PLAID: a Syndrome of Complex Patterns of Disease and Unique Phenotypes

Milner, Joshua D.

doi:10.1007/s10875-015-0177-x

Cited by 71 publications

(55 citation statements)

References 14 publications

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“…While the IP3/DAG/Ca+2 signaling pathway is active in many cells and tissues, in brain, PLCG2 is primarily expressed in microglial cells. PLCG2 variants also cause Antibody Deficiency and Immune Dysregulation (PLAID) and Autoinflammation and PLAID (APLAID) 39 . Genomic deletions (PLAID) and missense mutations (APLAID) affect the cSH2 autoinhibitory regulatory region.…”

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confidence: 99%

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Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Sims¹,

Lee²,

Naj³

et al. 2017

Nat Genet

847

733

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Introduction We identified rare coding variants associated with Alzheimer’s disease (AD) in a 3-stage case-control study of 85,133 subjects. In stage 1, 34,174 samples were genotyped using a whole-exome microarray. In stage 2, we tested associated variants (P<1×10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, an additional 14,997 samples were used to test the most significant stage 2 associations (P<5×10-8) using imputed genotypes. We observed 3 novel genome-wide significant (GWS) AD associated non-synonymous variants; a protective variant in PLCG2 (rs72824905/p.P522R, P=5.38×10-10, OR=0.68, MAFcases=0.0059, MAFcontrols=0.0093), a risk variant in ABI3 (rs616338/p.S209F, P=4.56×10-10, OR=1.43, MAFcases=0.011, MAFcontrols=0.008), and a novel GWS variant in TREM2 (rs143332484/p.R62H, P=1.55×10-14, OR=1.67, MAFcases=0.0143, MAFcontrols=0.0089), a known AD susceptibility gene. These protein-coding changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified AD risk genes. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to AD development.

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confidence: 99%

“…Genomic deletions (PLAID) and missense mutations (APLAID) affect the cSH2 autoinhibitory regulatory region. The result is a complex mix of loss and gain of function in cellular signalling 39 .…”

mentioning

confidence: 99%

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Sims¹,

Lee²,

Naj³

et al. 2017

Nat Genet

847

733

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“…The steering committee is aware that diseases such as PLCG2-associated antibody deficiency and immune dysregulation (PLAID) or Heme-oxidised IRP2 ubiquitin ligase1 (HOIL-1) deficiency, traditionally included among the AIDs, will not be part of this group, because they may contain components of the adaptive immune system such as autoantibodies 60. The ‘Interferonopathies’ include some disorders also manifesting autoantibodies.…”

Section: Resultsmentioning

confidence: 99%

Consensus proposal for taxonomy and definition of the autoinflammatory diseases (AIDs): a Delphi study

et al. 2018

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Autoinflammatory diseases (AIDs) are a relatively new family of disorders, defined about 19 years ago. Some of them are hereditary and some are not. The names given to these diseases do not follow any systematic guidelines, and sometimes the same disorder carries several names. The aim of this study is to refine the definition of AIDs and to provide some conventions for their naming. We focused mainly on monogenetic AIDs. Delphi technique, which enables consensus among a group of experts through internet and mail communication and questionnaires, was employed. After achieving 100% consensus among six members of a steering committee, the questionnaire containing AID definitions and the agreed-upon conventions were sent to 26 physicians and researchers working in the field of AIDs in order to gain broader support for the committee's proposals. The committee proposed the following definition for AIDs: "Autoinflammatory diseases are clinical disorders caused by defect(s) or dysregulation of the innate immune system, characterized by recurrent or continuous inflammation (elevated acute phase reactants-APR) and the lack of a primary pathogenic role for the adaptive immune system (autoreactive T-cells or autoantibody production)." Several rules were defined for guiding the naming of these diseases among which are: abandoning eponyms and preferring the name of the gene over its encoded protein. The new definition for AIDs allows inclusion of clinical disorders mainly associated with defects in the innate immune system. The new conventions propose names with clinical meaning and in some cases even clues for treatment.

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“…Interestingly, this variant is protective in AD, with an odds ratio of 0.68. PLCG2 is primarily expressed in microglia, with PLCG2 variants leading to PCLG2 ‐associated antibody deficiency and immune dysregulation disorders (Milner, ). ABI3 is suggested to have a role in the innate immune response, in particular through IFN‐mediated pathways (Sims et al, ).…”

Section: Gwas Microgliamentioning

confidence: 99%

The involvement of microglia in Alzheimer's disease: a new dog in the fight

Moore

Crack

2018

British J Pharmacology

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First described clinically in 1906, Alzheimer's disease (AD) is the most common neurodegenerative disease and form of dementia worldwide. Despite its prevalence, only five therapies are currently approved for AD, all dealing with the symptoms rather than the underlying causes of the disease. A multitude of experimental evidence has suggested that the once thought inconsequential process of neuroinflammation does, in fact, contribute to the AD pathogenesis. One such CNS cell type critical to this process are microglia. Plastic in nature with varied roles, microglia are emerging as key contributors to AD pathology. This review will focus on the role of microglia in the neuroinflammatory response in AD, highlighting recent studies implicating aberrant changes in microglial function in disease progression. Of critical note is that with these advances, a reconceptualization of the framework in which we view microglia is required. Linked Articles This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc

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PLAID: a Syndrome of Complex Patterns of Disease and Unique Phenotypes

Cited by 71 publications

References 14 publications

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease

Consensus proposal for taxonomy and definition of the autoinflammatory diseases (AIDs): a Delphi study

The involvement of microglia in Alzheimer's disease: a new dog in the fight

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