Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PN mice spontaneously develop, with age, a lupus-like disease. The present study further evaluated autoantibody production in female PN mice. As early as 1 month of age, all PN mice had detectable IgM antibodies to dsDNA and ssDNA and two-thirds produced IgM anticardiolipin antibodies. By 3 months of age, all PN mice exhibited evidence of isotype switch in their autoantibody response; 88-100% had serum IgG antibodies to ssDNA and dsDNA, respectively. By 6-12 months of age, essentially all female PN mice had IgG antibodies to ssDNA, dsDNA, cardiolipin and other phospholipids (PS, PC, PI, and PG), and IgG and 63% produced IgG anti-mouse erythrocyte antibodies. In addition, 50-100% produced IgA antibodies to dsDNA and ssDNA, and one-third produced IgA anti-IgG antibodies. Antibodies to U1RNP and Sm were present in 81% of 6- to 12-month-old PN mice and 39-94% had IgG or IgM antibodies to mouse thymocytes. Although all four IgG isotypes were represented in the anti-dsDNA response, IgG1 antibodies dominated the IgG anticardiolipin response. The presence of IgA autoantibodies and the predominance of IgG1 in the IgG anticardiolipin response suggest that IL-4 and either IL-5 and/or TGF-beta serve as B cell stimulatory cytokines for autoreactive B cells in PN mice.
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PMID:Further characterization of the autoantibody response of Palmerston North mice. 1008 Jan 4

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.
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PMID:Exogenous IL-10 and IL-4 down-regulate IL-6 production by SLE-derived PBMC. 1021 49

Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are autoimmune disorders with a preponderance in females. RA and SLE differ in their response to sex hormones. Disease development of RA is mitigated by estrogen and pregnancy whereas SLE tends to flare during pregnancy and in response to estrogen. Pregnancy improves the symptoms of RA in about 75% of pregnant patients, but relapses within six months postpartum in 90% of cases. RA is regarded as a T cell-mediated and TH1 immune response-driven disease. Pregnancy induces a shift from TH1 to TH2 immune response, increasing the anti-inflammatory cytokines IL-4 and IL-10, which may contribute to gestational amelioration of RA. Prospective studies of SLE pregnancies indicate that about 50% of patients experience a flare, however, with no permanent aggravation of the disease. Lupus nephritis, presence of antiphospholipid antibodies, and a previous history of pregnancy loss increase the risk of complications during pregnancy and fetal loss. The marked increase of estrogen and progesterone during pregnancy seems to enhance some of the manifestations of SLE. The shift to a TH2 immune response may trigger SLE manifestations that are dependent on humoral immune responses such as lupus nephritis. Another factor stimulating immune responses is the pituitary hormone prolactin, which has been found elevated in SLE patients of both sexes and correlated to disease activity in several studies. The hyperprolactinemia of lactation seems to influence postpartum behavior of SLE as well as RA.
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PMID:Sex hormones and pregnancy in rheumatoid arthritis and systemic lupus erythematosus. 1041 1

We tested 154 peptides spanning the entire length of core histones of nucleosomes for the ability to stimulate an anti-DNA autoantibody-inducing T helper (Th) clone, as well as CD4(+) T-cell lines and T cells, in fresh PBMCs from 23 patients with lupus erythematosus. In contrast to normal T cells, lupus T cells responded strongly to certain histone peptides, irrespective of the patient's disease status. Nucleosomal peptides in histone regions H2B(10-33), H4(16-39) (and overlapping H4(14-28)), H4(71-94), and H3(91-105) (and overlapping H3(100-114)) were recurrently recognized by CD4 T cells from the patients with lupus. Remarkably, these same peptides overlap with major epitopes for the Th cells that induce anti-DNA autoantibodies and nephritis in lupus-prone mice. We localized 2 other recurrent epitopes for human lupus T cells in H2A(34-48) and H4(49-63). All the T-cell autoepitopes have multiple HLA-DR binding motifs, and the epitopes are located in histone regions recognized by lupus autoantibodies, suggesting a basis for their immunodominance. Native nucleosomes and their peptides H4(16-39), H4(71-94), and H3(91-105) induced a stronger IFN-gamma response, whereas others, particularly, H2A(34-48), favored an IL-10- and/or IL-4-positive T-cell response. The major autoepitopes may reveal the mechanism of autoimmune T-cell expansion and lead to antigen-specific therapy of human lupus.
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PMID:Major peptide autoepitopes for nucleosome-specific T cells of human lupus. 1043 Jun 16

It has been reported that production of interleukin (IL)-4, a T helper (Th)-2-type cytokine, might play an important role in the pathogenesis of systemic lupus erythematosus (SLE). On the other hand, it is known that NK1.1(+) cells which belong to CD4, CD8 double-negative, or CD4(+) cells are associated with initial IL-4 production and Th2 differentiation in mice although human equivalent cells are unknown. In order to study the profile of IL-4-producing cells in SLE, cytoplasmic IL-4 and various surface antigens on peripheral mononuclear cells were analyzed. Peripheral mononuclear cells were stimulated for 5 h by phorbol ester and ionomycin in the presence of monensin, fixed, and permeabilized with paraformaldehyde and saponin solution. Then cytoplasmic IL-4 and various surface antigens were analyzed by flow cytometry. IL-4-producing cells in SLE were phenotypically the same as those which produce IL-4 normally and frequently bore activated T-cell (CD7, CD25, CD28, CD29) and NK-cell markers (CD56, CD57). Double-negative T cells and CD57(+) T cells were increased in number and were more frequently positive for cytoplasmic IL-4 in SLE compared with normal controls and various infectious diseases. It was suggested that T cells with NK cell markers, CD57(+) T cells, which are known to extrathymically differentiate, might be involved in the pathogenesis of SLE as a counterpart of mouse NK1.1(+) cells.
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PMID:Increased interleukin-4 production by NK T cells in systemic lupus erythematosus. 1044 64

Male, but not female, BXSB mice develop severe lupus associated with multiple immune system defects. It was recently shown that one immunological abnormality found in male BXSB mice encompasses B cell expression of CD40 ligand (CD40L) by an expanded population of large B cells. The present study was undertaken to determine how the CD40L-expressing large B cells in male BXSB mice compared with size-matched B cells from female mice in terms of their ability to secrete antibody. It was shown that the large B cells from female mice, similar to the small B cells from either male or female mice, required CD40 signalling, immunoglobulin cross-linking and cytokines for optimal antibody synthesis. In contrast, large B cells from male BXSB mice produced high levels of antibody when stimulated with only two of the three signals, and made significantly more total IgM and IgG, and anti-ssDNA antibody than size-matched B cells from female mice when stimulated with IL-4/IL-5 alone, IL-4/IL-5 plus low levels of anti-IgD-dextran, or IL-4/IL-5 plus anti-CD40 MoAb. The ability of the large B cells from male mice to produce antibody under suboptimal stimulatory conditions correlated with their expression of CD40L, and was inhibited by CD40-immunoglobulin. Taken together, these findings suggested that large CD40L-expressing B cells from male BXSB mice may be able to bypass a need for CD40 signalling from T cells, thus contributing to autoimmune disease by promoting antibody production in the absence of cognate T cell help.
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PMID:Antibody production in autoimmune BXSB mice. I. CD40L-expressing B cells need fewer signals for polyclonal antibody synthesis. 1054 Jan 72

Although systemic lupus erythematosus appears to be a humorally mediated disease, both Th1 and Th2 type responses have been implicated in its pathogenesis. The Th1 response, as exemplified by IFN-gamma production, has been uniformly shown in mouse lupus models to be critical for disease induction. The role of Th2 type responses, however, is more complicated, with some studies showing detrimental and others beneficial effects of IL-4 in these models. To further address this issue, we generated and analyzed IL-4 gene-deficient BXSB mice. Mice homozygous for this deletion had significantly lower serum levels of total IgG1 compared with wild-type BXSB, consistent with the lack of IL-4. However, no significant differences were observed in mortality, spleen weight, severity of glomerulonephritis, levels of anti-chromatin and anti-ssDNA Abs, or frequency of activated (CD44high) CD4+ T cells. The anti-chromatin Ab isotype response was virtually all Th1 type in both the knockout and wild-type BXSB. These findings directly demonstrate that IL-4 and, by inference, Th2 cells are not obligatory participants in the induction and maintenance of lupus in this strain.
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PMID:Development of lupus in BXSB mice is independent of IL-4. 1060 90

We have previously observed that aged lupus-prone (NZB/NZW)Fl (BWF1) mice when infected with Plasmodium chabaudi show an improvement in their clinical lupus-like symptoms. In order to study the mechanisms involved in the long-lasting protective effect of the P. chabaudi infection in lupus-prone mice we analysed specific aspects of the cellular response, namely the profiles of cytokine mRNA expression and cytokine secretion levels in old BWF1 mice, in comparison with uninfected age-matched BWF1 mice and infected or uninfected BALB/c mice. Two months after infection, cells from BWF1 mice were stimulated with concanavalin A (Con A) and demonstrated a recovery of T cell responsiveness that reached the levels obtained with BALB/c cells. Old BWF1 mice showed high levels of interferon-gamma (IFN-gamma) and IL-5 production and correspondingly low levels of IL-2 and IL-4 secretion before infection with P. chabaudi. Infection did not modify the IFN-gamma levels of BWF1 T cells, whereas it considerably increased the secretion of the Th2-related cytokines IL-4, IL-5 and IL-10. In addition, only BWF1 T cells showed increased mRNA expression of tumour necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta). This counter-regulatory cytokine network of infected BWF1 mice may be involved in the improvement of their lupus symptoms. The results of our investigations using the complex model of P. chabaudi infection can be extended and, by using more restricted approaches, it may be possible to explain the multiple regulatory defects of lupus-prone mice.
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PMID:Changes in the cytokine profile of lupus-prone mice (NZB/NZW)F1 induced by Plasmodium chabaudi and their implications in the reversal of clinical symptoms. 1063 72

In our previous reports, we found polyclonal anti-double-stranded DNA antibodies (anti-dsDNA) purified from patients with active systemic lupus erythematosus (SLE) exerted inhibitory effect on [3H]thymidine incorporation of human mononuclear cells (MNC). However, the other immunological effects of anti-dsDNA on the functions of MNC have not yet been reported. In this study, two monoclonal antibodies, 12B3 and 9D7, with different anti-dsDNA activity were evaluated for their effects on the expression and release of different cytokines from human MNC. We confirmed absence of endotoxin in the two monoclonal antibody preparations and the used medium as detected by Limulus amoebocyte lysate test. The mRNA expression and release of different cytokines including interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) were measured. We found the two monoclonal anti-dsDNA not only dose-responsively suppressed the phytohaemagglutinin (PHA)-induced thymidine uptake of human MNC but stimulated the mRNA expression of IL-1beta, IL-6 and IL-8 in normal human MNC detected by reverse transcription-polymerase chain reaction (RT-PCR). Enzyme-linked immunosorbent assay (ELISA) measurement of cytokines in MNC culture supernatants revealed that anti-dsDNA enhanced IL-1beta, IL-8, TNF-alpha and IL-10 release from resting MNC. These effects of anti-dsDNA antibodies were not affected by polymyxin B, a potent binder and neutralizer of lipopolysaccharide (LPS). These in vitro studies suggest that anti-dsDNA possess a dual effect on normal human MNC: (a) to enhance the release of proinflammatory cytokines (IL-1beta, IL-8 and TNF-alpha) from MNC to augment inflammatory reaction; and (b) to polarize the immune reaction towards the T helper 2 (Th2) (increased IL-10 production) pathway. This unique effect of anti-dsDNA may play a role in lupus pathogenesis by augmenting inflammatory reactions and autoantibody production which are commonly found in patients with active SLE.
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PMID:Monoclonal anti-double-stranded DNA autoantibody stimulates the expression and release of IL-1beta, IL-6, IL-8, IL-10 and TNF-alpha from normal human mononuclear cells involving in the lupus pathogenesis. 1071 64

Antiphospholipid syndrome (APS) is an autoimmune disease that accompanies anti-phospholipid antibodies measured as either anti-cardiolipin antibodies (aCL) or lupus anticoagulant. beta(2)-glycoprotein I (beta(2)GPI) is the most common and apparently the best-characterized antigenic target for aCL. To investigate T-cell responses to beta(2)GPI, we stimulated PBMC of 18 APS or systemic lupus erythematosus (SLE) patients carrying anti-beta(2)GPI and 10 healthy controls, using a peptide library covering the beta(2)GPI sequence. We established seven CD4(+) T cell lines reactive with beta(2)GPI peptide. Three of four epitopes for patient-derived T cell lines were p244-264, whereas one T cell line from a control subject also recognized p244-264. Furthermore, there was no tendency for particular HLA class II molecules to present beta(2)GPI peptides. However, cytokine producing patterns were significantly different between T cell lines from patients and those from healthy individuals (p =.028); patients' T cells tend to exhibit higher IL-4 and lower IFN-gamma responses. These T cell lines did not react to beta(2)GPI purified from human plasma. These results indicate that beta(2)GPI-reactive CD4(+) T cells of APS/SLE patients mainly recognize cryptic p244-264 in the context of various HLA class II molecules, and exhibit Th0-Th2-type responses. Our findings may provide a clue to the pathogenesis of APS.
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PMID:Analysis of T cell responses to the beta 2-glycoprotein I-derived peptide library in patients with anti-beta 2-glycoprotein I antibody-associated autoimmunity. 1071 14


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