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)

The objective of this work was to determine whether HIV-1 and HIV-2 could be involved in the pathogenesis of systemic lupus erythematosus (SLE). Seventy-five consecutive Caucasian patients with SLE presenting at one institution over a 2-year period were studied. Serum samples were surveyed for anti-HIV-1 antibodies by a commercial ELISA coated with HIV-1-p24. For confirmation, conventional immunoblots were performed with the following antigens: HIV-1-gp41, p31, p24 and p17 (recombinant) and HIV-2-gp36 (synthetic peptide). Additionally, Western blots with HIV-1-gp160, gp120, gp41, p65, p51, p24 and p18 bands were applied. Seventeen (23%) patients exhibited reactivity with HIV-1-p24 in the ELISA, but in the immunoblots and Western blots these sera samples were negative. Patients with SLE may exhibit a reactivity with HIV-1-p24 in the ELISA for HIV infection screening but not in the confirmatory blots. This false-positive reactivity is probably due to molecular mimicry between autoantigens and retroviruses or a contaminant or artefacts in the antigen preparation procedure.
Lupus 1995 Feb
PMID:Lack of relationship between human immunodeficiency virus infection and systemic lupus erythematosus. 776 39

Antibodies reactive with retroviral gag proteins have been detected in patients with systemic lupus erythematosus (SLE). We investigated the immune responses against human immunodeficiency virus (HIV) 1 antigens in the sera of 44 Turkish patients with SLE. Serum samples were tested by using two different commercial enzyme immunoassay (EIA) kits and by Western blotting. EIA studies revealed positive results in 12 patients (27%) for HIV-1 antigens by one of the kits that coated with purified viral antigens. Immunoblot analysis showed antibodies mainly to retroviral gag proteins in 23 patients (52%). The most frequent reactivity was against the p18 gag protein (n = 9). Although antibodies reactive particularly with p24 antigen were described in the previous reports, antibodies to p24 were found in only two patients. These findings might reflect a serologic diversity in different ethnic groups and also suggest the involvement of different triggers in the etiopathogenesis of SLE.
Lupus 1996 Apr
PMID:Antibodies reactive with HIV-1 antigens in systemic lupus erythematosus. 874 24

Sle2c1 is an NZM2410- and NZB-derived lupus susceptibility locus that induces an expansion of the B1a cell compartment. B1a cells have a repertoire enriched for autoreactivity, and an expansion of this B cell subset occurs in several mouse models of lupus. A combination of genetic mapping and candidate gene analysis presents Cdkn2c, a gene encoding for cyclin-dependent kinase inhibitor p18(INK4c) (p18), as the top candidate gene for inducing the Slec2c1-associated expansion of B1a cells. A novel single nucleotide polymorphism in the NZB allele of the Cdkn2c promoter is associated with a significantly reduced Cdkn2c expression in the splenic B cells and peritoneal cavity B1a cells from Sle2c1-carrying mice, which leads to a defective G1 cell cycle arrest in splenic B cells and increased proliferation of peritoneal cavity B1a cells. As the cell cycle is differentially regulated in B1a and B2 cells, these results suggest that Cdkn2c plays a critical role in B1a cell self-renewal and that its impaired expression leads to an accumulation of these cells with high autoreactive potential.
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PMID:Cyclin-dependent kinase inhibitor Cdkn2c regulates B cell homeostasis and function in the NZM2410-derived murine lupus susceptibility locus Sle2c1. 2154 44

We have previously shown that a novel -74 C-to-T mutation in the promoter of the cyclin-dependent kinase inhibitor p18(Ink4c) (p18) gene was associated with a reduced p18 expression in B cells from mice carrying the Sle2c1 lupus susceptibility locus. To determine the function of the -74 C/T single nucleotide polymorphism, we have characterized the proximal promoter of the mouse p18 gene. Functional analysis of the 5' flanking region by sequential deletions revealed crucial elements between -300 and +1, confirming the in silico prediction that the -74 T allele created a novel Yin-Yang 1 (YY-1) binding site adjacent to an existing one common to both alleles. Moreover, we found that YY-1, E2F1, and Sp-1 can synergistically enhance the activity of the p18 promoter. Mutational inactivation revealed that YY-1 binding regulates the p18 activity in an allele-dependent fashion. EMSAs with splenic B cell extracts directly demonstrated that YY-1 binds to the p18 promoter with differences between the C and the T alleles. We also determined in vivo by chromatin immunoprecipitation that the T allele resulted in increased YY-1 and decreased Nrf-2 binding to the p18 promoter as compared with the C allele in B cells. Thus, YY-1 is a direct regulator of p18 gene expression in an allele-dependent fashion that is consistent with the lupus-associated T allele, inducing a lower p18 transcriptional activity by increasing YY-1 binding. These results establish the p18 -74 C/T mutation as the leading causal variant for the B1a cell expansion that characterizes the NZB and NZM2410 lupus-prone strains.
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PMID:Genetic variation at a Yin-Yang 1 response site regulates the transcription of cyclin-dependent kinase inhibitor p18INK4C transcript in lupus-prone mice. 2250 41

The lupus-prone NZM2410 mice present an expanded B1a cell population that we have mapped to the Sle2c1 lupus susceptibility locus. The expression of Cdkn2c, a gene encoding for cyclin-dependent kinase inhibitor p18(Ink4c) and located within Sle2c1, is significantly lower in B6.Sle2c1 B cells than in B6 B cells. To test the hypothesis that the B1a cell expansion in B6.Sle2c1 mice was due to a defective p18 expression, we analyzed the B1a cell phenotypes of p18-deficient C57BL/6 mice. We found a dose-dependent negative correlation between the number of B1a cells and p18 expression in B cells, with p18-deficient mice showing an early expansion of the peritoneal B1a cell pool. p18 deficiency enhanced the homeostatic expansion of B1a cells but not of splenic conventional B cells, and the elevated number of B6.Sle2c1 B1a cells was normalized by cyclin D2 deficiency. These data demonstrated that p18 is a key regulator of the size of the B1a cell pool. B6.p18(-/-) mice produced significant amounts of anti-DNA IgM and IgG, indicating that p18 deficiency contributes to humoral autoimmunity. Finally, we have shown that Sle2c1 increases lpr-associated lymphadenopathy and T cell-mediated pathology. B6.p18(-/-).lpr mice showed a greater lymphadenopathy than B6.Sle2c1.lpr mice, but their renal pathology was intermediate between that of B6.lpr and B6.Sle2c1.lpr mice. This indicated that p18-deficiency synergizes, at least partially, with lpr-mediated pathology. These results show that Cdkn2c contributes to lupus susceptibility by regulating the size of the B1a cell compartment and hence their contribution to autoimmunity.
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PMID:Cyclin-dependent kinase inhibitor Cdkn2c deficiency promotes B1a cell expansion and autoimmunity in a mouse model of lupus. 2289 39

Hematopoietic stem cells (HSCs) are protected in a metabolically dormant state within the bone marrow stem cell niche. Inflammation has been shown to disrupt HSC dormancy and cause multiple functional changes. Here, we investigated whether HSC functions were altered in systemic lupus erythematosus (SLE)-prone mice and whether this contributed to clinical manifestations of SLE. We found that HSCs were significantly expanded in lupus mice. The increase in HSC cellularity was caused by both genetic lupus risk factors and inflammatory cytokines in lupus mice. In addition, the inflammatory conditions of lupus led to HSC mobilization and lineage-biased hematopoiesis. Strikingly, these functionally altered HSCs possessed robust self-renewal capacity and exhibited repopulating advantages over wild-type HSCs. A single-nucleotide polymorphism in the cdkn2c gene encoding p18(INK4c) within a SLE susceptibility locus was found to account for reduced p18(INK4c) expression and the increase in HSC self-renewal capacity in lupus mice. Lupus HSCs with enhanced self-renewal capacity and resistance to stress may compete out transplanted healthy HSCs, thereby leading to relapses after HSC transplantation.
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PMID:The function of hematopoietic stem cells is altered by both genetic and inflammatory factors in lupus mice. 2331 65

The NZM2410 Sle2c1 lupus susceptibility locus is responsible for the expansion of the B1a cell compartment, and for the induction of T-cell induced renal and skin pathology on a CD95-deficient (Fas(lpr)) background. We have previously shown that deficiency in the cyclin-dependent kinase inhibitor p18(INK4c) (p18) was responsible for the B1a cell expansion but was not sufficient to account for the pathology in B6.lpr mice. This study was designed to map the additional Sle2c1 loci responsible for autoimmune pathology when co-expressed with CD95 deficiency. The production, fine-mapping and phenotypic characterization of five recombinant intervals indicated that three interacting subloci were responsive for inducting autoimmune pathogenesis in B6.lpr mice. One of these subloci corresponds most likely to p18 deficiency. Another major locus mapping to a 2-Mb region at the telomeric end of Sle2c1 is necessary to both renal and skin pathology. Finally, a third locus centromeric to p18 enhances the severity of lupus nephritis. These results provide new insights into the genetic interactions leading to systemic lupus erythematosus disease presentation, and represent a major step towards the identification of novel susceptibility genes involved in T-cell-mediated organ damage.
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PMID:The combination of two Sle2 lupus-susceptibility loci and Cdkn2c deficiency leads to T-cell-mediated pathology in B6.Fas(lpr) mice. 2369 9