Human phagocyte defect caused by a Rac2 mutation detected by means of neonatal screening for T-cell lymphopenia

Accetta, D.J.; Bonacci, Benedetta; Reddy, Sreelatha T.; Bengtson, Christine; Surfus, Jean E.; Harbeck, Ronald J.; Huttenlocher, Anna; Grossman, William; Routes, John M.; Verbsky, James

doi:10.1016/j.jaci.2010.10.013

Cited by 80 publications

(89 citation statements)

References 14 publications

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“…To address further the function of neutrophils, we used a transgenic line of larvae with a human dominant negative allele of Rac2 expressed specifically in neutrophils [Tg(mpx: mCherry-2A-Rac2D57N), referred to here as Rac2 D57N larvae]. Rac2 is a small Rho GTPase which is required for normal neutrophil function, and patients with the Rac2D57N mutation have impaired immune function resulting in severe recurrent infections (71). While neutrophils are present in the circulation of these transgenic larvae, their adhesion and migration are impaired, and the neutrophils also likely have deficits in intracellular killing (41,42,58).…”

Section: Resultsmentioning

confidence: 99%

A Zebrafish Model of Cryptococcal Infection Reveals Roles for Macrophages, Endothelial Cells, and Neutrophils in the Establishment and Control of Sustained Fungemia

et al. 2016

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Cryptococcal meningoencephalitis is a fungal infection that predominantly affects immunocompromised patients and is uniformly fatal if left untreated. Timely diagnosis is difficult, and screening or prophylactic measures have generally not been successful. Thus, we need a better understanding of early, asymptomatic pathogenesis. Inhaled cryptococci must survive the host immune response, escape the lung, and persist within the bloodstream in order to reach and invade the brain. Here we took advantage of the zebrafish larval infection model to assess the process of cryptococcal infection and disease development sequentially in a single host. Using yeast or spores as infecting particles, we discovered that both cell types survived and replicated intracellularly and that both ultimately established a sustained, low-level fungemia. We propose that the establishment and maintenance of this sustained fungemia is an important stage of disease progression that has been difficult to study in other model systems. Our data suggest that sustained fungemia resulted from a pattern of repeated escape from, and reuptake by, macrophages, but endothelial cells were also seen to play a role as a niche for cryptococcal survival. Circulating yeast collected preferentially in the brain vasculature and eventually invaded the central nervous system (CNS). As suggested previously in a mouse model, we show here that neutrophils can play a valuable role in limiting the sustained fungemia, which can lead to meningoencephalitis. This early stage of pathogenesis-a balanced interaction between cryptococcal cells, macrophages, endothelial cells, and neutrophils-could represent a window for timely detection and intervention strategies for cryptococcal meningoencephalitis. R ecent data from Uganda and Tanzania indicate that there are over 10,000 cases of HIV-related cryptococcosis per year in these countries alone (1, 2). Of those, roughly 5,000 to 8,000 (54 to 79%) are fatal. At a global scale, the survival rate is similarly poor, and over 600,000 deaths are attributed to Cryptococcus neoformans every year (3). The high mortality rate is in part due to difficulties in timely diagnosis; even in susceptible hosts, clinical signs of the initial pulmonary infection can be subtle or essentially absent (4). Studies in this population using serum cryptococcal antigen testing suggest that antigenemia (which may or may not represent actual fungemia) is a harbinger of meningoencephalitis but can precede it by weeks or more (5, 6). Once the infection has progressed to clinical meningoencephalitis, the prognosis is grim even with aggressive treatment. Beyond the HIV-infected population, a growing transplant and otherwise immunosuppressed population is also vulnerable, and even an immunocompetent host may be susceptible to infection and disease caused by the closely related species Cryptococcus gattii (7). An understanding of the events prior to fulminant disease is critical to better management of patients at risk for cryptococcal meningoencephalitis.While ...

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Section: Resultsmentioning

confidence: 99%

A Zebrafish Model of Cryptococcal Infection Reveals Roles for Macrophages, Endothelial Cells, and Neutrophils in the Establishment and Control of Sustained Fungemia

et al. 2016

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“…The first infant identified by means of NBS for SCID/sTCL who required HCT presented with multiple abscesses and was found to have a dominant negative mutation in the RAC2 gene, resulting in defects in both neutrophil and T-lymphocyte numbers. 10 One infant with SCID had adenosine deaminase deficiency. One infant with SCID exhibited deficiencies of T and B cells with normal NK cell numbers, although sequencing for mutations in recombination-activating gene (RAG) 1 and 2 or the DNA cross-link repair 1C gene (DCLRE1C) were negative.…”

Section: Results Of 3 Years Of Nbs In Wisconsinmentioning

confidence: 99%

“…The infant with a de novo mutation in the RAC2 gene had relatively normal T-cell counts and T-cell proliferative responses but had zero TRECs on initial testing and had a serious immune defect affecting neutrophils and T cells. 10 When infants are born with absent TRECs but with greater than 200/mm 3 naive T cells and no known molecular defect, it becomes an even more difficult diagnostic and ethical dilemma to confidently state that the infant has a form of TCL that requires HCT. In our cohort of 5 infants with sTCL, 2 infants had greater than 200/mm 3 T cells and no genetic defect (Table II).…”

Section: Pitfalls and Dilemmasmentioning

confidence: 99%

“…9 Results from the first year of screening in Wisconsin demonstrated that the TREC assay detects infants with profound T-cell lymphopenia (TCL) and led to the diagnosis and successful HCT of an infant with RAS-related C3 botulinum toxin substrate 2 RNaseP (RAC2) mutation. 10 With proof that the TREC assay could detect TCL in conjunction with compelling evidence that SCID met the conventional criteria for NBS, the Secretary's Advisory Committee on Heritable Disorders in Newborns and Children unanimously agreed that the TREC assay should be added to the uniform panel of tests recommended by the US government for NBS of infants in all states. This recommendation was approved by the Secretary of Health and Human Services, Kathleen Sibelius, in 2010.…”

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The Wisconsin approach to newborn screening for severe combined immunodeficiency

Verbsky

Thakar

Routes

2012

Journal of Allergy and Clinical Immunology

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“…Despite some disagreement about what disorders are classified as SCID as compared with 'combined immunodeficiency', at the time of this publication, four infants with severe T-cell Additionally, one infant was identified with immunodeficiency due to a de novo mutation in the RAC2 gene, the second reported case of this primary immunodeficiency [39]. The previously described case of a RAC2 muation resulted in immunodeficiency secondary to dysfunction of neutrophils [40].…”

Section: Introduction To Trec Screening and The Experience Of Implementmentioning

confidence: 96%

Screening newborns for primary T-cell immunodeficiencies: consensus and controversy

Pedersen

Verbsky

Routes

2011

Expert Review of Clinical Immunology

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Newborn screening for early identification of T-cell lymphopenia and severe combined immunodeficiency has recently been recommended as an addition to the newborn screening programs in all states. This article will review the evidence supporting the use of this newborn screening test, and will outline the barriers to nationwide implementation, which include issues specific to this test and controversies regarding newborn screening in general.

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Human phagocyte defect caused by a Rac2 mutation detected by means of neonatal screening for T-cell lymphopenia

Cited by 80 publications

References 14 publications

A Zebrafish Model of Cryptococcal Infection Reveals Roles for Macrophages, Endothelial Cells, and Neutrophils in the Establishment and Control of Sustained Fungemia

A Zebrafish Model of Cryptococcal Infection Reveals Roles for Macrophages, Endothelial Cells, and Neutrophils in the Establishment and Control of Sustained Fungemia

The Wisconsin approach to newborn screening for severe combined immunodeficiency

Screening newborns for primary T-cell immunodeficiencies: consensus and controversy

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