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)

Antinuclear antibodies are an almost universal feature of SLE. Over the years they have been the subject of intensive study to understand the underlying pathogenesis of the disease. It is clear that ANA in the context of lupus are directed against highly selected targets and are not just the result of nonspecific polyclonal B cell activation. Frequently they react with components of nucleoprotein complexes involved in important cellular processes which are very specific targets for autoimmunity in this condition. The antibodies themselves belong primarily to the IgG1 and IgG3 subclasses of immunoglobulin, are high affinity, occur in large amounts, have important associations with particular HLA class II genes and show all the features of an antigen-driven, T cell-dependent immune response. Although at first glance there is a wide range of antibody specificities associated with SLE, in the individual patient the autoantibody profile is much more restricted. Methods to detect these antibodies have provided the clinician with valuable tools to assist both in diagnosis and assessment of lupus patients. It has been possible to recognise distinctive serological subsets within the spectrum of lupus which are associated with certain patterns of disease expression. This can be helpful in determining both disease classification and prognosis.
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PMID:Autoantibodies in SLE. Disease associations. 1059 35

The objective of this study was to determine the HLA class II associations of the anticardiolipin (aCL) and anti-beta2GPI (abeta2GPI) antibodies in a large series of European patients with systemic lupus erythematosus (SLE). A cohort of 577 European SLE patients was enrolled. aCL and abeta2GPI were measured by ELISA methods. Molecular typing of HLA-DRB1, DRB3, DRB4, DRB5, DQA1 and DQB1 loci was performed by the polymerase chain reaction-sequence specific oligonucleotide probes (PCR-SSOP) method. aCL of IgG, IgM and IgA isotypes were detected in 22.8%, 14% and 13.9% of patients, respectively. IgG and IgM abeta2GPI were detected in 20% of patients. aCL showed positive association with HLA DRB1*04, DRB1*0402, DRB1*0403, DRB1*07, DRB3*0301, DQA1*0201, DQA1*0301, DQB1*0302, and negative association with DQA1*0501, DRB3*0202. abeta2GPI showed positive association with DRB1*0402, DRB1*0403, DQB1*0302. DRB1*0402 carried the highest relative risk for the presence of both aCL (RR=8. 1) and abeta2GPI (RR=4.6). Our results confirm the already described associations of aCL with HLA DR4 and DR7, but also demonstrate that, among the alleles at the DRB1*04 locus, the *0402 was most represented both in aCL and in abeta2GPI positive patients. In addition, HLA class II associations of abeta2GPI are for the first time extensively examined in a large cohort of European SLE patients.
Lupus 2000
PMID:HLA class II alleles associations of anticardiolipin and anti-beta2GPI antibodies in a large series of European patients with systemic lupus erythematosus. 1071

Antiphospholipid syndrome (APS) is an autoimmune disease that accompanies anti-phospholipid antibodies measured as either anti-cardiolipin antibodies (aCL) or lupus anticoagulant. beta(2)-glycoprotein I (beta(2)GPI) is the most common and apparently the best-characterized antigenic target for aCL. To investigate T-cell responses to beta(2)GPI, we stimulated PBMC of 18 APS or systemic lupus erythematosus (SLE) patients carrying anti-beta(2)GPI and 10 healthy controls, using a peptide library covering the beta(2)GPI sequence. We established seven CD4(+) T cell lines reactive with beta(2)GPI peptide. Three of four epitopes for patient-derived T cell lines were p244-264, whereas one T cell line from a control subject also recognized p244-264. Furthermore, there was no tendency for particular HLA class II molecules to present beta(2)GPI peptides. However, cytokine producing patterns were significantly different between T cell lines from patients and those from healthy individuals (p =.028); patients' T cells tend to exhibit higher IL-4 and lower IFN-gamma responses. These T cell lines did not react to beta(2)GPI purified from human plasma. These results indicate that beta(2)GPI-reactive CD4(+) T cells of APS/SLE patients mainly recognize cryptic p244-264 in the context of various HLA class II molecules, and exhibit Th0-Th2-type responses. Our findings may provide a clue to the pathogenesis of APS.
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PMID:Analysis of T cell responses to the beta 2-glycoprotein I-derived peptide library in patients with anti-beta 2-glycoprotein I antibody-associated autoimmunity. 1071 14

The lack of phenotype/genotype association in X-linked adrenoleukodystrophy (X-ALD) has prompted the search for disease modifying factors. We previously demonstrated increased serum antibody responses against myelin oligodendrocyte glycoprotein (MOG) in various clinical phenotypes of X-ALD allowing speculations that myelin specific humoral immune responses might be involved in phenotype generation of X-ALD. In the present study, we investigated the possible association of (1) a naturally occurring variable number tandem repeat (vntr) polymorphism (C allele) in the 3' flanking region of the interleukin-6 gene (IL-6), previously demonstrated to modify the course of Alzheimer's disease, systemic lupus erythematodes and Multiple Sclerosis (MS), (2) a tetranucleotide repeat polymorphism (TAAA)(n) in the 3' flanking region of the MOG gene and (3) HLA class II alleles with adult clinical phenotypes and serum antibody responses to MOG in 70 adult X-ALD patients. HLA class II alleles, (TAAA)(n) MOG gene polymorphisms, and IL-6 C allele were not associated with clinical phenotypes. Anti-MOG antibodies were detectable in 17/54 X-ALD patients (31.5%). Anti-MOG antibodies were associated with the 226 bp (TAAA)(n) MOG gene polymorphism but not with distinct clinical phenotypes.
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PMID:Genetic variations and humoral immune responses to myelin oligodendroglia glycoprotein in adult phenotypes of X-linked adrenoleukodystrophy. 1257 35

These genetic studies of primary pulmonary hypertension (PPH) initially tried to define immunogenetic subsets. Because only small subsets could be classified when defined by HLA/autoantibody associations and the familial form of PPH failed to segregate with the HLA class II locus, the focus shifted to a genome scan of families with PPH (FPPH). This approach identified a gene on chromosome 2q33,34 called PPH1. Mutations in this gene, now known to be bone morphogenetic protein receptor 2 (BMPR2), can cause PPH. Mutations in a second gene, ALK-1, present in families with hereditary hemorrhagic telangiectasia type 2, also causes PPH. Both genes, involved in TGF-B signaling, provide exciting clues for defining the pathogenesis of PPH.
Lupus 2003
PMID:Genetic studies of pulmonary arterial hypertension. 1270 84

To assess whether the major histocompatibility complex (MHC) profile of patients presenting with primary antiphospholipid syndrome (PAPS) is different from that of patients with secondary antiphospholipid syndrome (SAPS), we studied 123 patients, 34 of whom presented PAPS and 35 SAPS due to systemic lupus erythematosus (SLE), 54 SLE patients without antiphospholipid syndrome (APS), and 166 controls. HLA-DRB1 and DQB1 alleles were typed using amplified DNA hybridized with sequence-specific primers. Compared to controls, PAPS patients exhibited a nonsignificantly increased frequency of DR53-associated alleles, and SAPS patients presented an increased frequency of HLA-DRB1*03 alleles (corrected P = 0.05). In addition, HLA-DRB1*03 alleles were over-represented in SAPS patients presenting anticardiolipin antibody (aCL) (Pc = 0.02), in SLE patients as a whole (Pc < 0.0001), and in SLE patients without APS (Pc = 0.02). The frequency of aCL among SLE patients presenting or not HLA-DRB1*03 alleles was closely similar. A trend to an increase in the frequency of the DQB1*0604 allele (14.3 versus 4.2%, P = 0.03) and of the DQB1*0302 allele (31.4 versus 12.7%, P = 0.01) was observed in SAPS. Taken together, these results indicate that the association of SAPS with HLA-DRB1*03 is due to the association with SLE and is not due to aCL, and suggest that the HLA class II profile of PAPS is different from that of SAPS.
Lupus 2004
PMID:Is HLA class II susceptibility to primary antiphospholipid syndrome different from susceptibility to secondary antiphospholipid syndrome? 1499 6

Peptides from VH regions of antibodies to DNA drive immune responses in systemic lupus erythematosus (SLE). We studied peptide-induced cytokine release by peripheral blood mononuclear cells (PBMC) of patients, the influence of peptide concentration, disease characteristics and HLA-D haplotypes. Cells secreting cytokines (IFNgamma, IL-2, IL-4 and IL-10) were measured by ELISPOT in PBMC from 31 patients with SLE and 20 matched healthy controls in response to seven peptides (A-G) from the CDR1/FR2 to CDR2/FR3 VH regions of human anti-DNA MAbs. Disease activity was assessed by SELENA-SLEDAI. HLA-DR and -DQ alleles were determined by molecular typing techniques. PBMC from significantly higher proportions of SLE patients than controls responded to VH peptides by generating IFNgamma and IL-10. Type of cytokines released in response to at least one peptide (D) depended on antigen concentration. Cytokine release was not associated with clinical features of SLE except for disease duration. A shift occurred from IFNgamma, IL-4 and IL-10 production in early disease to IL-4 and IL-10 in late disease (suggesting increasing TH2-like responses over time). Three peptides (B, D, G) were more stimulatory in the SLE patients than controls. Although none of the peptides was restricted by any particular MHC class II allele, among responders there was increased prevalence of HLA- DQB1*0201 and/or DRB1*0301, alleles known to predispose to SLE. Thus, responses to some VH peptides are more frequent in SLE and vary with disease duration. Increased responses in individuals with HLA class II genotypes that predispose to SLE suggest that peptide presentation by those molecules permits brisker peripheral blood cell responses to autoantibody peptides, thus increasing risk for disease.
Lupus 2004
PMID:Peptides from antibodies to DNA elicit cytokine release from peripheral blood mononuclear cells of patients with systemic lupus erythematosus: relation of cytokine pattern to disease duration. 1535 17

There is a clear propensity of individuals with lupus anticoagulant (LA) for thromboembolic disease (TE). Yet, it is not clear how individuals at risk for TE can be differentiated from those who are not. The Fc gammaRIIa receptor is the only Fc receptor expressed by platelets. As platelets can be activated via this receptor, we have compared gene frequencies of the Fc gammaRIIa polymorphism R/H131 in 46 and 27 patients with (LA/TE+) and without TE (LA/TE-), respectively, in an exploratory study. Furthermore, we investigated the presence of autoantibodies against Fc gammaRIIa and/or GPIb alpha, which is in close proximity to the Fc gammaRIIa and interacts with it functionally, and a possible linkage of antibody formation to HLA class II alleles. The Fc gammaRIIa-R/R131 genotype was significantly less frequent in patients with LA compared to controls (p<0.025). These findings were due to an increased frequency of heterozygous patients in the LA/TE+ cohort (odds ratio 6.76, 95% confidence interval 1.55-62.03, p<0.008). For the first time, heterozygosity, rather than homozygosity, can be linked to disease, which may be explained by the dual function of the Fc gammaRIIa, namely binding of antibodies to platelets and thereby their activation, and, on the other hand, clearance of antibody coated platelets by the phagocyte system. There was no correlation between the presence of anti-Fc gammaRIIa or anti-GPIb alpha autoantibodies and the Fc gammaRIIa-R/H131 polymorphism, nor the incidence of TE, nor HLA class II alleles.
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PMID:The Fc gammaRIIa polymorphism R/H131, autoantibodies against the platelet receptors GPIb alpha and Fc gammaRIIa and a risk for thromboembolism in lupus anticoagulant patients. 1573 7

A peptide encompassing residues 131-151 of the spliceosomal U1-70K protein and its analog phosphorylated at Ser140 were synthesized as potential candidates for the treatment of patients with lupus. Studies in the MRL/lpr and (NZB x NZW)F1 lupus models have demonstrated that these sequences contain a CD4+ T cell epitope but administration of the phosphorylated peptide only ameliorates the clinical manifestations of treated MRL/lpr mice. Binding assays with soluble HLA class II molecules and molecular modeling experiments indicate that both peptides behave as promiscuous epitopes and bind to a large panel of human DR molecules. In contrast to normal T cells and T cells from non-lupus autoimmune patients, we found that PBMCs from 40% of lupus patients selected randomly and CFSE-labeled CD4+ T cells proliferate in response to peptide 131-151. Remarkably, however, we observed that phosphorylation of Ser140 prevents CD4+ T cells proliferation but not secretion of regulatory cytokines, suggesting a striking immunomodulatory effect of phosphorylated analog on lupus CD4+ T cells that was unique to patients. The analog might act as an activator of regulatory T cells or as a partial agonist of TCR.
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PMID:Selective modulation of CD4+ T cells from lupus patients by a promiscuous, protective peptide analog. 1623 76

To evaluate the association of human leukocyte antigen (HLA)-DRB1 alleles with systemic lupus erythematosus (SLE) and lupus nephritis (LN) in the Taiwanese population, and to investigate the possible association of HLA-DRB1 alleles with disease severity in LN. HLA-DRB1 alleles were studied in 105 SLE patients (82 patients with LN, 23 patients without LN) and 855 healthy controls by polymerase chain reaction and sequence-based typing assays. The frequency of the HLA class II alleles DRB1*0301 (Odds ratio [OR] = 2.01, 95% confidence interval [CI] = 1.31-3.10, Pc = 0.02) and DRB1*1501 (OR = 2.06, 95% CI = 1.36-3.13, Pc = 0.01) were both increased in SLE patients, compared to healthy controls. The frequency of DRB1*1202 was significantly lower in LN patients than in SLE patients without nephritis (OR = 0.23, 95% CI = 0.09-0.57, Pc = 0.01). No specific allele was significantly associated with an increased or decreased risk for severity of LN in this sample. In Taiwanese people, the DRB1*0301 and DRB1*1501 alleles are significant risk factors for SLE, while the DRB1*1202 allele is protective for LN.
Lupus 2009 Jul
PMID:Molecular analysis of HLA-DRB1 allelic associations with systemic lupus erythematous and lupus nephritis in Taiwan. 1950 65


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