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)

MRL/Mp-lpr/lpr (MRL-lpr) mice have been used for a model of human systemic lupus erythematosus. This strain of mice homozygous for an autosomal recessive mutation, lpr (lymphoproliferation), develops massive lymphadenopathy with the expansion of CD4-CD8- (double negative; DN) T cells. Recently it was demonstrated that lpr mice have defects in the gene of Fas antigen which mediates apoptosis, indicating a possibility of defect in negative selection of autoreactive T cells in the thymus of lpr mice. However, the mechanisms that control the accumulation of DN T cells in lymph nodes, and the involvement of DN T cells in the clinical manifestation of disease, have not been well understood. In this study, the expression of various cell adhesion molecules on lymphocytes from MRL-lpr mice was examined. The strong expression of CD44 antigen as well as heat stable antigen (HSA) on abnormal DN T cells of lymph nodes was characteristic in MRL-lpr mice. Furthermore, the accumulation of DN T cells in lymph nodes might result from augmented binding of lymphocytes to endothelial cell surface of lymph nodes, possibly due to the failure of Mel-14 antigen shedding from DN T cell surface. In addition, it was found that monoclonal antibodies reactive with cell adhesion molecules such as CD44, Mel-14, CD45R and HSA expressed on DN T cells, could trigger the lytic activity of DN T cells and redirected DN T cell-mediated lysis of Fc-receptor-positive target cells (EL-4). In contrast to T cell receptor (TCR)-mediated cytotoxicity, this redirected cytotoxicity was not inhibited by anti-lymphocyte function associated antigen-1 (LFA-1) antibody. Thus, cell adhesion molecules may play a major role in delivering the transmembrane signal to DN T cells of MRL-lpr mice that trigger the lytic activity. It is likely that DN T cells of MRL-lpr mice induce tissue damages by the interaction with ligand on vascular endothelium or extracellular matrix in vivo.
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PMID:[Functional studies of adhesion molecules on CD4-CD8- double negative T cells of autoimmune MRL/Mp-lpr/mice]. 822 81

Biopsied specimens from skin lesions of SLE were studied for expression of 70 KD heat shock protein (HSP70). The pattern of HSP70 expression in SLE was diffuse in whole epidermis, hair follicles, and sweat gland cells and rather more intense than that in other control groups or normal skin. No significant differences in HSP70 expression were observed between sun-exposed and protected areas of SLE skin lesions. Unlike SLE, reduced or no expression of HSP70 was observed in skin lesions of DLE. In tissue culture, UVB radiation in vitro induced relatively intense expression of HSP70 in the nuclear area of keratinocytes. A few gamma delta T cell receptor positive cells which might respond to HSP70 expressing cells were detected in the basal layer of skin lesions of diseases. These studies suggest that aberrant expression of HSP70 in skin lesions of SLE might contribute to both skin lesions and antibody formation in SLE.
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PMID:Analysis of 70 KD heat shock protein (HSP70) expression in the lesional skin of lupus erythematosus (LE) and LE related diseases. 840 20

Only a fraction (12%) of 268 "autoreactive" T cell clones derived from lupus-prone mice can selectively induce the production of pathogenic anti-DNA autoantibodies in vitro and accelerate the development of lupus nephritis when transferred in vivo. The CDR3 loops of T cell receptor beta chains expressed by these pathogenic T helper (Th) clones contain a recurrent motif of anionic residues suggesting that they are selected by autoantigens with cationic residues. Herein, we found that approximately 50% of these pathogenic Th clones were specific for nucleosomal antigens, but none of them responded to cationic idiopeptides shared by variable regions of pathogenic anti-DNA autoantibodies. Nucleosomes did not stimulate the T cells as a nonspecific mitogen or superantigen. Only the pathogenic Th cells of lupus responded to nucleosomal antigens that were processed and presented via the major histocompatibility class II pathway. Although the presentation of purified mononucleosomes to the Th clones could be blocked by inhibitors of endosomal proteases, neither of the two components of the nucleosomes--free DNA or histones by themselves--could stimulate the Th clones. Thus critical peptide epitopes for the Th cells were probably protected during uptake and processing of the nucleosome particle as a whole. The nucleosome-specific Th clones preferentially augmented the production of IgG autoantibodies to histone-DNA complex in vitro. In vivo, nucleosome-specific, CD4+ T cells were not detectable in normal mice, but they were found in the spleens of lupus-prone mice as early as 1 mo of age, long before other autoimmune manifestations. Immunization of young, preautoimmune lupus mice with nucleosomes augmented the production of autoantibodies and markedly accelerated the development of severe glomerulonephritis. Previously, crude preparations containing nucleosomes were shown by others to have polyclonal mitogenic activity for B cells from normal as well as lupus mice. Identification here of pure mononucleosome as a lupus-specific immunogen for the Th cells that selectively help the pathogenic anti-DNA autoantibody producing B cells of lupus could lead to the design of specific therapy against this pathogenic autoimmune response.
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PMID:Nucleosome: a major immunogen for pathogenic autoantibody-inducing T cells of lupus. 847 12

The production of class-switched antibodies, particularly immunoglobulin (Ig) G1 and IgE, occurs efficiently in T cell receptor (TCR) alpha-/- mice that are congenitally devoid of alpha/beta T cells. This finding runs counter to a wealth of data indicating that IgG1 and IgE synthesis are largely dependent on the collaboration between B and alpha/beta T cells. Furthermore, many of the antibodies synthesized in TCR alpha-/- mice are reactive to a similar spectrum of self-antigens as that targeted by autoantibodies characterizing human systemic lupus erythematosus (SLE). SLE, too, is most commonly regarded as an alpha/beta T cell-mediated condition. To distinguish whether the development of autoantibodies in TCR alpha-/- mice is due to an intrinsic de-regulation of B cells, or to a heretofore poorly characterized collaboration between B and "non-alpha/beta T" cells, the phenotype has been reconstituted by transfer of various populations of B and non-alpha/beta T cells including cloned gamma/delta T cells derived from TCR alpha-/- mice, to severe combined immunodeficient (SCID) mice. The results establish that the reproducible production of IgG1 (including autoantibodies) is a product of non-alpha/beta T cell help that can be provided by gamma/delta T cells. This type of B-T collaboration sustains the production of germinal centers, lymphoid follicles that ordinarily are anatomical signatures of alpha/beta T-B cell collaboration. Thus, non-alpha/beta T cell help may drive Ig synthesis and autoreactivity under various circumstances, especially in cases of alpha/beta T cell immunodeficiency.
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PMID:Germinal center formation, immunoglobulin class switching, and autoantibody production driven by "non alpha/beta" T cells. 864 36

Recently it has been observed that administration of intravenous immunoglobulin (IVIG) can have profound effects on a wide variety of diseases related to the dysregulation of the immune system. The mechanisms which explain these activities are poorly understood. Human IVIG and various Cohn plasma fractions contain autoantibodies directed against T cell receptors (Tcr). Previous studies have shown that IVIG contains autoantibodies against T cell receptor peptides. In order to further our understanding of autoantibody specificities, a single chain Tcr (scTcr) was constructed by recombinant DNA techniques from the variable alpha and variable beta chains of the Jurkat cell line. Anti-Tcr autoantibodies were isolated from IVIG and Cohn fractions I + III using a scTcr affinity column. This scTcr affinity purified material reacted with the surfaces of T cells at 10 micrograms/ml whereas non-purified IVIG did not. Sera from patients with rheumatoid arthritis (RA) as well as serum from patients with systemic lupus erythematosus (SLE) reacted with the scTcr at levels above that of normals.
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PMID:Characterization of autoantibodies directed against T cell receptors. 864 5

The specificity of T cell help for B cell activation and differentiation is maintained by the brief expression on the T cell surface, following T cell receptor-mediated triggering, of CD40 ligand (CD40L). Interaction of T helper (Th) cell CD40L with B cell CD40 induces B cell activation, cell surface expression of activation antigens, proliferation, and initiation of immunoglobulin isotype switch. We predicted that in patients with systemic lupus erythematosus (SLE), in whom Th cell-dependent production of autoantibodies results in immune complex-mediated tissue damage, CD40L expression might be augmented, prolonged, or abnormally regulated. Baseline expression of CD40L was increased in some SLE patients studied, when compared with control subjects. While Th cells from normal subjects (n = 14) and rheumatic disease control patients (n = 9) showed maximal expression of CD40L, after in vitro activation with phorbol myristate acetate (PMA) and ionomycin, at 6 h of culture with diminished levels observed at 24 and 48 h, Th cells from SLE patients (n = 19) maintained high level cell surface expression of CD40L through 24 and 48 h of culture. The prolonged expression of CD40L was functionally significant, as 24 h-activated SLE T cells, when cocultured with target B cells, induced greater B cell surface CD80 (B7-1) expression than did 24 h-activated normal T cells. These results document impaired regulation of CD40L expression in SLE T cells and identify an important potential target for therapy in this systemic autoimmune disease.
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PMID:Increased expression of CD40 ligand on systemic lupus erythematosus lymphocytes. 869 75

Autoantibodies (AAbs) to T cell receptor (TCR) determinants are produced in humans during the course of rheumatoid arthritis and systemic lupus erythematosus as well as in retroviral infections. We have examined the binding specificity of a panel of monoclonal antibodies derived from mutant viable motheaten (mev) mice against several TCR peptide determinants representing the complementary determining region 1 (CDR1) regions of various Vbeta families, and have identified one mAb, UN37-5, that shows high affinity binding with specificity for two CDR1 peptide determinants. The light and heavy chain V genes of UN37-5 were sequenced and compared to known V genes. The UN37-5 V H gene sequence represents the V H J6O6 family and is most similar to a previously reported V H gene derived from a germ line DNA fragment representing a unique J606 family V H gene. This germ line V H gene is also used by previously characterized mev derived mAbs directed against thymocyte and RBC antigens. The UN37-5 V L gene sequence represents the V K 4/5 gene family. It has 87% homology with the V K Ox-1 germline gene. The UN37-5 V K sequence has greater than 95% identity at the amino acid level with VK L chains from IgM hybridomas specific for DNA and the influenza virus hemagglutinin. The specificity of this AAb is determined by the V H CDR3 and a V K chain which has not been utilized in previously reported mev autoantibodies.
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PMID:Peptide epitope binding specificity and V K and V H gene usage in a monoclonal IgM natural autoantibody to T cell receptor CDR1 from a viable motheaten mouse. 886 Jun 95

Studies reported during the past year have added new knowledge to our understanding of cellular abnormalities in systemic lupus erythematosus: 1) Antigen-specific and "pathogenic" T cells display a limited T cell receptor repertoire in lupus. 2) The ratio of interleukin-10 to interferon gamma-secreting cells in the peripheral blood of patients with lupus is increased in patients with active disease. 3) CD3-mediated increases in free intracytoplasmic calcium occur specifically in lupus T cells and lines; this finding provides additional evidence that cell-signaling events are defective in patients with lupus. 4) Aberrant expression of adhesion molecules on the surface membrane of leukocytes and endothelial cells was shown, a finding with important mechanistic and therapeutic implications. 5) Lupus antigen-presenting cells fail to upregulate the expression of B7-1 (CD80) in response to interferon gamma; defective expression of B7-1 is responsible for the decreased response of lupus cells to recall antigens.
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PMID:Lymphocytes, cytokines, inflammation, and immune trafficking. 894 41

Systemic lupus erythematosis (SLE) is a multifactorial disease with both genetic and environmental etiology. The complexity of factors contributing to SLE are considered in an analogy with a card game. The hears suit represents sex hormones. SLE is a disease of marked female prevalence and abnormal estrogen metabolism has been described in women with SLE. The clubs suit considers complement and other genetic factors. Increased risk of SLE has been described in association with some HLA markers and the complement C4A0 null allele. Although convincing evidence has not yet emerged, other candidate genes of importance are T cell receptor genes and genes encoding B cell immunoglobulin receptors and antibodies. Recently, abnormalities of apoptosis and of expression of the protooncogene Bcl-2 have been investigated. Overall different genes have been shown to increase the risk of SLE, and/or to influence the development of particular antibodies, and particular subsets of disease. The diamonds suit considers antigens and antibodies in the etiopathogenesis of SLE. Numerous autoantibodies have been described that bind a variety of targets on the cell surface, within the cytoplasm, or in the nucleus. It is generally agreed that autoantibodies develop as a consequence of both generalized polyclonal activation and antigen drive. The final suit of spades considers infectious, environmental, and other agents such as drugs, as triggers in the development of SLE.
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PMID:Systemic lupus erythematosus: immunopathogenesis and the card game analogy. 915 Jan 21

We investigated the role of T cell receptor (TCR) V alpha 24+ T cells in the pathogenesis of systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). The invariant V alpha 24 J alpha Q was expanded and comprised 50-90% of the total V alpha 24 in healthy individuals. In contrast, patients with SSc and SLE showed the selective reduction of the invariant V alpha 24 J alpha Q with oligoclonal expansion of V alpha 24 TCR other than V alpha 24 J alpha Q. Because human V alpha 24 J alpha Q TCR is analogous to murine invariant V alpha 14 J alpha 281 TCR which is the major genotype of NK T cells, these results suggest that the selective reduction of T cells with invariant V alpha 24 J alpha Q TCR might play an important role of the generation of autoreactive T cells including T cells bearing other V alpha 24 TCR in autoimmune disease patients.
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PMID:[Role of TCR V alpha 24 J alpha Q+ T cells in autoimmune diseases]. 920 Sep 27


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