Signaling impairments in maternal T cells engrafted in an infant with a novel IL-2 receptor γ mutation

Khanolkar, Aaruni; Wilks, Jeffrey D.; Jennings, Lawrence J.; Davies, John Q.; Zollett, Joshua A.; Lott, Loren L.; Fullmer, Erin R.; Bensen, Nicolas; Carlson-Leuer, Katrin M.; Tse, William T.; Fuleihan, Ramsay

doi:10.1016/j.jaci.2015.02.012

Cited by 6 publications

(8 citation statements)

References 15 publications

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“…Therefore, we undertook a comprehensive survey of the immunomodulatory-mediator-induced signaling properties of leukemic blasts and mature B and T cells present in pediatric B-ALL diagnostic samples. As part of this effort, we evaluated the phosphorylation status of proximal signaling nodes that engage with the cognate receptors for the following cytokines: IL-7, IL-2, IL-4, IL-21, IFNγ and IL-10, as well as the phosphorylation of p65-NFκB following the engagement of the CD40 receptor ( Figure 2 a–g) [ 49 , 50 , 51 , 52 , 53 , 54 , 55 ]. The majority of responses were clearly divergent between the leukemic blasts and mature B cells.…”

Section: Resultsmentioning

confidence: 99%

“…Hematogones also expressed higher levels of IL-7Rα compared to their mature counterparts in non-leukemic specimens, but this level was significantly lower compared to leukemic blasts ( Figure 3 c). The common γ chain (CD132) is the signaling subunit shared by IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 [ 49 , 50 ]. In order to further resolve the disparate signaling profile observed in leukemic blasts and mature B cells associated with IL-7 treatment, we also examined the surface expression of CD132.…”

Section: Resultsmentioning

confidence: 99%

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Defining the Basal and Immunomodulatory Mediator-Induced Phosphoprotein Signature in Pediatric B Cell Acute Lymphoblastic Leukemia (B-ALL) Diagnostic Samples

Khanolkar,

Liu,

Simpson Schneider

2023

IJMS

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It is theorized that dysregulated immune responses to infectious insults contribute to the development of pediatric B-ALL. In this context, our understanding of the immunomodulatory-mediator-induced signaling responses of leukemic blasts in pediatric B-ALL diagnostic samples is rather limited. Hence, in this study, we defined the signaling landscape of leukemic blasts, as well as normal mature B cells and T cells residing in diagnostic samples from 63 pediatric B-ALL patients. These samples were interrogated with a range of immunomodulatory-mediators within 24 h of collection, and phosflow analyses of downstream proximal signaling nodes were performed. Our data reveal evidence of basal hyperphosphorylation across a broad swath of these signaling nodes in leukemic blasts in contrast to normal mature B cells and T cells in the same sample. We also detected similarities in the phosphoprotein signature between blasts and mature B cells in response to IFNγ and IL-2 treatment, but significant divergence in the phosphoprotein signature was observed between blasts and mature B cells in response to IL-4, IL-7, IL-10, IL-21 and CD40 ligand treatment. Our results demonstrate the existence of both symmetry and asymmetry in the phosphoprotein signature between leukemic and non-leukemic cells in pediatric B-ALL diagnostic samples.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Defining the Basal and Immunomodulatory Mediator-Induced Phosphoprotein Signature in Pediatric B Cell Acute Lymphoblastic Leukemia (B-ALL) Diagnostic Samples

Khanolkar,

Liu,

Simpson Schneider

2023

IJMS

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“…Notably, a variable frequency in different studies has been previously reported in IL-7Rα-deficient patients (7, 12). The engrafted T cells are usually oligoclonal memory/effector cells, which are non-functional based on in vitro studies (7, 12, 15). In line with this, on the circulating T cells, which are almost exclusively of maternal origin, the expression of IL7Rα showed a bimodal pattern.…”

Section: Discussionmentioning

confidence: 99%

Novel Compound Heterozygous Mutations in IL-7 Receptor α Gene in a 15-Month-Old Girl Presenting With Thrombocytopenia, Normal T Cell Count and Maternal Engraftment

et al. 2019

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Patients with severe combined immunodeficiency (SCID) exhibit T lymphopenia and profound impairments in cellular and humoral immunity. IL-7 receptor α (IL-7Rα) deficiency is a rare form of SCID that usually presents in the first months of life with severe and opportunistic infections, failure to thrive and high risk of mortality unless treated. Here, we reported an atypical and delayed onset of IL7Rα-SCID in a 15-month-old girl presenting with thrombocytopenia. Immunological investigations showed a normal lymphocyte count with isolated CD4-penia, absence of naïve T cells, marked hypergammaglobulinemia, and maternal T cell engraftment. Targeted next generation sequencing (NGS) revealed two novel compound heterozygous mutations in the IL-7Rα gene: c.160T>C (p.S54P) and c.245G>T (p.C82F). The atypical onset and the unusual immunological phenotype expressed by our patient highlights the diagnostic challenge in the field of primary immunodeficiencies (PID) and in particular in SCID patients where prompt diagnosis and therapy greatly affects survival.

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“…Integrating sequencing data with other technologies can also provide leads to discover the underlying mutation in undiagnosed diseases where sequencing is inconclusive [194,195]. Here, we provide examples from metabolomics [12,196], methyl profiling [197], proteomics [194], and immunology [198][199][200] that assisted in a patient's genetic diagnosis. The choice of assay is often driven by the patient's phenotype.…”

Section: Complementary Technologiesmentioning

confidence: 99%

A guide for the diagnosis of rare and undiagnosed disease: beyond the exome

2022

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Rare diseases affect 30 million people in the USA and more than 300–400 million worldwide, often causing chronic illness, disability, and premature death. Traditional diagnostic techniques rely heavily on heuristic approaches, coupling clinical experience from prior rare disease presentations with the medical literature. A large number of rare disease patients remain undiagnosed for years and many even die without an accurate diagnosis. In recent years, gene panels, microarrays, and exome sequencing have helped to identify the molecular cause of such rare and undiagnosed diseases. These technologies have allowed diagnoses for a sizable proportion (25–35%) of undiagnosed patients, often with actionable findings. However, a large proportion of these patients remain undiagnosed. In this review, we focus on technologies that can be adopted if exome sequencing is unrevealing. We discuss the benefits of sequencing the whole genome and the additional benefit that may be offered by long-read technology, pan-genome reference, transcriptomics, metabolomics, proteomics, and methyl profiling. We highlight computational methods to help identify regionally distant patients with similar phenotypes or similar genetic mutations. Finally, we describe approaches to automate and accelerate genomic analysis. The strategies discussed here are intended to serve as a guide for clinicians and researchers in the next steps when encountering patients with non-diagnostic exomes.

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Signaling impairments in maternal T cells engrafted in an infant with a novel IL-2 receptor γ mutation

Cited by 6 publications

References 15 publications

Defining the Basal and Immunomodulatory Mediator-Induced Phosphoprotein Signature in Pediatric B Cell Acute Lymphoblastic Leukemia (B-ALL) Diagnostic Samples

Defining the Basal and Immunomodulatory Mediator-Induced Phosphoprotein Signature in Pediatric B Cell Acute Lymphoblastic Leukemia (B-ALL) Diagnostic Samples

Novel Compound Heterozygous Mutations in IL-7 Receptor α Gene in a 15-Month-Old Girl Presenting With Thrombocytopenia, Normal T Cell Count and Maternal Engraftment

A guide for the diagnosis of rare and undiagnosed disease: beyond the exome

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