Copy number variation of the activating FCGR2C gene predisposes to idiopathic thrombocytopenic purpura

Breunis, Willemijn B.; Mirre, Edwin van; Bruin, Marrie C.A.; Geissler, Judy; Boer, Martin de; Peters, Marjolein; Roos, Dirk; Haas, Masja de; Koene, Harry R.; Kuijpers, Taco W.

doi:10.1182/blood-2007-03-079913

Cited by 180 publications

(264 citation statements)

References 46 publications

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“…These results suggested that the NKG2C genotype might modulate the proliferation and/or survival of circulating NKG2C + cells, ultimately influencing the magnitude and/or persistence of the NKG2C + expansion. Functional consequences of gene copy number variation have been reported for some immunoreceptors [58,59]. This view would indirectly reinforce the hypothesis of an active involvement of the activating KLR in this process.…”

Section: Discussionsupporting

confidence: 61%

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Influence of congenital human cytomegalovirus infection and the NKG2C genotype on NK‐cell subset distribution in children

Noyola¹,

Fortuny

Muntasell

et al. 2012

Eur J Immunol

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Human cytomegalovirus (HCMV) has been reported to reshape the NK-cell receptor (NKR) distribution, promoting an expansion of CD94/NKG2C + NK and T cells. The role of NK cells in congenital HCMV infection is ill-defined. Here we studied the expression of NKR (i.e., NKG2C, NKG2A, LILRB1, CD161) and the frequency of the NKG2C gene deletion in children with past congenital infection, both symptomatic (n = 15) and asymptomatic (n = 11), including as controls children with postnatal infection (n = 11) and noninfected (n = 20). The expansion of NKG2C + NK cells in HCMV-infected individuals appeared particularly marked and was associated with an increased number of LILRB1 + NK cells in cases with symptomatic congenital infection. Increased numbers of NKG2C + , NKG2A + , and CD161 + T cells were also associated to HCMV infection. The NKG2C deletion frequency was comparable in children with congenital HCMV infection and controls. Remarkably, the homozygous NKG2C +/+ genotype appeared associated with increased absolute numbers of NKG2C + NK cells. Moreover, HCMV-infected NKG2C +/+ children displayed higher absolute numbers of NKG2A + and total NK cells than NKG2C +/− individuals. Our study provides novel insights on the impact of HCMV infection on the homeostasis of the NK-cell compartment in children, revealing a modulatory influence of NKG2C copy number. Eur. J. Immunol. 2012. 42: 3256-3266 Immunity to infection 3257 lifelong latent state, occasionally undergoing reactivation, but may have a pathogenic role in immunodeficient and immunosuppressed patients [1][2][3]. Moreover, HCMV has been associated with atherosclerosis, lymphoproliferative disorders, and glioblastoma, as well as with an accelerated immunosenescence and a shorter lifespan [4][5][6][7]. Vertical transmission of HCMV during pregnancy is considered the most common cause of congenital infection worldwide, affecting ∼0.2-2% of infants and potentially causing fetal lesions [8][9][10]. Though most infected newborns are asymptomatic, ∼10% display a variety of clinical disorders [8,11] potentially leading to important sequelae such as mental retardation and deafness. The type of maternal infection (i.e., primary versus reactivation/reinfection) conditions the risk of congenital infection and the pregnancy stage at which transmission occurs is related to clinical severity [12][13][14][15][16]. Maternal antibodies with neutralizing activity are transferred to the fetus predominantly during the third trimester of gestation and may prevent congenital CMV disease [17]. Among other factors, fetal immune immaturity may determine the outcome of congenital infection [18,19]. An effective defense against HCMV requires the participation of T and NK cells, and the virus has developed different immune evasion strategies [20]. Patients with congenital HCMV infection have been shown to display mature CD8 + T-cell responses [21,22], and an expansion and differentiation of a specific TcR γδ + cell subset has been recently reported [23]. In contrast, information on the role of...

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Section: Discussionsupporting

confidence: 61%

“…Further studies in a larger cohort are required to address whether the NKG2C genotype might have a more subtle influence on the [58,59]. This view would indirectly reinforce the hypothesis of an active involvement of the activating KLR in this process.…”

Section: Discussionmentioning

confidence: 88%

Influence of congenital human cytomegalovirus infection and the NKG2C genotype on NK‐cell subset distribution in children

Noyola¹,

Fortuny

Muntasell

et al. 2012

Eur J Immunol

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“…Although FCGR2C has been associated with idiopathic thrombocytopenic purpura, 18 CN variation is unlikely to have a major biological effect; in most individuals the gene contains a premature stop codon. It is the presence of a SNP (found in B18% of the population) within this stop codon that creates an open reading frame and results in the expression of this inhibitory receptor that appears to be the aetiological variant.…”

Section: Discussionmentioning

confidence: 99%

Evidence that deletion at FCGR3B is a risk factor for systemic sclerosis

et al. 2012

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There is increasing evidence that gene copy number (CN) variation influences clinical phenotype. The low-affinity Fc receptor 3B (FCGR3B) located in the FCGR gene cluster is a CN polymorphic gene involved in the recruitment of polymorphonuclear neutrophils to sites of inflammation and their activation. Given the genetic overlap between systemic lupus erythematosus and systemic sclerosis (SSc) and the strong evidence for FCGR3B CN in the pathology of SLE, we hypothesised that FCGR3B gene dosage influences susceptibility to SSc. We obtained FCGR3B deletion status in 777 European Caucasian cases and 1000 controls. There was an inverse relationship between FCGR3B CN and disease susceptibility. CN of p1 was a significant risk factor for SSc (OR ¼ 1.55 (1.13-2.14), P ¼ 0.007) relative to CNX2. Although requiring replication, these results suggest that impaired immune complex clearance arising from FCGR3B deficiency contributes to the pathology of SSc, and FCGR3B CN variation is a common risk factor for systemic autoimmunity.

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“…For example, we and others found that the copy number of segmental duplication on chromosome 17q that contains the gene encoding the chemokine CC chemokine ligand 3-like 1 (CCL3L1) influences HIV-AIDS susceptibility, [5][6][7][8][9] and the risk of developing Kawasaki's disease, 10 systemic lupus erythematosus (SLE) 11 and rheumatoid arthritis (RA). 12 CNV in the gene encoding the complement component C4 and FCGR2C has been associated with SLE 13 and idiopathic thrombocytopenic purpura, 14 respectively.…”

Section: Introductionmentioning

confidence: 99%

Association of copy number variation in the FCGR3B gene with risk of autoimmune diseases

Mamtani

Anaya

et al. 2009

Genes Immun

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Copy number variation of the activating FCGR2C gene predisposes to idiopathic thrombocytopenic purpura

Cited by 180 publications

References 46 publications

Influence of congenital human cytomegalovirus infection and the NKG2C genotype on NK‐cell subset distribution in children

Influence of congenital human cytomegalovirus infection and the NKG2C genotype on NK‐cell subset distribution in children

Evidence that deletion at FCGR3B is a risk factor for systemic sclerosis

Association of copy number variation in the FCGR3B gene with risk of autoimmune diseases

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