Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

We investigated whether IL1RN alleles separately or in combination with MHC class II variants, contribute to susceptibility to SLE and to analysed if IL1RN alleles are markers of disease severity. We investigated 81 patients from a defined area in southern Sweden diagnosed between 1981-1992 and 10 consecutive Caucasian families with multiple cases of SLE. As control group 189 healthy blood donors was used. PCR amplification of defined gene sequences was used in determining the IL1RN polymorphism as well as the MHC class II variants. The IL-1RA levels were measured by an immunoassay. We found an increased frequency of IL1RN*2 in both the epidemiological cohort and in the multicase families (P < 0.01). Alone IL1RN*2 and MHC class II (DR17,DQ2) separately increased the SLE risk moderately. The occurrence of IL1RN*2 and MHC class II variants DR17 and DQ2 together increased the risk to develop SLE by a sevenfold. The IL-1RA gene polymorphism did not correlate with disease severity or with renal involvement. We found an association between IL1RN*1 and arthritis (P < 0.001). Serum level of IL-1RA did not correspond to any specific IL1RN allele. An increased frequency of IL1RN*2 suggests the presence of a gene, implemented in SLE-susceptibility, in the IL1RN region of chromosome 2. IL1RN*2 and specific variants of MHC class II act in synergy to increase disease susceptibility. IL1RN*1 may be a marker of risk for development of arthritis.
Lupus 1999
PMID:Synergetic effect between interleukin-1 receptor antagonist allele (IL1RN*2) and MHC class II (DR17,DQ2) in determining susceptibility to systemic lupus erythematosus. 1019 3

Two case reports and a review of the literature on paraneoplastic figurate erythemas with lupus erythematosus (LE)-specific histolopathology illustrate cutaneous paraneoplasia as an immunological phenomenon. Subacute cutaneous lupus erythematosus (SCLE) is characterized by photosensitive, annular or papulosquamous skin lesions with LE-specific histopathology in association with circulating anti-SS-A (Ro) auto-antibodies. The SS-A (Ro) antigen is a complex of cytoplasmic ribonucleoproteins that translocate to the surface of keratinocytes under UV irradiation. Sequestered cytosolic antigen that is expressed on the cell surface is presented to T lymphocytes by professional antigen presenting cells in the context of specific MHC class II molecules. The initiation of the specific immune response, the expansion of antigen-specific T helper cells, and the differentiation of B cells to antibody producing plasma cells depend on the further interaction with antigen. The risk of a self-perpetuating autoimmune response relies on further release of auto-antigen. It is conceivable that in paraneoplastic SCLE tumor antigen with homology to SS-A (Ro) leads to photosensitive autoreactivity. The review of the literature reveals 9 other cases of SCLE associated with internal malignancy. The most common associated tumors were bronchial and mammary carcinoma. The latency between the appearance of skin lesions and the diagnosis of an underlying tumor was between one month and three years (mean: 10 months). In all cases, skin lesions improved with cancer therapy, in three cases they (re)appeared in association with relapse of tumor.
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PMID:[Cutaneous paraneoplastic syndrome as an immunologic phenomenon exemplified by paraneoplastic subacute cutaneous lupus erythematosus]. 1058 50

A high-level expression of a transgene, Ead, encoding the I-Ed alpha-chain is very effective in protection against murine lupus. To investigate the specific contribution of select H-2 haplotypes on the Ead transgene-mediated disease-suppressing effect, we generated H-2 congenic (NZB x BXSB)F1 hybrid mice bearing either H-2b/b, H-2d/b, or H-2d/d haplotype, and compared the transgene-mediated protective effect on the clinical development (autoantibody production and glomerulonephritis) of lupus in these F1 hybrids. The level of protection was most remarkable in mice bearing the I-E- H-2b/b haplotype but was only minimal in I-E+ H-2d/d F1 hybrids. Additional analysis demonstrated a marked suppression of lupus in I-E+ H-2k/k (MRL x BXSB)F1 hybrid mice, indicating that the transgene is able to suppress autoimmune responses even in mice already expressing I-E molecules at a homozygous level. Our results indicate that the level of the transgene-mediated protection is dependent on the host H-2 haplotype. This suggests that the autoimmune suppressive activity of the Ead transgene is likely to be determined through the interaction of the transgene product with the host MHC class II molecules, providing new insight into the role of MHC in lupus-like autoimmunity.
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PMID:Protection of murine lupus by the Ead transgene is MHC haplotype-dependent. 1060 48

A molecular homology has been demonstrated between sequences of the heavy chain variable regions of the anti-DNA, anti-cardiolipin monoclonal antibody, 2C4C2, isolated from C3H.SW mice with induced systemic lupus erythematosus, and sequences of the anti-DNA monoclonal antibody BW16 originating in the lupus-prone (NZBXNZW)F1 mice. It was of interest to determine whether these homologous sequences function also as immunodominant T-cell epitopes, in order to establish a connection between spontaneous and induced experimental models. Therefore, three peptides were designed and synthesized based on the complementarity determining region (CDR)1, CDR2 and CDR3 of the heavy chain of the monoclonal antibody 2C4C2. In the present study, we compare these peptides with the CDR1- and CDR3-based peptides of another murine anti-DNA antibody; namely, 5G12. The comparison was carried out by analyzing the ability of the peptides to induce T-cell activation in (NZBXNZW)F1 lupus-prone mice and in mouse strains susceptible to induction of experimental systemic lupus erythematosus. Immunization of (NZBXNZW)F1 mice with the 2C4C2 mAb or with its CDR-based peptides, as well as immunization with the 5G12-based CDR peptides, induced significant lymph node proliferation to the pCDR3 of the 5G12 mAb. Naive (NZBXNZW)F1 splenocytes exhibited activation to the same peptide. It is also shown that MHC class II molecules of (NZBXNZW)F1 macrophages bind preferentially the 5G12-based pCDR3. It is proposed that the CDR3-based peptide of 5G12 mAb of experimental lupus is also a dominant and relevant epitope in the (NZBXNZW)F1 lupus-prone mice.
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PMID:A peptide based on the CDR3 of an anti-DNA antibody of experimental SLE origin is also a dominant T-cell epitope in (NZBXNZW)F1 lupus-prone mice. 1078 83

Genes from New Zealand Black and New Zealand White mice have been implicated in the development of a disease similar to human systemic lupus erythematosus. In an attempt to define the MHC class II genes involved in disease, we previously studied similarly designed backcrosses of New Zealand Black mice with C57BL/6 (B6) mice transgenic for Ez genes or with C57BL/10 (B10) mice transgenic for Az genes. Although the transgenes showed no effect on the development of autoantibody production or lupus nephritis in either backcross, surprisingly, there was greatly increased expression of these disease traits in the backcrosses involving B10 compared with B6 mice. These studies therefore implicated genetic contributions in B10 vs B6 backgrounds, despite their 98% identity. A genome-wide linkage analysis uncovered a B10 locus on mid-chromosome 13, which enhanced nephritis and was strongly linked with the production of pathogenic retroviral gp70-anti-gp70 immune complexes when contributed by B10, but not B6, mice. The subsequent identification of a single marker polymorphic between B10 and B6, along with the extreme genetic similarity between the two strains in this region, is likely to permit expedited identification of the lupus-susceptibility gene from this nonautoimmune strain.
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PMID:Enhanced susceptibility to lupus contributed from the nonautoimmune C57BL/10, but not C57BL/6, genome. 1079 20

Male BXSB mice, unlike female BXSB mice, develop an early-onset, lupus-like disease characterized by high levels of anti-nuclear antibodies (Abs) and total Ig. It has recently been shown that the male BXSB mice contain an expanded population of large B cells which are hyperresponsive to stimulation by anti-CD40 mAb. The present study was undertaken to determine whether their potential for extra CD40 signaling enabled the B cells from male BXSB mice to hyper-respond to CD40L-expressing CD4+ T cells. In contrast to expectations, large B cells from male BXSB mice did not interact with CD4+ T cells in a positive manner; cultures of B cells from antigen (Ag)-primed male BXSB mice, unlike cultures of B cells from Ag-primed female mice, generated few antibody forming cells (AFC) following interaction with activated CD4+T cells. In addition, B cells from male BXSB mice, unlike B cells from female BXSB mice, failed to upregulate MHC class II molecules following interaction with activated CD4+ T cells. Subsequent experiments revealed that the inability of the B cells from the male mice to upregulate MHC class II molecules in response to T cell-mediated activation resided primarily in the population of large B cells. Large B cells from male BXSB mice were also defective in their ability to proliferate following stimulation with activated CD4+ T cells. Taken together, these findings demonstrated that similar to B cells in lupus patients, large B cells from male BXSB mice could function in a hyporesponsive manner, and that this hyporesponsiveness related to the inability of the B cells to interact in a positive manner with CD4+T cells.
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PMID:B cells from autoimmune BXSB mice are hyporesponsive to signals provided by CD4+ T cells. 1093 11

Systemic lupus erythematosus is characterized by the presence of high titers of autoantibodies reacting with various components of the U1 small nuclear ribonucleoprotein particle (snRNP). It has been suggested that these antibodies are produced by an antigen-driven mechanism under the dependence of antigen-specific T cells. To investigate the role of T cell help in this process, we sought, with 20 overlapping peptides, the Th epitopes on the U1-70K snRNP in unprimed H-2(k) MRL / lpr lupus mice and immunized CBA normal mice. The peptide 131 - 151 was recognized by both IgG autoantibodies and CD4(+) T cells from 7 - 9-week-old MRL / lpr mice. In this test, antigen-presenting cells (APC) from MRL / lpr mice were required; APC from naive CBA mice failed to stimulate CD4(+) cells from MRL / lpr mice. The potential role of MRL / lpr B cells as APC, the expression of MHC class II molecules at their surface and their activation state (expression of CD69, CD80 / B7-1 and CD86 / B7-2 molecules) were studied. Peptide 131 - 151 bound both I-A(k) and I-E(k) class II molecules and favored an IL-2-positive T cell response but not IFN-gamma, IL-6 and IL-10 secretion. Segment 131 - 151 is localized within the RNP80 motif and contains residues that are highly conserved in many nuclear, nucleolar and cytoplasmic RNA binding proteins.
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PMID:B and T cell immune response to small nuclear ribonucleoprotein particles in lupus mice: autoreactive CD4(+) T cells recognize a T cell epitope located within the RNP80 motif of the 70K protein. 1094 Sep 10

Systemic lupus erythematosus (SLE) is a complex multigenic disease in which the contributing genetic systems are being rapidly identified. Most of the currently recognized genes have been discovered from case-control association studies, but, increasingly, family linkage studies are being employed to confirm previous genetic associations, to examine their relative contributions, and to identify new susceptibility loci. Most of the loci identified thus far appear to contribute only modest effects on susceptibility overall but rather influence more strongly disease expression and/or severity. MHC class II alleles, for example, seem to show only weak linkage to SLE itself but instead mediate specific T cell driven pathogenic autoantibodies which produce many of the clinical disease features, similar to their effects in many other autoimmune diseases. On the other hand, complete and partial hereditary deficiencies of early complement components are more lupus-specific. Homozygous complement deficiencies, while powerful risk factors, are rare causes of lupus and heterozygous deficiencies exert only modest effects on susceptibility. Other genes, such as low-binding IgG Fc receptor alleles (FcgammaIIa and FcgammaIIIa), appear to promote nephritis by modifying the efficiency of immune complex clearance. A variety of cytokine genes appear also to promote severity, including those for TNFalpha, IL-10, IL1 receptor antagonist, and perhaps others (IL-6, IL-4 and TNFalpha receptor). Family studies and recent genome-wide scans in lupus and other autoimmune diseases support the likelihood that some susceptibility loci, as yet unidentified, predispose to several or many autoimmune diseases. Only thorough the identification and elucidation of function of these many genes is the pathogenic picture of lupus likely to be complete.
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PMID:Genetic studies of human lupus in families. 1101 21

In this report we summarize evidence to support a model for the development of Graves' disease. The model suggests that Graves' disease is initiated by an insult to the thyrocyte in an individual with a normal immune system. The insult, infectious or otherwise, causes double strand DNA or RNA to enter the cytoplasm of the cell. This causes abnormal expression of major histocompatibility (MHC) class I as a dominant feature, but also aberrant expression of MHC class II, as well as changes in genes or gene products needed for the thyrocyte to become an antigen presenting cell (APC). These include increased expression of proteasome processing proteins (LMP2), transporters of antigen peptides (TAP), invariant chain (Ii), HLA-DM, and the co-stimulatory molecule, B7, as well as STAT and NF-kappaB activation. A critical factor in these changes is the loss of normal negative regulation of MHC class I, class II, and thyrotropin receptor (TSHR) gene expression, which is necessary to maintain self-tolerance during the normal changes in gene expression involved in hormonally-increased growth and function of the cell. Self-tolerance to the TSHR is maintained in normals because there is a population of CD8- cells which normally suppresses a population of CD4+ cells that can interact with the TSHR if thyrocytes become APCs. This is a host self-defense mechanism that we hypothesize leads to autoimmune disease in persons, for example, with a specific viral infection, a genetic predisposition, or even, possibly, a TSHR polymorphism. The model is suggested to be important to explain the development of other autoimmune diseases including systemic lupus or diabetes.
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PMID:Graves' disease: a host defense mechanism gone awry. 1112 19

Nucleobindin (Nuc) is a DNA- and calcium-binding protein that was originally identified as an anti-DNA antibody-enhancing factor in MRL/MpJ-lpr/lpr (MRL/lpr) mice. In MRL/lpr mice, both expression of Nuc mRNA in enlarged lymph nodes and serum concentration of Nuc protein are shown to increase as disease progresses. Administration of recombinant (r) Nuc to young MRL/MpJ-+/+ and normal BALB/c mice leads to augmentation or induction of IgG anti-double-stranded (ds) DNA autoantibodies. In this study, spleen cells prepared from MRL/lpr mice were found to show a proliferative response to rNuc, indicating existence of T cells that are specific to this autoantigen in peripheral lymphoid tissues. Furthermore, CD4+ T cell lines were generated from a BALB/c mouse that had been producing anti-dsDNA antibodies as a result of repeated injections of rNuc. These T cell lines were confirmed to be autoreactive, because they proliferated in culture with syngeneic but not with allogeneic spleen cells without addition of any exogenous antigens. Their proliferation was enhanced by rNuc, and inhibited by an anti-MHC class II monoclonal antibody. Upon in vivo inoculation, these T cells provided help for rNuc-injected BALB/c mice to produce anti-DNA antibodies. These results suggest that Nuc is able to activate autoreactive peripheral T cells through an MHC-class II pathway leading to acceleration or induction of anti-DNA antibody production when it is excessively produced in lupus-prone mice or experimentally administered into normal mice.
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PMID:Activation of autoreactive T cells that help nucleobindin-injected mice produce anti-DNA antibodies. 1113 34


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