Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant

Vang, Torkel; Congia, Mauro; Macis, Maria Doloretta; Musumeci, Lucia; Orrù, Valeria; Zavattari, Patrizia; Nika, Konstantina; Tautz, Lutz; Taskén, Kjetil; Cucca, Francesco; Mustelin, Tomas; Bottini, Nunzio

doi:10.1038/ng1673

Cited by 642 publications

(632 citation statements)

References 14 publications

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“…For example in PTPN22, the minor allele of the R620W SNP is associated with greater risk of developing RA, JIA, T1D and SLE but is protective for Crohn's disease. 24,25 There is also emerging data suggesting that one of the associated SNPs at the IL2RA locus confers differing risk and protective effects for T1D and multiple sclerosis. 26,27 JIA is a phenotypically heterogeneous disease and can be classified into more clinically homogeneous diseases using the ILAR classification criteria (Supplementary Table 1).…”

Section: Resultsmentioning

confidence: 99%

Association of the AFF3 gene and IL2/IL21 gene region with juvenile idiopathic arthritis

Hinks

Eyre

et al. 2010

Genes Immun

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Recent genetic studies have led to identification of numerous loci that are associated with susceptibility to autoimmune diseases. The strategy of using information from these studies has facilitated the identification of novel juvenile idiopathic arthritis (JIA) susceptibility loci, specifically, PTPN22 and IL2RA. Several novel autoimmune susceptibility loci have recently been identified, and we hypothesise that single-nucleotide polymorphisms (SNPs) within these genes may also be JIA susceptibility loci. Five SNPs within the genes AFF3, IL2/IL21, IL7R, CTLA4 and CD226, previously associated with multiple autoimmune diseases were genotyped, in a large data set of Caucasian JIA patients and controls, and tested for association with JIA. We identified two susceptibility loci for JIA, AFF3 and the IL2/IL21 region and additional weak evidence supporting an association with the CTLA4 and IL7R genes, which warrant further investigation. All results require validation in independent JIA data sets. Further characterisation of the specific causal variants will be required before functional studies can be performed.

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Section: Resultsmentioning

confidence: 99%

Association of the AFF3 gene and IL2/IL21 gene region with juvenile idiopathic arthritis

Hinks

Eyre

et al. 2010

Genes Immun

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“…In contrast, another study indicates that in carriers of the PTPN22 T allele, 1730 VAN DER HELM-VAN MIL ET AL the intrinsic phosphatase activity is increased, revealing a gain of function (36). These authors suggested that the paradoxical findings might be explained by a less sufficient activity of T regulatory cells in the presence of the PTPN22 T allele (36). Moreover, PTPN22 is expressed not only on T cells but also on B cells, natural killer cells, and macrophages (where its function is unknown), indicating that the action of PTPN22, in addition to its capacity to modulate T cell receptor signaling, might also be routed through manipulation of other aspects of the immune system.…”

Section: Risk Factors For Acpa-positive Ramentioning

confidence: 92%

Section: Risk Factors For Acpa-positive Ramentioning

confidence: 97%

Emerging patterns of risk factor make‐up enable subclassification of rheumatoid arthritis

Mil¹,

Huizinga²,

Vries³

et al. 2007

Arthritis & Rheumatism

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“…They showed that B‐cells from carriers of this PTPN22 risk allele contained high frequencies of autoreactive clones compared with those from non‐carriers showing how a single polymorphism at one genetic locus can affect the B‐cell repertoire 61. This PTPN22 polymorphism is a gain‐of‐function variant leading to reduced B‐ and T‐cell receptor signalling,62, 63 and has been associated with a range of autoimmune diseases, including RA,64, 65 type 1 diabetes66 and SLE 67. Similar studies on variation in other genes are likely to provide further useful information on how specific biological pathways regulate the B‐cell repertoire.…”

Section: Slementioning

confidence: 99%

Antibody repertoire analysis in polygenic autoimmune diseases

2018

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SummaryHigh‐throughput sequencing of the DNA/RNA encoding antibody heavy‐ and light‐chains is rapidly transforming the field of adaptive immunity. It can address key questions, including: (i) how the B‐cell repertoire differs in health and disease; and (ii) if it does differ, the point(s) in B‐cell development at which this occurs. The advent of technologies, such as whole‐genome sequencing, offers the chance to link abnormalities in the B‐cell antibody repertoire to specific genomic variants and polymorphisms. Here, we discuss the current research using B‐cell antibody repertoire sequencing in three polygenic autoimmune diseases where there is good evidence for a pathological role for B‐cells, namely systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis. These autoimmune diseases exhibit significantly skewed B‐cell receptor repertoires compared with healthy controls. Interestingly, some common repertoire defects are shared between diseases, such as elevated IGHV4‐34 gene usage. B‐cell clones have effectively been characterized and tracked between different tissues and blood in autoimmune disease. It has been hypothesized that these differences may signify differences in B‐cell tolerance; however, the mechanisms and implications of these defects are not clear.

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Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant

Cited by 642 publications

References 14 publications

Association of the AFF3 gene and IL2/IL21 gene region with juvenile idiopathic arthritis

Association of the AFF3 gene and IL2/IL21 gene region with juvenile idiopathic arthritis

Emerging patterns of risk factor make‐up enable subclassification of rheumatoid arthritis

Antibody repertoire analysis in polygenic autoimmune diseases

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