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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There are distinct microenvironmental abnormalities of thymic architecture in several murine models of SLE defined using immunohistochemistry and a panel of mAb dissected at thymic epithelial markers. To address the issue of the relationship between the thymic microenvironment and autoimmunity, we studied backcross (NZB x NZW) F1 x NZW mice in which 50% of offspring develop nephritis associated with proteinuria and anti-DNA antibodies. We reasoned that if thymic abnormalities are associated with development of disease, the correlation of abnormalities with lupus-like disease in individual backcross mice will form the foundation for identification of the mechanisms involved. In parallel, we directed a genetic linkage analysis, using markers previously shown to be linked to nephritis and IgG autoantibody production, to determine if such loci were similarly associated with microenvironmental changes. Our data demonstrate that all (NZB x NZW) F1 x NZW backcross mice with disease have microenvironmental defects. Although the microenvironmental defects are not sufficient for development of autoimmune disease, the severity of thymic abnormalities correlates with titers of IgG autoantibodies to DNA and with proteinuria. Consistent with past studies of (NZB x NZW) F1 x NZW mice, genetic markers on proximal chromosome 17 (near MHC) and distal chromosome 4 showed trends for linkage with nephritis. Although the markers chosen only covered about 10-15% of the genome, the results demonstrated trends for linkage with thymic medullary abnormalities for loci on distal chromosome 4 and distal chromosome 1. We believe it will be important to define the biochemical nature of the molecules recognized by these mAbs to understand the relationships between thymic architecture and immunopathology.
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PMID:Thymic microenvironment and NZB mice: the abnormal thymic microenvironment of New Zealand mice correlates with immunopathology. 1007 68

The linkage between xenobiotic exposures and autoimmune diseases remains to be clearly defined. However, recent studies have raised the possibility that both genetic and environmental factors act synergistically at several stages or checkpoints to influence disease pathogenesis in susceptible populations. These observations predict that individuals susceptible to spontaneous autoimmunity should be more susceptible following xenobiotic exposure by virtue of the presence of predisposing background genes. To test this possibility, mouse strains with differing genetic susceptibility to murine lupus were examined for acceleration of autoimmune features characteristic of spontaneous systemic autoimmune disease following exposure to the immunostimulatory metals nickel and mercury. Although NiCl(2) exposure did not exacerbate autoimmunity, HgCl(2) significantly accelerated systemic disease in a strain-dependent manner. Mercury-exposed (NZB X NZW)F1 mice had accelerated lymphoid hyperplasia, hypergammaglobulinemia, autoantibodies, and immune complex deposits. Mercury also exacerbated immunopathologic manifestations in MRL+/+ and MR -lpr mice. However, there was less disease acceleration in lpr mice compared with MRL+/+ mice, likely due to the fact that environmental factors are less critical for disease induction when there is strong genetic susceptibility. Non-major histocompatibility complex genes also contributed to mercury-exacerbated disease, as the nonautoimmune AKR mice, which are H-2 identical with the MRL, showed less immunopathology than either the MRL/lpr or MRL+/+ strains. This study demonstrates that genetic susceptibility to spontaneous systemic autoimmunity can be a predisposing factor for HgCl(2)-induced exacerbation of autoimmunity. Such genetic predisposition may have to be considered when assessing the immunotoxicity of xenobiotics. Additional comparative studies using autoimmune-prone and nonautoimmune mice strains with different genetic backgrounds will help determine the contribution that xenobiotic exposure makes in rendering sensitive populations susceptible to autoimmune diseases.
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PMID:Lupus-prone mice as models to study xenobiotic-induced acceleration of systemic autoimmunity. 1050 38

Keratinocyte cytotoxicity is an important component of the immunopathology of photosensitive lupus erythematosus, and antibody-dependent cell-mediated cytotoxicity (ADCC) has been shown to be an important mechanism by which autoantibodies, especially those specific for SS-A/Ro, can induce keratinocyte damage in models of photosensitive lupus. We provide further evidence that keratinocytes from patients with photosensitive lupus show significantly greater ultraviolet radiation (UVR)-induced cytotoxicity, and that ADCC of these targets is especially enhanced by autologous patient's serum or by anti-SS-A/Ro+ sera. Keratinocytes from normal uninvolved skin of 29 patients with cutaneous lupus erythematosus (LE) were grown in cell culture and tested as targets in cytotoxicity experiments in vitro. Cultured keratinocytes from patients with systemic lupus erythematosus (SLE) and subacute cutaneous lupus erythematosus (SCLE) showed significantly greater cytotoxicity following UVR treatment than did keratinocytes from normal adult controls or from neonatal foreskins (P < 0.01). The same cultures also showed greater UVR-induced binding of IgG from fractionated anti-SS-A/Ro+ preparations. ADCC experiments were also performed using keratinocytes cultured from patients with SLE, SCLE, discoid lupus erythematosus (DLE), and normal controls. When keratinocytes were incubated in autologous serum plus a standard mononuclear cell effector population, the percentage of ADCC observed was significantly greater in cultures containing keratinocytes and sera from the SLE and SCLE patients (P < 0.001). When cultured keratinocytes were added to different IgG antibody probes, plus standard mononuclear effector populations, greater ADCC was seen using the anti-SS-A/Ro probe and keratinocytes from patients with SLE or SCLE. With normal human neonatal keratinocyte targets, the anti-SS-A/Ro probe induced greater ADCC than that seen with anti-ssDNA or normal human serum. We have shown that keratinocytes from patients with some forms of lupus erythematosus (SLE and SCLE) show greater cytotoxicity in vitro when irradiated with UVR, and greater susceptibility to ADCC whether the antibody source is their own serum or an anti-SS-A/Ro probe.
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PMID:Keratinocytes from patients with lupus erythematosus show enhanced cytotoxicity to ultraviolet radiation and to antibody-mediated cytotoxicity. 1054 Jan 74

In the past few years, considerable evidence has accumulated to suggest the existence of functionally polarized responses by the CD4+ T helper (Th)--and the CD8+ T cytotoxic (Tc)-cell subsets that depend on the cytokines they produce. The Th1 and Th2 cellular immune response provide a useful model for explaining not only the different types of protection, but also the pathogenic mechanisms of several immunopathological disorders. The factors responsible for the polarization of specific immune response into a predominant Th1 or Th2 profile have been extensively investigated in mice and humans. Evidence has accumulated from animal models to suggest that Th1-type lymphokines are involved in the genesis of organ-specific autoimmune diseases, such as experimental autoimmune uveitis, experimental allergic encephalomyelitis, or insulin-dependent diabetes mellitus. Accordingly, data so far available in human diseases favor a prevalent Th1 lymphokine profile in target organs of patients with organ-specific autoimmunity. By contrast, Th2-cell predominance was found in the skin of patients with chronic graft-versus host disease, progressive systemic sclerosis, systemic lupus erythematosus, and allergic diseases. The Th1/Th2 concept suggests that modulation of relative contribution of Th1- or Th2-type cytokines regulate the balance between protection and immunopathology, as well as the development and/or the severity of some immunologic disorders. In this review, we have discussed the paradigm of Th1 and Th2 cytokines in relation to autoimmunity and allergy.
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PMID:The paradigm of Th1 and Th2 cytokines: its relevance to autoimmunity and allergy. 1058 Jun 39

To determine whether reproducible results from direct immunofluorescent tissue staining could be obtained after storing the slides at room temperature. We examined the original slides of 22 cases noted to be positive for direct immunofluorescence. Diagnoses include pemphigus, pemphigoid, lupus, dermatitis herpetiformis, lichen planus, and vasculitis. These specimens, initially evaluated during the period January 1997 to September 1998, were prepared with a standard immunofluorescence staining technique, and then a permanent aqueous mounting medium was added. All specimens were stored at room temperature in vertical slide holding trays. We focused on the presence and relative intensity of the immunofluorescence staining, as well as the final diagnosis. We then compared our readings to that of the original reports. Twenty of the 22 cases studied (91%) were read as having the same diagnosis as the initial immunopathology report. Seventeen of the 22 cases (77%) were found to have the identical or slightly less fluorescence intensity. The original reports in 3 of the cases did not comment on the original intensity of fluorescence. Thus, a comparison of fluorescence preservation could not be made. In 2 of the cases, the quality of tissue preservation was poor, and though fluorescent staining was noted, we were unable to render a diagnosis. Our results suggest that direct immunofluorescent studies, using a permanent aqueous mounting medium, can be stored over long periods of time at room temperature without significant degradation of staining.
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PMID:Long-term preservation of direct immunofluorescence staining in slides stored at room temperature. 1084 46

The author highlights some of the clinical and serological signs associated with systemic lupus erythematosus and use them as keys to enter into the most recent advances in the immunopathology of the disease, in particular the mechanisms underlying the production of pathogenic autoantibodies. He stresses that a better knowledge of the pathophysiology of the disease, combined to the progresses in basic immunology and biotechnology, has raised hopes for a more targeted immunointervention.
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PMID:[Lupus erythematosus: from clinical aspects to immunopathology]. 1085 38

Lupus nephritis is a frequent and severe complication of SLE. In the last decades, animal models for SLE have been studied widely to investigate the immunopathology of this autoimmune disease because abnormalities can be studied and manipulated before clinical signs of the disease become apparent. In this review an overview is given of our current knowledge on the development of lupus nephritis, as derived from animal models, and a hypothetical pathway for the development of lupus nephritis is postulated. The relevance of the studies in experimental models in relationship with our knowledge of human SLE is discussed.
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PMID:Lupus nephritis: lessons from experimental animal models. 1128 19

Although evidence indicates that environmental factors play a major role in precipitating systemic autoimmunity in genetically susceptible individuals, little is known about the mechanisms involved. Certain heavy metals, such as mercury, are potent environmental immunostimulants that produce a number of immunopathologic sequelae, including lymphoproliferation, hypergammaglobulinemia, and overt systemic autoimmunity. Predisposition to such metal-induced immunopathology has been shown to be influenced by both MHC and non-MHC genes, as well as susceptibility to spontaneous lupus, in mice and other experimental animals. Among the various mouse strains examined to date, the DBA/2 appears to uniquely lack susceptibility to mercury-induced autoimmunity (HgIA), despite expressing a susceptible H-2 haplotype (H-2d). To define the genetic basis for this trait, two genome-wide scans were conducted using F2 intercrosses of the DBA/2 strain with either the SJL or NZB strains, both of which are highly susceptible to HgIA. A single major quantitative trait locus on chromosome 1, designated Hmr1, was shown to be common to both crosses and encompassed a region containing several lupus susceptibility loci. Hmr1 was linked to glomerular immune complex deposits and not autoantibody production, suggesting that DBA/2 resistance to HgIA may primarily involve the later stages of disease pathogenesis. Identification and characterization of susceptibility/resistance genes and mechanisms relevant to the immunopathogenesis of mercury-induced autoimmunity should provide important insights into the pathogenesis of autoimmunity and may reveal novel targets for intervention.
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PMID:Resistance to xenobiotic-induced autoimmunity maps to chromosome 1. 1149 30

Intrinsic defects in the B lymphoid lineage are involved in predisposition for systemic lupus erythematosus in (NZB x NZW)F(1) (NZB/W) mice. In addition, a contribution of CD4(+) T cells has been shown to be crucial for the development of fatal glomerulonephritis. To further dissect the role of B and T cells in lupus immunopathology we used Ig mu-heavy chain (muHC) transgenic (Tg) NZB/W mice that we recently established to study mechanisms of B cell tolerance. The Tg NZB/W mice have a very restricted B cell repertoire and only a very minor population of B cells having endogenously rearranged muHC Ig loci are able to undergo isotype switch. Here we analyzed the influence of the restricted B cell repertoire on the development of IgG anti-DNA antibodies and glomerulonephritis as well as the hyperactivation of T(h) cells. IgG anti-DNA antibodies developed delayed but consistently in the Tg NZB/W mice, suggesting that a strong selective mechanism for the development of these autoantibodies is operative. Despite significant autoantibody titers in Tg NZB/W mice, very little immune deposits in the glomeruli and no evidence for renal inflammation were found. The Tg mice have a significantly prolonged survival time and most of the Tg mice lived much longer than 1 year. Interestingly, the generalized T cell activation that normally correlates and coincides with the progression of the disease in NZB/W mice is strongly reduced in older Tg animals. The absence of IgG3 anti-DNA antibodies and the strong reduction of IgG2a anti-DNA antibodies in the Tg mice suggests that particularly the activation of T(h)1 cells is inhibited. This result shows that a significant restriction in the B cell repertoire prevents hyperactivation of T(h) cells and supports the model that T cell hyperactivation in NZB/W mice is secondary to specific interactions with a subpopulation of presumably autoreactive B lymphocytes.
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PMID:An Ig mu-heavy chain transgene inhibits systemic lupus erythematosus immunopathology in autoimmune (NZB x NZW)F1 mice. 1171 87

Receptors for prolactin (PRL-R) are expressed in normal leukocytes from rat and man. PRL signals through PRL-R associated Janus tyrosine kinase (Jak)-2 and signal transducers and activators of transcription (Stat). In addition, in human leukocytes PRL also activates the p38 MAP kinase pathway. PRL, at physiological concentrations, stimulates the expression of the interferon regulatory factor (IRF)-1 gene in rat spleen and bone marrow cells. In man, genes induced by PRL include several members of the 'suppressors of cytokine signaling' (SOCS) family and inducible nitric oxide synthase (iNOS; in mononuclear cells and in granulocytes) and IRF-1 (in granulocytes). Thus, in normal leukocytes, PRL induces the expression of several genes relevant to innate and acquired immune responses. Sex hormones, such as estrogen and PRL, have been implicated in the pathogenesis of murine and human SLE. Also defective signaling in leukocytes is a feature of the disease. What the origin is of aberrant signaling processes in SLE lymphocytes and how they relate to tolerance breakdown and immunopathology is still unknown. It is not unlikely that PRL is a player at some level. The exact contribution of PRL to immune responses in normal subjects and in SLE patients is not known. Further work should also indicate whether PRL might contribute to the onset or progression of the disease and assess the possible benefits of manipulating PRL concentrations in patients.
Lupus 2001
PMID:Effects of prolactin on signal transduction and gene expression: possible relevance for systemic lupus erythematosus. 1172 98


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