLE patients have oligoclonal expansion of T cell that related with the pathogenesis of autoimmune disease. After APBSCT, T cell clones recover to normal distribution. T cell clones that related with disease have been suppressed during immunological reconstitution. It may be a main reason the SLE get remission after transplantation.

Adolescent↗

PubMed2005

Systemic lupus erythematosus (SLE) in Italy: an Italian prevalence study based on a two-step strategy in an area of Florence (Scandicci-Le Signe).

BACKGROUND: The goal was to ascertain the prevalence of SLE in the population over 18 years of age in the Scandicci-Le Signe area of Florence, Italy, based on the records of general practitioners (GPs). MATERIAL/METHODS: Twenty GPs screened 32,521 patients by administering the Lupus Screening Questionnaire (LQS) and found 30 patients with suspected or definite diagnosis of SLE. To confirm the diagnoses the patients were referred to a rheumatologist who conducted routine examinations and assessed antinuclear antibodies and SLE activity (ECLAM score). RESULTS: Total population >18 years of age in the three municipalities was 71,204 persons, with 42,474 in Scandicci, 15,368 in Lastra a Signa, and 13,362 in Signa. In 23/30 patients diagnosed with SLE the diagnosis was confirmed. Eleven of the 23 SLE patients were from Scandicci and 6 each from Lastra a Signa and Signa. An overall estimated prevalence of SLE of 71/100,000 (1/1408; 95% CI=49, 92) was found in the total population of the three municipalities. Scandicci (95% CI=42, 121) had a rate of 81/100.000, while Lastra a Signa (95% CI=32, 92) and Signa (95% CI=36, 94) had estimated rates of 62/100,000 and 65/100,000, respectively. Medium ECLAM score was 4.68+/-1.81 SD. CONCLUSIONS: This is the first epidemiological study on SLE prevalence in Italy. The prevalence and point prevalence are similar to other European studies. The LQS was also confirmed as an easy and reliable tool to assess SLE diagnosis in the Italian population.

Adult↗

PubMed1989

C-myc gene binding factors in peripheral blood mononuclear cells from patients with systemic lupus erythematosus (SLE).

We characterized the nuclear proteins with specific binding ability against c-myc gene by gel-shift assay in cell extracts of peripheral blood mononuclear cells (PBMC) from SLE patients and SLE-prone mice with use of distinct c-myc fragments. With the fragment named Fmyc in our experiments, two kinds of complexes which we call C1 and C2 respectively were found in PBMC from SLE patients and SLE-prone mice. The C1 was shown to be inducible in PBMC from healthy persons without nascent protein synthesis after lectin binding to the cell and found to be elevated in the SLE patients and in all of the established cell lines we examined. The C2 seemed to be peculiar to SLE subjects. The binding site of the C1 factor (C1F) and C2 factor (C2F) which forms C1 and C2 respectively with Fmyc appeared to be common and were found to reside at 51 kbp sequence (from XhoI to Sau3A) of exon I of c-myc gene. Interestingly, XhoI site of the binding site was highly demethylated in PBMC of SLE patients as compared with healthy persons. The roles of these binding factors for the pathogenesis of SLE are discussed.

DNA-Binding Proteins↗

PubMed1999

Exogenous IL-10 and IL-4 down-regulate IL-6 production by SLE-derived PBMC.

The elevated expression of IL-6 and IL-10 may have an important role in SLE pathogenesis. IL-6 production by normal monocytes can be inhibited by IL-10, and it has been suggested that SLE monocytes are refractory to this negative signal. To examine this possibility, the effects of regulatory factors on IL-6 expression by SLE PBMC (N = 51) were compared to effects on control PBMC (N = 21). We found that (1) exogenous rIL-10 and rIL-4 mediated reduction of constitutive and lectin-induced IL-6 in monocytes of SLE patients as effectively as that of controls; (2) IL-6 mRNA decay was significantly delayed in SLE with active disease (P < 0.001); (3) adding rIL-10 or neutralizing endogenous IL-1 beta and TNF-alpha down-regulated IL-6 mainly by destabilizing IL-6 transcripts, whereas exogenous IL-4 and TGF beta 1 down-regulated IL-6 transcriptionally; (4) time kinetics and levels of IL-10 were lower than those of IL-6 and IL-1 beta. Thus, contrary to a previous report, IL-6 production by SLE PBMC responds normally to regulatory signals, and the IL-6 overexpression in SLE may be due, at least in part, to the kinetics and availability of regulatory cytokines.

Adult↗

PubMed2001

Vitamin D(3) and its synthetic analogs inhibit the spontaneous in vitro immunoglobulin production by SLE-derived PBMC.

The production of high-affinity pathogenic autoantibodies in systemic lupus erythematosus (SLE) may result from aberrant immune regulation. Since 1,25 dihydroxy vitamin D(3) (1,25 D(3)) has immunoregulatory activity, we examined effects of 1,25 D(3) and its analogs HM, V, MC1288, and KH1060 on autoantibody production and proliferation of SLE PBMC. We found, in SLE, a higher percentage of T, B, and NK expressing vitamin D(3) receptors (VDRs) (P = 0.034, 0.006, 0.012, respectively). Incubating SLE PBMC with 1,25 D(3) compounds significantly reduced proliferation, polyclonal and anti-dsDNA IgG production, and the percentages of CD3(+)/DR(+) T and B (CD19(+)) cells, while elevating NK (CD16(+)) cells (P < 0.001). 1,25 D(3) analogs were more potent than the natural compound: KH1060 up-regulated CD14 expression by SLE monocytes (P < 0.001), inhibited polyclonal and anti-dsDNA IgG production by SLE-derived B lymphoblasts, and induced apoptosis of activated B lymphoblasts. These data suggest that 1,25 D(3) compounds can offer novel approaches to the clinical management of SLE.

Antibodies, Antinuclear↗

PubMedDate not supplied

Constitutive up-regulated activity of MAP kinase is associated with down-regulated early p21Ras pathway in lymphocytes of SLE patients.

Aberrant expression of the p21Ras proto-oncogene has been reported in lymphoid cells of SLE patients. We previously showed that the expression of the p21Ras stimulatory element, hSOS1, is reduced in PBMC from SLE patients with non-active disease. However, the significance of this finding regarding the regulation and function of the p21Ras pathway and its correlation to disease activity remained unclear. The expression, regulation and function of the p21Ras pathway were determined in 23 ambulatory SLE patients with active and non-active disease and eleven controls. Levels of p21Ras stimulatory element hSOS1 but not p21Ras and its inhibitory element p120GAP were significantly decreased in SLE patients. Early p21Ras signalling was down-regulated in SLE patients with active disease as indicated by the decreased membrane/cytoplasmic (M/C) ratios of the p21Ras regulatory elements hSOS1 and p120GAP and by the non-responsiveness of these ratios to cellular stimulation. Anchorage of p21Ras to the cellular membrane was also significantly decreased in these patients. In contrast, the late p21Ras signalling was up-regulated in SLE patients as indicated by the significantly higher constitutive activity of the p21Ras down stream key regulator enzyme MAP Kinase. Taken together, our data demonstrate for the first time a disease associated functional defect in p21Ras signalling in lymphocytes of SLE patients.

Adult↗

PubMed1994

Evidence for direct anti-heparin-sulphate reactivity in sera of SLE patients.

Recently it has been suggested that anti-ds-DNA antibodies (Abs) promote tissue damage in systemic lupus erythematosus (SLE) by cross-reactivity with highly negatively charged tissue components such as heparan sulphate (HS), the major glycosaminoglycan of the glomerular basement membrane (GBM). Other authors, however, support the theory of DNA-anti-dsDNA immune complex deposition in situ. To further elucidate the possible role of HS antibodies, we developed a new ELISA system with heparan sulphate bound to solid phase. SLE patients (n = 40) showed a higher reactivity against HS (mean = 28.4, SD = 34.3) as compared to normal donors (n = 28, mean = 15.2, SD = 6.3) and patients with rheumatoid arthritis (n = 35, mean = 14.3, SD = 6.4). The addition of native dsDNA or HS to SLE sera was followed by a dose-dependent reduction in anti-HS reactivity. In contrast, in an anti-dsDNA ELISA, no reduction was observed when HS was added to SLE sera. An increase in reactivity was observed when SLE sera with and without a prior incubation with dsDNA were digested with DNAse I or II. After the purification of serum samples by protein A sepharose under dissociative conditions, seven out of eight SLE patients showed an increase in anti-HS reactivity. No correlation of the anti-HS Abs was found with organ involvement or other serological parameters. We concluded, that there is evidence for a direct anti-HS Ab reactivity in SLE sera. A part of these antibodies seems to show low avidity anti-dsDNA cross-reactivity.

Antibodies, Anti-Idiotypic↗

PubMed1996

Amelioration of experimental systemic lupus erythematosus (SLE) by retrovirus infection.

Experimental SLE can be induced in susceptible 129/J mice by immunization with a human anti-DNA antibody bearing a common idiotype designated 16/6 Id. Immunized mice develop autoantibodies, leukopenia, proteinuria, and immune complex deposits in renal glomeruli. Case reports have described clinical improvement in SLE in individuals becoming infected with HIV-1. Because 129/J mice are susceptible to experimental SLE and to infection with the BM5def murine leukemia virus (MuLV) mixture but do not develop the lymphoproliferative/ immunodeficiency disorder known as murine AIDS (MAIDS), we superimposed this infection on immunization with the 16/6 Id. Multiple effects were observed. First, we noted an amelioration in the course of experimental SLE. Second, both in experimental SLE and in BM5def MuLV infection, immunoreactivity to HIV-1 gp120 was demonstrated, although gp120 is not present in the BM5def MuLV viruses. Third, production of autoantibodies characteristically found in SLE, e.g., anti-DNA, anti-RNP, and anti-SSA, was seen in BM5def MuLV-infected mice, demonstrating that an immune response as a consequence of infection had occurred despite the absence of MAIDS induction. We conclude that (1) retrovirus inoculation may ameliorate the course of experimental SLE; and (2) retrovirus inoculation, even in the absence of MAIDS induction, induces an immunologic response which promotes the production of potentially pathogenic autoantibodies.

Animals↗