Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Weekly injections of cyclophosphamide (Cy) at a dose of 20 mg/kg body weight prevented IgM to IgG class switch of serum anti-DNA antibodies and also immunoglobulin secreting cells in the spleen of MRL/Mp-lpr/lpr (MRL/1) mice. Culture experiments revealed that splenic B cells of Cy treated mice gave rise to more IgM and less IgG secreting cells than those of untreated mice in response to lipopolysaccharide. These results suggested that Cy suppressed enhanced differentiation of B cells into IgG secreting cells in MRL/1 mice, which would result in reduction of IgG anti-single stranded DNA antibodies and improvement of murine lupus like syndrome.
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PMID:Long term administration of cyclophosphamide into MRL/1 mice. II. The effects on the isotype of anti-DNA antibodies and immunoglobulin secreting cells in the spleen. 660 25

In a previous paper (Gleichmann, van Elven & van der Veen, 1982), it had been reported that, in contrast to lupus like autoantibodies such as anti-DNA, autoantibodies to mouse thyroglobulin (MTg) were not detectable in serum of F1 mice suffering from a lupus like graft versus host disease (GVHD) (GVH F1). In the present paper, possible explanations for this restricted autoantibody formation during the potent allogeneic stimulation were investigated. The main question was whether the natural level of circulating MTg was too low to induce the formation of anti-MTg antibodies in GVH F1 mice. Existence, in the F1 mice studied, of B cells capable of producing anti-MTg antibodies was demonstrated by injection of lipopolysaccharide (LPS) and exogeneous MTg. However, MTg injected into various F1 mice at the onset of the GVH reaction (GVHR) failed to overcome the lack of antibody formation to MTg even though the GVHR led to a severe lupus like disease. Furthermore, adult thymectomy (ATx) of either the recipients, the donors, or both also did not break tolerance to MTg during the GVHR, irrespective of administration of exogeneous MTg. Thus, neither intravenous injection of MTg nor ATx, designed to remove T suppressor (TS) cells, is adequate to enable an autoantibody response to MTg during lupus like GVHD. Hence, the non-specific T cell help that causes lupus like GVHD seems to be intrinsically insufficient to trigger the Tg reactive B cells. We suggest that globular proteins, such as Tg, require specific T cell help. In the presence of only non-specific T help, self-antigens such as DNA seem to be more apt than globular proteins to provide an effective signal 1 to the corresponding autoreactive B cells.
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PMID:Injection of mouse thyroglobulin and/or adult thymectomy do not break tolerance to thyroglobulin during the lupus like graft versus host disease in mice. 670 66

The acute-phase plasma protein response to disease activity in murine models of autoimmune lupus-like disease was investigated by measurement of the concentration of serum amyloid P component (SAP) in NZB X W and MRL/l mice. The levels of SAP, which is a major acute-phase protein in mice, did not rise at all in response to progression of disease in NZB X W mice between the ages of 1 and 9 mo. This resembles the behavior of acute-phase proteins such as C-reactive protein and serum amyloid A protein in human systemic lupus erythematosus, and just as in human lupus, where the occurrence of intercurrent microbial infection can stimulate an acute-phase response, so injection of bacterial lipopolysaccharide or casein into the NZB X W mice stimulated "normal" acute-phase SAP production. In marked contrast, MRL/l mice developed greatly increased levels of SAP, which correlated closely with progression of their pathology as they aged. The disease profile of the MRL/l strain includes rheumatoid factors and spontaneous polyarthritis and their SAP response resembles the behavior of acute phase proteins in human rheumatoid arthritis. Different patterns of acute-phase response in different autoimmune disorders may thus be a reflection of the genetic predisposition to particular diseases and/or contribute to their pathogenesis. The existence of animal counterparts for the various clinical patterns of human acute-phase protein production will assist in experimental investigation of the underlying mechanisms and of the biological role of the acute-phase response.
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PMID:The acute-phase response in (NZB X NZW)F1 and MRL/l MICE. 715 12

Multifactorial involvement in the pathogenesis of autoimmune NZB/W F1 mice has been well documented. To further elucidate the role of cytokines in the disease development of murine lupus, single spleen cells isolated from NZB/W F1 and non-autoimmune C57BL/6 mice were stimulated with T cell mitogens or anti-CD3 antibody at pre-determined optimal concentration. Supernatants were collected and assayed for production of cytokines including IL-2, gamma-IFN, IL-3, IL-4, IL-5 and IL-10. In both young and old mice, cytokine profiles by mitogen-stimulated T cells showed higher TH2 (type 2 T helper) cell-related cytokine production in NZB/W F1 mice compared to those in non-autoimmune C57BL/6 mice. In contrast, cytokines produced by TH1 (type 1 T helper) cells, such as gamma-IFN and IL-2, were lower in NZB/W F1 mice by stimulation with either mitogen or anti-CD3 antibody. In addition, cytokine production at different time points also demonstrated decreased gamma-IFN and increased IL-4 levels by anti-CD3 stimulated splenic cells in autoimmune NZB/W F1 mice. Furthermore, the IL-10 levels produced by lipopolysaccharide (LPS)-stimulated splenic and peritoneal exudate cells were higher in young NZB/W F1 mice compared to those in C57BL/6 mice. Our data suggest that dysregulation between TH1 and TH2 cells may play an important role in the pathogenesis of autoimmunity in NZB/W F1 mice.
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PMID:Dysregulation of T helper cell cytokines in autoimmune prone NZB x NZW F1 mice. 756 80

Previous studies have suggested that the CDR3 genetic element of the heavy chain variable region of autoantibodies is important in determining reactivity against self antigens, particularly against DNA. The lpr mutation was recently found to encode for a defective form of the fas protein, a molecule important for the transmission of the apoptotic signal into cells. Our aim was to determine whether CDR3 elements similar to those described for autoantibody-producing hybridomas derived from lupus-prone strains could be found in the preimmune repertoire of B cells in mice with the lpr mutation. The analysis of the junctions of the VH-C mu functional rearrangements derived by polymerase chain reaction (PCR) amplification of RNA obtained from splenic small, resting cells stimulated with lipopolysaccharide (LPS) from male lpr mice showed that a large proportion of them expressed D genes in the unusual reading frames 2 and 3. Two of the lpr joints were formed by D-D fusions. Similarly, nearly half of the lpr sequences had arginines, an amino acid which promotes binding to dsDNA and is seldom observed in normal junctions. Our results show that the preimmune repertoire of lpr animals has abnormal CDR3 elements which may result from a failure at different levels of selection. The antigen-dependent selection of such elements that leads to the expansion of specific, high-affinity anti-dsDNA antibody-producing clones might depend on other genetic factors not found in the C57B1/6-lpr strains but in the MRL-lpr.
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PMID:CDR3 regions in the preimmune VH B cell repertoire of lpr mice. 762 95

B cells are stimulated by antigens or by polyclonal activators such as bacterial lipopolysaccharide (LPS) to produce antibody. In nonautoimmune strains of mice, LPS-stimulated antibody responses are inhibited by crosslinking the B cell antigen-receptor (BCR), while antigen-driven responses are shut down by co-crosslinking the BCR and the receptor for the Fc portion of IgG (Fc gamma R). BCR signals are poor at shutting off LPS-induced antibody production, including anti-ssDNA antibody production, in B cells from NZB, NZB/WF1, and BXSB lupus-prone mice but not MRL/lpr or NZW mice. In the current studies, the defect in NZB B cells was shown to be independent of T cells and macrophages. The inheritance pattern of resistance to BCR ligation of LPS-induced Ig production in BXSB mice could not be assigned to either founding strain. In New Zealand mixed (NZM) recombinant inbred mice, slightly but significantly more resistance was found in a line (NZM2410) that demonstrates a greater degree of clinical autoimmunity than another line (NZM64) with fewer autoimmune problems. The autoimmune defect is specific to BCR signals because inhibition of LPS activation by ligation of MHC class II occurs normally in NZB B cells. Bypassing the BCR by direct stimulation of second messengers with phorbol esters or ionomycin did not overcome the defect, suggesting that defects in downstream signaling events, rather than in the BCR mechanism itself, are responsible for the reduced ability to inhibit the LPS response in NZB B cells. The inability of the BCR signaling pathway to control LPS-induced Ig production in NZB mice was apparent at the level of H mu-chain mRNA for secreted IgM. These results suggest that autoimmunity-associated B cell defects in BCR signaling and subsequent regulation of LPS-driven antibody responses have a number of inheritance patterns and involve downstream events in signaling pathways in B cells. The defect can result in aberrant regulation of H mu-chain mRNA levels for secreted IgM production, and may be a predisposing factor in murine systemic autoimmune disease.
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PMID:Defective antigen-receptor-mediated regulation of immunoglobulin production in B cells from autoimmune strains of mice. 763 46

NZB.H-2bm12 mice develop an autoimmune syndrome characterized by the overproduction of anti-DNA antibodies and the expansion of B-1 B cells. Thus, these animals provide a useful model to examine the antigenic specificity, cross-reactivity and functional capability of B-1 versus conventional lymphocytes. Neither the repertoire expressed by in vivo activated Ly-1+ splenic lymphocytes, nor their cross-reactivity, differed significantly from that of conventional splenic B cells. When Ly-1+ cells were cultured in vitro in the presence of lipopolysaccharide plus interleukin-4 or interferon gamma, they underwent isotype switching at the same frequency as conventional B cells. Of interest, B-1 cells from the peritoneal cavity were significantly less likely to undergo isotype switching than those from the spleen. These findings indicate that in vivo activated B-1a and conventional B cells from mice with lupus manifest similar functional characteristics.
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PMID:B-1a and conventional B cells from autoimmune NZB.H-2bm12 mice exhibit similar functional characteristics in vivo. 768 8

The lymphoproliferation (lpr) mutation in the MRL strain of mice is caused by the insertion of the early transposable element ETn in the Fas gene. The insertion causes a striking decrease in Fas mRNA expression and is associated clinically with marked acceleration of the lupus-like disease. To further explore the role of the Fas protein in T-cell selection in the thymus and tolerance in the peripheral immune system, we produced a monospecific polyclonal anti-murine Fas antibody that binds to a polymorphic region of the protein. Fas protein expression was detected on approximately 90% of BALB/c and MRL +/+ thymocytes, and the expression was highest on CD4+CD8+ thymocytes, the stage at which most thymocytes die by apoptosis. In contrast to the high level of expression of Fas on thymocytes, Fas was detected on < 10% of normal splenic T cells. After activation of splenic T cells with Con A or anti-CD3 and interleukin 2, Fas expression increased approximately 10-fold. Fas expression on splenic B cells was also markedly up-regulated after activation with lipopolysaccharide or anti-mu antibodies. The Fas protein was not detected on resting or activated lymphocytes obtained from MRL lpr/lpr mice. Together, these findings suggest that Fas plays a role in both thymic selection and T-cell survival in the periphery and that the accelerated autoimmunity in MRL lpr/lpr mice results from a defect in both of these pathways.
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PMID:The Fas protein is expressed at high levels on CD4+CD8+ thymocytes and activated mature lymphocytes in normal mice but not in the lupus-prone strain, MRL lpr/lpr. 769 92

Lupus prone NZB/W mice repeatedly exposed to bacterial lipopolysaccharide (LPS) develop enhanced polyclonal B cell activation and exacerbated nephritis by a mechanism that results in increased deposits of immunoreactants in kidneys without measurable impairment of mononuclear phagocyte function. In this paper, we investigate whether the referenced effects of LPS are reversible after withdrawal of LPS, or whether their persistence could contribute to progression of nephritis to chronicity. In NZB/W mice previously exposed to LPS, features of enhanced polyclonal B cell activation, more severe glomerulonephritis with tubulointerstitial involvement, increased deposits of immunoreactants in glomeruli, and altered protein excretion persisted 6 weeks after LPS was discontinued. Additionally, mononuclear phagocyte function, assessed through liver uptake of radiolabeled immune complexes, was found to be impaired. The results indicate that some of the effects of prior exposure to LPS may be partially reversible; however, they last long after LPS has been discontinued, and additional impairment of immune function develops together with permanent glomerular dysfunction, thereby contributing to progression of nephritis to chronicity.
Lupus 1994 Dec
PMID:Long-lasting effects of bacterial lipopolysaccharide promote progression of lupus nephritis in NZB/W mice. 770 9

Plasma procoagulant activity inducing factor (PIF) is a spontaneously occurring, potent inducer of macrophage procoagulant activity (PCA) in the male BXSB murine model of systemic lupus erythematosus. The physical characteristics of PCA induction by PIF, aggregated mouse IgG, and lipopolysaccharide (LPS) were compared. Both aggregated IgG and PIF-induced PCA were heat, acid and alkali sensitive. In contrast, LPS-induced PCA was heat resistant and only partially acid and alkali sensitive. Plasma containing PIF was fractionated on Sephacryl S-300. The PIF activity localized to the first protein peak, molecular weight 400,000 to 900,000 daltons. Analysis of peak 1 by an enzyme-linked immunosorbent assay showed the presence of IgM, IgA and IgG. This was confirmed by Western blot analysis using 125I-labelled goat anti-mouse IgM, IgA and IgG probes. The concentration of PIF increased with Sephacryl S-300 chromatography and was reduced by removal of IgG, but not IgA or IgM by affinity chromatography. Peak 1 did not contain DNA as revealed by ethidium bromide staining. Thus, IgG from the plasma of BXSB mice, a strain which develops lupus nephritis, stimulates macrophages to express PCA, accounting for PCA induction in the BXSB model of murine lupus.
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PMID:Characterization of the procoagulant-inducing factor derived from the plasma of BXSB mice. 773 36


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