MHC class II, tumour necrosis factor  , and lymphotoxin   gene haplotype associations with serological subsets of systemic lupus erythematosus

McHugh, Neil; Owen, Pat; Cox, Beverley; Dunphy, J. Englebert; Welsh, Ken I.

doi:10.1136/ard.2005.039842

Cited by 43 publications

(51 citation statements)

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“…The subjects of the study by McHugh et al [16] were mainly Caucasians, and the study was included in Caucasian population when stratifying by ethnicity. The allele and the genotype frequencies of the TNF-a promoter 2 238A/G polymorphism were extracted from 10 of the 11 eligible studies, while only G/A þ A/A and G/G genotypes were extracted from the study by Rood et al [20].…”

Section: Resultsmentioning

confidence: 99%

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Meta-analysis of TNF-α promoter − 238A/G polymorphism and SLE susceptibility

et al. 2010

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The tumor necrosis factor-alpha (TNF-alpha) promoter--238A/G polymorphism has been repeatedly associated with systemic lupus erythematosus (SLE), but findings are not consistent across studies. Our aim was to do a meta-analysis to assess the association between TNF-alpha promoter--238A/G polymorphism and SLE. Eleven published studies of this polymorphism with SLE in different ethnic groups were identified using a Medline search. Meta-analysis was performed for genotypes AA versus GG, GA versus GG, AA versus GG+GA, GA+AA versus GG, and A allele versus G allele in a fixed/random effect model. The overall odds ratio (OR) of the AA versus GG+GA genotypes was 3.46 (95% CI = 1.35-8.83, P = 0.01), and a similar result was found in Caucasian population (OR = 4.62, 95% CI = 1.20-17.80, P = 0.03); the overall OR of the AA versus GG genotypes was 3.36 (95% CI = 1.32-8.55, P = 0.01), and a similar result was found in Caucasian population (OR = 4.29, 95% CI = 1.11-16.53, P = 0.03); the OR of the GA versus GG genotypes was 0.48 (95% CI = 0.30-0.75, P = 0.001) in Caucasian population. In conclusion, this meta-analysis demonstrates the association between TNF-alpha promoter - 238A/G polymorphism and SLE, especially in Caucasian population.

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Section: Resultsmentioning

confidence: 99%

“…The remaining nine studies were retrieved for more detailed Meta-analysis of TNF-a promoter 2 238A/G 267 evaluation [14,15,17 -23]. One additional study was identified by reviewing the references of these studies [16]. Meanwhile, we excluded one study due to duplicate report [23].…”

Section: Resultsmentioning

confidence: 99%

Meta-analysis of TNF-α promoter − 238A/G polymorphism and SLE susceptibility

et al. 2010

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“…Genetic and epidemiological findings have strongly implicated polymorphic sites within MHC class II molecules in the pathogenesis of autoimmune diseases. [26][27][28] Recently HLA-DRB1*11 has been identified as a risk factor for the development of acquired TTP. It has been observed that the HLA-DRB1*11 is more frequent in patients with acquired TTP when compared with a control population.…”

Section: Introductionmentioning

confidence: 99%

Preferential HLA-DRB1*11–dependent presentation of CUB2-derived peptides by ADAMTS13-pulsed dendritic cells

Sorvillo

Haren

Kaijen

et al. 2013

Blood

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Key Points• ADAMTS13 derived peptides presented on HLA-DR; implications for acquired TTP.• CUB2 domain peptide binds to risk-allele HLA-DRB1*11.Autoantibodies directed against ADAMTS13 prohibit the processing of von Willebrand factor multimers, initiating a rare and life-threatening disorder called acquired thrombotic thrombocytopenic purpura (TTP). Recently, HLA-DRB1*11 has been identified as a risk factor for the development of acquired TTP. Here, we identified ADAMTS13-derived peptides presented on MHC class II alleles from 17 healthy donors. Dendritic cells from a panel of both HLA-DRB1*11-positive and -negative donors were pulsed with ADAMTS13, and the HLA-DR-presented peptide repertoire was analyzed by mass spectrometry. Interestingly, at low antigen concentrations, HLA-DRB1*11-or DRB1*03-positive donors presented a limited number of CUB2-derived peptides. Pulsing of dendritic cells using higher concentrations of ADAMTS13 resulted in the presentation of larger numbers of ADAMTS13-derived peptides by both HLA-DRB1*11-positive and -negative donors. Although the presented peptides were derived from several ADAMTS13 domains, inspection of the peptide profiles revealed that CUB2 domainderived peptides were presented with a higher efficiency when compared with other peptides. Remarkably, dendritic cells from DRB1*11 donors pulsed with higher concentrations of ADAMTS13-present derivatives of a single CUB2-derived peptide. We hypothesize that functional presentation of CUB2-derived peptides on HLA-DRB1*11 contributes to the onset of acquired TTP by stimulating low-affinity, self-reactive CD41 T cells. (Blood. 2013;121(17):3502-3510) Introduction Acquired thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening disorder characterized by the production of autoantibodies directed toward ADAMTS13, a plasma metalloprotease responsible for the cleavage of ultra-large von Willebrand factor (UL-VWF) multimers.1-3 Deficiency of ADAMTS13 causes the accumulation of UL-VWF strings on the surface of endothelial cells of the vessel wall and in the circulation. 4 Prolonged exposure of UL-VWF strings on the surface of endothelial cells promotes platelet adhesion, leading to low platelet counts and microvascular thrombosis. 5,6 The majority of the inhibitory anti-ADAMTS13 antibodies that develop in patients affected by acquired TTP targets a single epitope composed of Arg568, Phe592, Arg660, Tyr661, and Tyr665 on the outer surface of the spacer domain. This exposed region is crucial for binding of ADAMTS13 to unfolded VWF A2 domain.7-9 Antibodies targeting the CUB 1-2 and TSP2-8 regions of ADAMTS13 have also been detected in the plasma of several patients with acquired TTP. 10,11 The pathogenic role of anti-TSP2-8 and anti-CUB1-2 is still unclear. The carboxy-terminal ADAMTS13 TSP2-8 and CUB 1-2 regions not only modulate processing of VWF under flow 12-14 but are also necessary for the binding of ADAMTS13 to endothelial cells. 15A number of studies have shown that anti-ADAMTS13 antibodies detected in the plasma ...

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“…A strong association between HLA class II alleles and SLE was demonstrated by McHugh et al in 2006 (20). One of the suggested pathogenetic mechanisms of HLA class II molecules in SLE is their contribution to activation of CD4+ T cells.…”

Section: Discussionmentioning

confidence: 96%

An extensive screen of the HLA region reveals an independent association of HLA class I and class II with susceptibility for systemic lupus erythematosus

Martens¹,

Nolte²,

Steege

et al. 2009

Scandinavian Journal of Rheumatology

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MHC class II, tumour necrosis factor , and lymphotoxin gene haplotype associations with serological subsets of systemic lupus erythematosus

Abstract: The strongest association in this predominantly white population with SLE was between HLA-DR3 and anti-La, which seemed to account for any associations with TNFalpha alleles on an extended DR3 haplotype.

Cited by 43 publications

References 43 publications

Meta-analysis of TNF-α promoter − 238A/G polymorphism and SLE susceptibility

Meta-analysis of TNF-α promoter − 238A/G polymorphism and SLE susceptibility

Preferential HLA-DRB1*11–dependent presentation of CUB2-derived peptides by ADAMTS13-pulsed dendritic cells

An extensive screen of the HLA region reveals an independent association of HLA class I and class II with susceptibility for systemic lupus erythematosus

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