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)

A relatively large number of variable region genes (V) contribute, via gene rearrangements with smaller numbers of additional gene elements (D and J), to generate diversity in the immune response. While some VH gene families are thought to contain 100- 1000 members, the VH10 family has only two known functioning members with 99% sequence homology. Both members (monoclonal antibodies) are capable of binding DNA, and since they were derived from inbred mice afflicted with the lupus syndrome they are considered autoimmune antibodies. Relative uniqueness of the VH10 primary nucleotide sequence presents a model system with which to examine unrearranged VH genes and attempt to identify germline genes eventually expressed as autoantibodies. PCR amplified germline sequences of the VH10 family are highly conserved, with few base substitutions evenly distributed between both framework and CDR regions. It was determined that the PCR amplified germline sequences are highly similar to the DNA sequences of the two monoclonal VH10 antibodies, and a non-functional psuedo-germline gene was found that is identical to a non-functional cDNA derived from a hybridoma cell line. These findings indicate that the use of unique CDR DNA sequences for the identification and amplification of specific germline V genes via PCR can yield vital information that may answer fundamental questions about the origins of autoimmune anti-DNA antibodies in afflicted individuals. The nature of the germline gene populations and the possible microheterogeniety of these genes may prove to be important in understanding the role of autoimmune antibodies in normal and diseased individuals.
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PMID:Autoimmune VH gene family: PCR-generated murine germline VH10 genes. 155 50

Systemic lupus erythematosus (SLE) in humans and in mice is characterized by reduced suppressor T-cell activity. This observation suggests that selective loss or impaired function of suppressor T cells may contribute to the development of autoimmunity. To clarify the role of suppressor T cells in the pathogenesis of SLE, we used a rat MAb to selectively deplete Lyt-2+ ('suppressor/cytotoxic') T cells from lupus-prone NZB/NZW F1 (B/W) mice. Treatment consisted of weekly intraperitoneal injections of anti-Lyt-2 (2 mg/mouse) beginning at age 4 months, prior to the onset of overt clinical illness. Control mice received weekly injections of either non-immune rat IgG or saline. Despite sustained depletion of Lyt-2+ T cells, mice treated with anti-Lyt-2 were indistinguishable from control mice with respect to production of anti-DNA antibodies, development of renal disease, and mortality. These findings imply that Lyt-2+ T cells do not regulate autoimmunity in B/W mice. However, they do not exclude the possibility that Lyt-2+ T cells suppress autoimmunity in normal mice but are simply non-functional in B/W mice. Therefore, we also examined the consequences of depleting Lyt-2+ T cells from non-autoimmune C57BL/6 x NZW (B6/NZW) mice. Depletion of Lyt-2+ T cells from B6/NZW from age 4 to 10 months produced neither serologic nor clinical evidence of murine lupus. These observations suggest that suppressor T cell defects are not sufficient to cause murine lupus.
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PMID:The role of Lyt-2+ T cells in the regulation of autoimmunity in murine lupus. 297 13

Drugs which induce systemic lupus erythematosus as a toxic side effect have been shown to inhibit the covalent binding of C4, which is an important event in immune complex clearance in normal individuals. Human C4 is encoded at two polymorphic loci, C4A and C4B within the Major Histocompatibility Complex and patients with idiopathic SLE are more likely to have a non-functional (null) C4A gene. The C4A and C4B gene products differ in reactivity with C4A being more reactive with nitrogen nucleophiles, including hydralazine and isoniazid (drugs which induce SLE), than with oxygen nucleophiles. We have established an assay system which allows the effect of nucleophiles on C4 in animal sera to be investigated. It has been found that in comparing reactivity of guinea-pig C4 with human C4A and human C4B that guinea-pig C4 is like human C4A and shows greater reactivity towards nitrogen nucleophiles than towards oxygen nucleophiles. This suggests that the guinea-pig should be a good animal model for drug-induced SLE.
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PMID:Interaction of nucleophilic compounds with complement component C4. 314 61

The presence of lupus anticoagulant (LAC) is strongly correlated with a history of thrombosis in patients with SLE. LAC activity can be caused by anti-prothrombin (FII)- and/or anti-beta2glycoprotein I (beta2GPI)-antibodies. In the present study, the contribution of anti-FII-antibodies to LAC activity was measured in 28 LAC positive plasmas. Plasmas were incubated with prothrombin or BSA, immobilized on CNBr-activated Sepharose, to absorb all anti-FII-antibodies. In 4 out of the 28 plasmas LAC activity was completely dependent on anti-FII-antibodies. In 7 out of the 28 plasmas, anti-FII-antibodies did not contribute to LAC activity. These anti-FII-antibodies can be regarded as non-functional antibodies. In the majority (17/28) of the samples, LAC activity within a single plasma was caused by a combination of antibodies with different specificities. Both dRVVT and KCT showed comparable sensitivity for the detection of functional anti-FII-antibodies. In conclusion, in most samples LAC activity is not caused by anti-FII-antibodies alone but by a combination of different types of antibodies. The presence of LAC activity and anti-FII-antibodies in one plasma does not automatically implicate that these antibodies are responsible for the LAC activity.
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PMID:The contribution of anti-prothrombin-antibodies to lupus anticoagulant activity--discrimination between functional and non-functional anti-prothrombin-antibodies. 956 94

Mouse complement component C4 exists in two isoforms, C4 and a protein with expression restricted to male animals called sex-limited protein (Slp). Although Slp is about 95% homologous to C4, it is generally believed to be non-functional, at least in conventional haemolytic complement assays. In a previous study, however, we showed that Slp is haemolytically active in a C1-inhibitor (C1INH)-regulated, EDTA-resistant mouse complement activation pathway. To study other possible implications of this finding, we generated constitutively expressing Slp-transgenic mice. The transgene was crossed into otherwise Slp-deficient C57Bl/6J and NZB mice. Members of the third backcross generation of C57Bl/6J mice were tested for functional Slp and classical and alternative complement pathway activities (CH50 and AP50 levels, respectively). Slp-transgenic C57Bl/6J mice showed enhanced CH50, but normal AP50 levels when compared with non-transgenic littermates. To discover a possible protective role for Slp in spontaneous systemic lupus erythematosus (SLE) in NZBxNZW (NZBxW) mice, the third backcross generation of Slp-transgenic NZB mice was mated with NZW mice and the development of SLE in the female offspring was followed. In these introductory experiments, Slp-transgenic NZBxW animals presented with a significantly extended life span. Our results imply that Slp is a mouse complement component with functions which partially resemble some of those of human C4A.
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PMID:Sex-limited protein: in vitro and in vivo functions. 1036 Dec 25

Autoimmunity develops when a lupus-inducing drug is introduced into the thymus of normal mice, but the relevance of this model to the human disorder is unclear in part because it is widely assumed that the thymus is non-functional in the adult. We compared thymus function in 10 patients with symptomatic procainamide-induced lupus to that in 13 asymptomatic patients who only developed drug-induced autoantibodies. T cell output from the thymus was quantified using a competitive polymerase chain reaction that detects T cell receptor DNA excision circles in peripheral blood lymphocytes. Despite the advanced age of the patient population under study, newly generated T cells were detected in all subjects. Although there was no overall quantitative difference between the symptomatic and asymptomatic patients, we found a positive correlation between the level of T cell receptor excision circles in peripheral lymphocytes and serum IgG anti-chromatin antibody activity in patients with drug-induced lupus. The association between autoantibodies and nascent peripheral T cells supports the requirement for T cells in autoantibody production. Our observations are consistent with findings in mice in which autoreactive T cells derived from drug-induced abnormalities in T cell development in the thymus.
Lupus 2001
PMID:Thymus function in drug-induced lupus. 1178 89

Deficiency of both mannan-binding lectin (MBL) and complement components C4 and C2 has been associated with increased risk of systemic lupus erythematosus (SLE). MBL can activate the complement system either through C4 and C2 or directly through C3. Circulating immune complexes (CICs) are believed to play a pathogenic role in SLE and MBL has been shown to bind certain forms of immunoglobulins, including IgM, IgG and IgA. Thus, MBL might promote CIC clearance. In order to evaluate this, six individuals with non-functional classical pathway due to the rare homozygous C2 deficiency were chosen, as the classical pathway is known to have a fundamental role in CIC clearance. Four of the six C2-deficient individuals had SLE, two of whom also had MBL deficiency. MBL serum levels and genotypes were compared with the serum levels of CICs, as measured by their content of kappa, lambda, IgM, IgA, IgG and C3 opsonization. The C2-deficient individuals had higher serum levels of CICs than 16 healthy controls (P < 0.0001). Furthermore, an inverse association was observed between MBL and CIC levels in the C2-deficient individuals, which was strongest for IgM-CICs (r = - 0.84, P = 0.037). Moreover, C3 opsonization of the CICs correlated positively with MBL levels in the C2-deficient individuals (r = 0.89, P = 0.017). In conclusion, individuals with C2 deficiency have increased levels of CICs and MBL may facilitate their clearance. Defective CIC clearance might partly explain the increased risk of SLE associated with low MBL.
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PMID:Mannan-binding lectin may facilitate the clearance of circulating immune complexes--implications from a study on C2-deficient individuals. 1733 56

CCR5 and its ligands play important roles in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). A deletion of 32 bp in its gene leads to the production of a non-functional receptor. Although a protective effect of CCR5 Delta32 for the development of RA has been suggested, future study is required to establish the exact role of this deletion for susceptibility to SLE and lupus nephritis. Also, with regard to the association of CCR5 Delta32 with disease severity in RA and SLE, more data are needed to draw firm conclusions. This might become even more relevant as a CCR5 blocking agent is now available.
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PMID:Role of CCR5 Delta32 bp deletion in RA and SLE. 1981 Dec 70

The CCR5 is a chemokine receptor widely expressed by several immune cells that are engaged in inflammatory responses. Some populations have individuals exhibiting a 32bp deletion in the CCR5 gene (CCR5-delta32) that produces a truncated non-functional protein not expressed on the cell surface. This polymorphism, known to be associated with susceptibility to infectious and inflammatory diseases, such as osteomyelitis, pre-eclampsia, systemic lupus erythematous, juvenile idiopathic arthritis, rheumatoid arthritis and HIV/AIDS, is more commonly found in European populations with average frequency of 10%. However, it is also possible to observe a significant frequency in other world populations, such as the Brazilian one. We performed a systematic review and meta-analysis of CCR5-delta32 genetic association studies in Brazilian populations throughout the country to estimate the frequency of this polymorphism. We also compared CCR5-delta32 frequencies across Brazilian regions. The systematic literature reviewed studies involving delta32 allele in Brazilian populations published from 1995 to 2015. Among the reviewed literature, 25 studies including 30 Brazilian populations distributed between the North, Northeast, South and Southeast regions were included in our meta-analysis. We observed an overall allelic frequency of 4% (95%-CI, 0.03-0.05), that was considered moderate and, notably, higher than some European populations, such as Cyprus (2.8%), Italy (3%) and Greece (2.4%). Regarding the regional frequency comparisons between North-Northeast (N-NE) and South-Southeast (S-SE) regions, we observed an allelic frequency of 3% (95%-CI, 0.02-0.04) and 4% (95%-CI, 0.03-0.05), respectively. The populations from S-SE regions had a slightly higher CCR5-delta32 frequency than N-NE regions (OR=1.41, p=0.002). Although there are several studies about the CCR5-delta32 polymorphism and its effect on the immune response of some infectious diseases, this report is the first meta-analysis study that provides a descriptive study of the distribution of CCR5-delta32 allele in Brazilian population.
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PMID:Frequency of the CCR5-delta32 allele in Brazilian populations: A systematic literature review and meta-analysis. 2720 5

C1q deficiency is a rare immunodeficiency, which is strongly associated with the development of systemic lupus erythematosus (SLE). A mutation in one of the C1q genes can either lead to complete deficiency or to low C1q levels with C1q polypeptide in the form of low-molecular weight (LMW) C1q. Patients with C1q deficiency mainly present with cutaneous and renal involvement. Although less frequent, neuropsychiatric (NP) involvement has also been reported in 20% of the C1q-deficient patients. This involvement appears to be absent in other deficiencies of early components of the complement classical pathway (CP) (C1r/C1s, C2, or C4 deficiencies). We describe a new case with C1q deficiency with a homozygous G34R mutation in C1qC-producing LMW-C1q presenting with a severe SLE flare with NP involvement. The serum of this patient contained very low levels of a LMW variant of C1q polypeptides. Cell lysates contained the three chains of C1q, but no intact C1q was detected, consistent with the hypothesis of the existence of a LMW-C1q. Furthermore, we provide a literature overview of NP-SLE in C1q deficiency and hypothesize about the potential role of C1q in the pathogenesis of NP involvement in these patients. The onset of NP-SLE in C1q-deficient individuals is more severe when compared with complement competent NP-SLE patients. An important number of cases present with seizures and the most frequent findings in neuroimaging are changes in basal ganglia and cerebral vasculitis. A defective CP, because of non-functional C1q, does not protect against NP involvement in SLE. The absence of C1q and, subsequently, some of its biological functions may be associated with more severe NP-SLE.
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PMID:C1q Deficiency and Neuropsychiatric Systemic Lupus Erythematosus. 2808 82


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