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PubMed1998

SLE nephritis is associated with an oligoclonal expansion of intrarenal T cells.

Autoimmune systemic lupus erythematosus (SLE) nephritis is characterized by the influx of mononuclear inflammatory cell infiltrates within the glomeruli and renal interstitium. To evaluate the possibility that intrarenal T cells result from the expansion of lymphocytes using limited T-cell receptor (TCR) genes, we analyzed the TCR Vbeta gene expression among infiltrating lymphocytes in renal tissue compared with simultaneous peripheral blood lymphocytes of four children with new-onset SLE nephritis. The TCR Vbeta gene expression in peripheral blood T cells from patients with SLE nephritis, when compared with normal controls, showed no preferential expansion or deletion of select Vbeta gene families. In contrast, when paired peripheral blood and renal tissue were analyzed, intrarenal lymphocytes in SLE nephritis demonstrated evidence of expansion of select Vbeta gene families. Sequence analysis of the V(D)J joining regions of the TCRbeta with the expanded families demonstrated a striking oligoclonality. These observations suggest that infiltrating T cells within renal tissue may use TCR Vbeta genes targeted toward nephritogenic antigens.

Cell Division↗

PubMed2002

The polymorphism of monocyte chemoattractant protein-1 is associated with the renal disease of SLE.

BACKGROUND: Renal involvement in patients with systemic lupus erythematosus (SLE) varies from none to full-blown disease. Monocyte chemoattractant protein (MCP-1) is implicated in the activation of inflammatory cells and has been suggested to affect the progression of lupus nephritis (LN). METHODS: In the 5' flanking region of the MCP-1 gene, a guanine (G)/adenine (A) transition identified at position -2518 upstream from the transcription site was reported to be associated with circulating levels. We investigated whether the G/A polymorphism was associated with clinical manifestations of SLE in terms of renal involvement and the biological significance of this polymorphism. RESULTS: Frequencies of MCP-1/-2518 polymorphisms were similar in patients and controls. Serum MCP-1 levels in patients with SLE were significantly greater than those of healthy controls, but amount of proteinuria did not correlate with serum MCP-1 level in patients. In AA homozygotes, patients with LN showed greater serum MCP-1 levels than patients without LN. In addition, urinary excretion of MCP-1 was greater in AA homozygotes compared with other genotypes in patients with LN. A positive correlation between urinary excretion of MCP-1 and proteinuria was observed in patients with SLE. Genetic constructs containing G at this site showed that G construct had lower activity (39%) than that shown by a construct containing A, and this response, which depended on MCP-1 genotype, was maintained after stimulation with tumor necrosis factor-alpha. CONCLUSION: These results suggest that a genetic polymorphism in the 5' flanking region of the MCP-1 gene would be associated with nephritis in lupus through modulating MCP-1 expression.

5' Flanking Region↗

PubMed1998

Can we advise ovulation induction in patients with SLE?

The prognosis of systemic lupus erythematosus (SLE) has greatly improved during the last two decades, now allowing most patients to have a very long survival including a satisfactory quality of life. Initially considered contraindicated in SLE due to its overwhelming risks, pregnancy is nowadays allowed in a majority of patients, and fair results are usually obtained under appropriate management (1-3). Consequently, patients thought to have infertility ask the question of a possible therapy, i.e. ovulation induction (OI) associated or not with in vitro fertilization (IVF). Considering the importance of estrogens in the pathogenesis of the disease, the use of such procedures raise several questions in SLE. Though data remain to date extremely scarce, the theoretical and practical aspects of OI in SLE will be briefly reviewed here.

Adult↗

PubMedDate not supplied

Transcriptional regulation of interleukin 2 in SLE T cells.

Interleukin-2 (IL-2) is a central cytokine required for the activation of T, B, and NK cells. It propagates the immune response and terminates it by promoting the activation induced cell death of T cells. IL-2 production is altered in T cells of patients with systemic lupus erythematosus (SLE). The consequence of reduced IL-2 production in SLE is decreased immune response to infectious agents. Decreased IL-2 production by SLE T cells is the result of transcriptional repression of the IL-2 gene. This article will review the defective transcription regulation of IL-2 in SLE T cells, which is the result of decreased expression of the enhancers NF-kappa B and AP1 and the increased expression of the transcriptional repressor CREM.

Gene Expression Regulation↗

PubMed2002

Treatment of induced murine SLE with a peptide based on the CDR3 of an anti-DNA antibody reverses the pattern of pathogenic cytokines.

A peptide based on the complementarity determining region (CDR) 3 of a pathogenic anti-DNA monoclonal antibody that bears the 16/6 idiotype (Id) was shown previously to be a dominant T-cell epitope in experimental SLE, and to be capable of inhibiting SLE-associated responses. When injected, concomitant with active immunization with the pathogenic human anti-DNA, 16/6 Id+ mAb, pCDR3 inhibited the proliferation of LN-derived T cells stimulated in vitro with the 16/6 Id mAb. The inhibition of the specific proliferative responses could be reversed by the addition of exogenous IL-2 to the cultures. Analysis of secreted cytokine profile in supernatants of these cultures demonstrated that pCDR3 treatment reduced significantly the levels of both IL-2 and IFN-gamma that were elevated further in cells of the 16/6 Id-immunized mice. The CDR3-based peptide was shown here to immunomodulate in vivo experimental SLE, induced by the human anti-DNA 16/6 Id+ antibody. The beneficial effects of pCDR3 on the clinical manifestations of SLE were associated with downregulation of the Th1-type (IL-2, IFN-gamma) and proinflammatory (TNF-alpha) cytokines, whereas the immunosuppressive cytokine TGF-beta was up regulated.

Animals↗

PubMed2006

Selective dysregulation of the FcgammaIIB receptor on memory B cells in SLE.

The inappropriate expansion and activation of autoreactive memory B cells and plasmablasts contributes to loss of self-tolerance in systemic lupus erythematosus (SLE). Defects in the inhibitory Fc receptor, FcgammaRIIB, have been shown to contribute to B cell activation and autoimmunity in several mouse models of SLE. In this paper, we demonstrate that expression of FcgammaRIIB is routinely up-regulated on memory B cells in the peripheral blood of healthy controls, whereas up-regulation of FcgammaRIIB is considerably decreased in memory B cells of SLE patients. This directly correlates with decreased FcgammaRIIB-mediated suppression of B cell receptor-induced calcium (Ca2+) response in those B cells. We also found substantial overrepresentation of African-American patients among those who failed to up-regulate FcgammaRIIB. These results suggest that the inhibitory receptor, FcgammaRIIB, may be impaired at a critical checkpoint in SLE in the regulation of memory B cells; thus, FcgammaRIIB represents a novel target for therapeutic interventions in this disease.

Adult↗

PubMed2004

Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE.

We genotyped 525 independent North American white individuals with systemic lupus erythematosus (SLE) for the PTPN22 R620W polymorphism and compared the results with data generated from 1,961 white control individuals. The R620W SNP was associated with SLE (genotypic P=.00009), with estimated minor (T) allele frequencies of 12.67% in SLE cases and 8.64% in controls. A single copy of the T allele (W620) increases risk of SLE (odds ratio [OR]=1.37; 95% confidence interval [CI] 1.07-1.75), and two copies of the allele more than double this risk (OR=4.37; 95% CI 1.98-9.65). Together with recent evidence showing association of this SNP with type 1 diabetes and rheumatoid arthritis, these data provide compelling evidence that PTPN22 plays a fundamental role in regulating the immune system and the development of autoimmunity.

Alleles↗

PubMed2004

Phenotypic and functional deficiencies of monocyte-derived dendritic cells in systemic lupus erythematosus (SLE) patients.

Systemic lupus erythematosus (SLE) represents an autoimmune disease for which alterations of T cells, B cells as well as various antigen-presenting cell (APC) populations have been described. In order to better define APC-associated deficiencies, we analyzed morphologic, phenotypic and functional characteristics of in vitro-generated monocyte-derived dendritic cells (MoDC) from SLE patients as compared with healthy controls. Analysis of MoDC at different stages of maturation revealed substantial phenotypic and functional defects of MoDC from SLE patients as compared with healthy controls. In particular, we observed a significantly reduced up-regulation of MHC class II molecules on MoDC upon activation which correlated with disease activity scores and functional deficiencies in mixed lymphocyte reaction experiments. Our data imply a crucial role of APC in the immunological imbalance in SLE for foreign and self-antigen reactivity.

Adult↗

PubMed2005

SLE--a disease of clearance deficiency?

Systemic lupus erythematosus (SLE) is a multifactorial disease and its pathogenesis and precise aetiology remain unknown. Under physiological conditions, neither apoptotic nor necrotic cell material is easily found in tissues because of its quick removal by a highly efficient scavenger system. Autoantigens are found in apoptotic and necrotic material and they are recognized by autoimmune sera from SLE patients. The clearance of dying cells is finely regulated by a highly redundant system of receptors on phagocytic cells and bridging molecules, which detect molecules specific for dying cells. Changes on apoptotic and necrotic cell surfaces are extremely important for their recognition and further disposal. Some SLE patients seem to have an impaired ability to clear such apoptotic material from tissues, and this could cause the breakdown of central and peripheral mechanisms of tolerance against self-antigens. In this article, we address the cells, receptors and molecules involved in the clearance process and show how deficiencies in this process may contribute to the aetiopathogenesis of SLE.

Apoptosis↗

PubMed1991

The H3 anti-phospholipid idiotype is found in patients with systemic lupus erythematosus (SLE) but not in patients with syphilis.

The human H3 idiotype, defined by a mouse monoclonal antibody S2.9, is commonly found in patients with SLE where it is correlated with the amount of anti-cardiolipin antibodies. No correlation between the amount of anti-cardiolipin antibody and the H3 idiotype is found in patients with syphilis. Using the S2.9 antibody, serum from each of 10 patients with SLE and eight patients with syphilis was separated into H3-bearing and H3-negative fractions. Comparison of the partition of anti-cardiolipin antibody in these two groups of patients revealed that much of the anti-cardiolipin antibody (44-91%) was found in the H3+ fraction in patients with SLE; in patients with syphilis, virtually none of the anti-cardiolipin antibody was H3+. In patients with SLE, the H3+ fraction contained both IgG and IgM and antibodies of both kappa and lambda light chains. The H3+ fraction was polyspecific and frequently reacted with dsDNA.

Antibody Specificity↗

PubMed1991

Characterization of anti-endothelial cell antibodies in systemic lupus erythematosus (SLE).

IgG anti-endothelial antibodies (AEA), as measured by ELISA or immunoblotting technique could be detected in serum samples of 56 out of 64 patients with SLE (88%) and mainly occurred in monomeric form. AEA were not cell specific, because the binding reactivity was absorbed partially by both fibroblasts and peripheral blood mononuclear cells. No correlation was found between the presence of AEA and anti-nuclear antibodies. Immunoblotting revealed reactivity of AEA against endothelial antigens ranging in size from 15 to 200 kD. AEA titres were significantly higher in patients with joint or skin abnormalities, compared with patients without these abnormalities. A significant correlation was found between nephritis in SLE and the presence of AEA reactivity against endothelial membrane antigens of 38, 41 and 150 kD. These data show that the pattern of AEA reactivity in serum of SLE patients is heterogeneous, and suggest that AEA against a limited number of antigens may be involved in the pathogenesis of nephritis in SLE.

Antibodies, Anti-Idiotypic↗

PubMed1992

Detection and characterization of immunoconglutinins in patients with systemic lupus erythematosus (SLE): serial analysis in relation to disease course.

The levels of IgA, IgG and IgM immunoconglutinins (IK) were assessed in sera from 20 patients with SLE which were followed for 8-month periods. At the time of the exacerbation, IgG IKs were significantly increased to 226 +/- 90 arbitrary units (mean +/- s.e.m.) compared with both the minimum value of 75 +/- 28 in the SLE patients and with 31 +/- 2 in healthy controls (P < 0.05). There was no difference between SLE patients and controls in the levels of IgM and IgA IKs. Most of the SLE patients in this material showed maximal IgG IK levels before exacerbation, but there was no correlation between the clinical disease index and the levels of IgG IK. The specificity of IgG IKs showed a broad diversity for microtitre-fixed C3b, iC3b, C3c and C3dg. The antibodies were of IgG1, IgG3 and in two patients, IgG4 subclass. IgG IKs were correlated to the C3d/C3 ratio which suggested that the IK responses were secondary to C3 activation. In summary, unlike other conditions associated with complement activation where elevated IgM IKs are common, an increase in IgG IK levels was observed. It is possible that this diverging IK response contributes to the pathophysiology of the disease.

Antibody Specificity↗

PubMed1994

Suppression of experimental systemic lupus erythematosus (SLE) with specific anti-idiotypic antibody-saporin conjugate.

The importance of the idiotypic network is represented in experimental SLE induced by active immunization of naive mice with an anti-DNA idiotype (Ab1) emulsified in adjuvant. The mice after 4 months of incubation generate Ab3 having anti-DNA activity. In addition, the mice develop other serological markers for SLE associated with clinical and histopathological manifestations characteristic of the disease. To confirm further the etiological role of the idiotype in this experimental model, the mice were treated with specific anti-idiotypic antibodies (anti-Id) which were also conjugated to a toxin-saporin (Immunotoxin (IT)). Pretreatment of hybridoma cell line producing the anti-anti-Id (anti-DNA = (Ab3)) for 48 h with the anti-Id MoAb (Ab2) reduced the production of anti-DNA by 58%, while pretreatment with the IT resulted in 86% decrease in anti-DNA secretion (saporin alone had only 12% effect). The anti-Id MoAb had no effect on the production of immunoglobulin by an unrelated cell line. In vivo treatment of mice with experimental SLE led to a significant decrease in titres of serum autoantibodies, with diminished clinical manifestations. The results were more remarkable when the IT was employed. These suppressive effects were specific, since an anti-Id treatment of experimental anti-phospholipid syndrome was of no avail. The anti-Id effect was mediated via a reduction in specific anti-DNA antibody-forming cells, and lasted only while anti-Id injections were given. Discontinuation of the anti-Id injection was followed by a rise in titres of anti-DNA antibodies. No immunological escape of new anti-DNA Ids was noted. Our results point to the importance of pathogenic idiotypes in SLE and to the specific potential of implementing anti-idiotypic therapy, enhanced by the conjugation of the anti-Id to an immunotoxin, in particular one with low spontaneous toxicity.

Animals↗

PubMed1994

Levels of soluble VCAM-1, soluble ICAM-1, and soluble E-selectin during disease exacerbations in patients with systemic lupus erythematosus (SLE); a long term prospective study.

Active SLE is characterized by immune deposits and subsequent vascular inflammation in many organs. Expression and up-regulation of adhesion molecules is basic to migration of inflammatory cells into the tissues. Recently, soluble isoforms of these molecules have been described which might be an expression of their up-regulation in the tissues and, as such, of disease activity. The purpose of this study was to evaluate whether changes in levels of soluble adhesion molecules reflect disease activity. We analysed serial sera in a 6-month period preceding 22 consecutive exacerbations of SLE for levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), and sE-selectin. Levels were related to clinical disease activity (SLEDAI), and levels of anti-dsDNA and complement. At the time of maximal disease activity, levels of sVCAM-1 in patients with SLE were higher than those in controls (P < 0.0001), levels in patients with renal involvement being higher than in those without (P < 0.02). Levels of sVCAM-1 correlated with SLEDAI scores (P < 0.05) and, inversely, with levels of C3 (P = 0.01). In addition, in the presence of anti-dsDNA, levels of sVCAM-1 tended to correlate with levels of these autoantibodies (P < 0.1). Levels of sICAM-1 were normal and sE-selectin levels even decreased compared with controls. Levels of sVCAM-1 were higher at the moment of relapse (P = 0.001) than at 6 months before this time point. This rise correlated with the rise in SLEDAI score (P < 0.02). Levels of sICAM-1 and sE-selectin did not rise, and remained in the normal range in all exacerbations studied. In conclusion, in contrast to sICAM-1 and sE-selectin, levels of sVCAM-1 are increased, rise parallel to disease activity during exacerbations in SLE, and are associated with decreasing levels of complement factors. This favours the hypothesis of immune deposit formation, activation of the complement cascade and activation of endothelial cells. Concurrent up-regulation of vascular adhesion molecules may thus result in transmigration of activated inflammatory cells inducing tissue damage.

Adult↗

PubMed1995

Suppression of haematopoiesis by IgG autoantibodies from patients with systemic lupus erythematosus (SLE).

The inhibiting activity of serum on haematopoiesis has been described in patients with SLE. To explore further the features of serum inhibitor, we first examined the suppression of granulocytic and erythroid colony formation in vitro by serum from patients with SLE using methylcellulose culture. The potent inhibiting activity was demonstrated in six of 20 patients. All of these six patients were associated with leukocytopenia and/or anaemia. Five of 10 sera from patients with active SLE suppressed the colony formation of both burst-forming units of erythrocyte (BFU-E) and colony-forming units of granulocyte/macrophage (CFU-GM), and one serum suppressed BFU-E only. IgG fraction isolated from sera with inhibiting activity suppressed colony formation without complement involvement. The elimination of monocytes and lymphocytes from target mononuclear cells did not affect the suppression by the IgG fractions. The suppressive effect was completely eliminated after incubation of the IgG fractions with progenitor-enriched mononuclear cells. Flow cytometric analysis showed these IgG bound to CD34+ haematopoietic progenitor cells, but not to CD33+ cells. These data suggest that (i) the inhibitor of colony formation in serum was observed in IgG fraction; (ii) its suppressive effect on colony formation was mediated by neither monocytes and lymphocytes nor complements; and (iii) IgG fraction could bind to primitive haematopoietic progenitor cells and suppress the growth of these cells. Thus, IgG autoantibodies to primitive haematopoietic progenitor cells are demonstrated to be present in the sera of a significant proportion of active SLE patients with anaemia and leukocytopenia and to suppress the progenitor cell growth.

Adolescent↗

PubMed1995

Low serum levels of dehydroepiandrosterone may cause deficient IL-2 production by lymphocytes in patients with systemic lupus erythematosus (SLE).

The principal cause of IL-2 deficiency, a common feature of both murine lupus and human SLE, remains obscure. Recent studies of our own as well as others have shown that dehydroepiandrosterone (DHEA), an intermediate compound in testosterone synthesis, significantly up-regulates IL-2 production of T cells, and that administration of exogenous DHEA or IL-2 via a vaccinia construct to murine lupus dramatically reverses their clinical autoimmune diseases. Thus, we have examined serum levels of DHEA in patients with SLE to test whether abnormal DHEA activity is associated with IL-2 deficiency of the patients. We found that nearly all of the patients examined have very low levels of serum DHEA. The decreased DHEA levels were not simply a reflection of a long term corticosteroid treatment which may cause adrenal atrophy, since serum samples drawn at the onset of disease, which are devoid of corticosteroid treatment, also contained low levels of DHEA. In addition, exogenous DHEA restored impaired IL-2 production of T cells from patients with SLE in vitro. These results indicate that defects of IL-2 synthesis of patients with SLE are at least in part due to the low DHEA activity in the serum.

Adult↗

PubMed1980

Studies of anti-lymphocyte antibody in patients with active SLE. II. Effect of anti-lymphocyte antibody on autoreactive cell clones.

The effect of anti-lymphocyte antibodies of active systemic lupus erythematosus (SLE) on the immune regulation of autoantibody production was studied. The present study demonstrated that there were native DNA (nDNA)-sensitized T lymphocytes even in inactive SLE and no or few nDNA-sensitized T lymphocytes in normal individuals, and that in the inactive stages of SLE suppressor T lymphocytes might inhibit the activation of nDNA-sensitized T lymphocytes eliciting the production of anti-DNA antibodies by B lymphocytes. In the active stage of SLE, the anti-lymphocyte antibodies could eliminate the suppressor function of T lymphocytes or a subset of cells capable of either regulating their appearance or differentiating into them, which inhibited such responses. The different suppression of DNA and extractable nuclear antigen (ENA)-stimulated blastogenic response is further discussed.

Antibodies, Antinuclear↗

PubMed2006

The generation of extracellular DNA in SLE: the role of death and sex.

DNA is a large macromolecule that plays a central role in the pathogenesis of systemic lupus erythematosus (SLE), serving as a target antigen of autoantibodies as well as a major component of immune complexes. These complexes can both promote immune disturbances as well as deposit in the kidney to incite inflammation. While the origin of anti-DNA autoantibodies in SLE has received intense investigation, the mechanisms by which DNA exits cells to form immune complexes in the circulation is not well understood. To determine the origin of DNA circulating in the blood in SLE, our laboratory has been using a murine model system to track the in vivo fate of DNA from Jurkat T cells that have been made apoptotic or necrotic in vitro and then administered to mice. Results of these studies indicate that DNA from apoptotic and necrotic cells appears in the blood in a time- and dose-dependent manner. Irrespective of origin, this DNA has properties of nucleosomes as shown by its molecular weight. The process of release requires the presence of macrophages and can be modified by glucocorticoids as well as inflammation. In addition, sex may play a role in the generation of extracellular DNA from dead cells as male and female mice differ in their responses in this model. Together, these studies clarify the origin of extracellular DNA circulating in the blood in SLE and suggest steps in this process that can be interdicted by novel therapy.

Animals↗