Characterization of Infants with Idiopathic Transient and Persistent T Cell Lymphopenia Identified by Newborn Screening—a Single-Center Experience in New York State

Jongco, Artemio M.; Sporter, Robert; Hon, Elise; Elshaigi, Omer; Zhang, Shouling; Daian, Foysal; Bae, Emily; Innamorato, Amanda; Capo, Catherine; Navetta-Modrov, Brianne; Rosenthal, David W.; Bonagura, V.R.

doi:10.1007/s10875-020-00957-6

Cited by 10 publications

(5 citation statements)

References 50 publications

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“…Here we establish that blood levels of TRECs are a robust and quantifiable biomarker for cumulative stress exposure and its physiological consequences. TRECs are an established proxy for thymic output, which is reduced following thymic involution and is reflected by decreases in new thymic emigrants (e.g., naive T-cells) [ 81 , 82 ]. Thymic involution is known to occur in response to physical and psychosocial stress as well as in the presence of and in conjunction with elevated endogenous or exogenous glucocorticoids [ 76 – 78 , 83 ].…”

Section: Discussionmentioning

confidence: 99%

Blood levels of T-Cell Receptor Excision Circles (TRECs) provide an index of exposure to traumatic stress in mice and humans

et al. 2022

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Exposure to stress triggers biological changes throughout the body. Accumulating evidence indicates that alterations in immune system function are associated with the development of stress-associated illnesses such as major depressive disorder and post-traumatic stress disorder, increasing interest in identifying immune markers that provide insight into mental health. Recombination events during T-cell receptor rearrangement and T-cell maturation in the thymus produce circular DNA fragments called T-cell receptor excision circles (TRECs) that can be utilized as indicators of thymic function and numbers of newly emigrating T-cells. Given data suggesting that stress affects thymus function, we examined whether blood levels of TRECs might serve as a quantitative peripheral index of cumulative stress exposure and its physiological correlates. We hypothesized that chronic stress exposure would compromise thymus function and produce corresponding decreases in levels of TRECs. In male mice, exposure to chronic social defeat stress (CSDS) produced thymic involution, adrenal hypertrophy, and decreased levels of TRECs in blood. Extending these studies to humans revealed robust inverse correlations between levels of circulating TRECs and childhood emotional and physical abuse. Cell-type specific analyses also revealed associations between TREC levels and blood cell composition, as well as cell-type specific methylation changes in CD4T + and CD8T + cells. Additionally, TREC levels correlated with epigenetic age acceleration, a common biomarker of stress exposure. Our findings demonstrate alignment between findings in mice and humans and suggest that blood-borne TRECs are a translationally-relevant biomarker that correlates with, and provides insight into, the cumulative physiological and immune-related impacts of stress exposure in mammals.

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Section: Discussionmentioning

confidence: 99%

Blood levels of T-Cell Receptor Excision Circles (TRECs) provide an index of exposure to traumatic stress in mice and humans

et al. 2022

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“…Cases without a clear secondary cause, birth defect, or syndrome were classified as idiopathic. TCL which resolved within a year was considered transient, while those that lasted more than a year were considered persistent ( 28 ). Figure 2 outlines the immunological and genetic investigations performed in a step-wise manner for all positive cases.…”

Section: Methodsmentioning

confidence: 99%

Implementation of Universal Newborn Screening for Severe Combined Immunodeficiency in Singapore While Continuing Routine Bacille-Calmette-Guerin Vaccination Given at Birth

et al. 2022

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IntroductionSevere Combined Immunodeficiency (SCID) is generally fatal if untreated; it predisposes to severe infections, including disseminated Bacille-Calmette-Guerin (BCG) disease from BCG vaccination at birth. However, delaying BCG vaccination can be detrimental to the population in tuberculosis-endemic regions. Early diagnosis of SCID through newborn screening followed by pre-emptive treatment with anti-mycobacterial therapy may be an alternative strategy to delaying routine BCG vaccination. We report the results of the first year of newborn SCID screening in Singapore while continuing routine BCG vaccination at birth.MethodNewborn screening using a T-cell receptor excision circle (TREC) assay was performed in dried blood spots received between 10 October 2019 to 9 October 2020 using the Enlite Neonatal TREC kit. Patients with low TREC had lymphocyte subset analysis and full blood count performed to determine the severity of lymphopenia and likelihood of SCID to guide further management.ResultsOf the 35888 newborns screened in 1 year, no SCID cases were detected, while 13 cases of non-SCID T-cell lymphopenia (TCL) were picked up. Using a threshold for normal TREC to be >18 copies/μL, the retest rate was 0.1% and referral rate to immunologist was 0.04%. Initial low TREC correlated with low absolute lymphocyte counts (ALC), and subsequent normal ALC corresponded with increases in TREC, thus patients with normal first CD3+ T cell counts were considered to have transient idiopathic TCL instead of false positive results. 7/13 (54%) had secondary TCL (from sepsis, Trisomy 21 with hydrops and stoma losses or chylothorax, extreme prematurity, or partial DiGeorge Syndrome) and 6/13 (46%) had idiopathic TCL. No cases of SCID were diagnosed clinically in Singapore during this period and for 10 months after, indicating that no cases were missed by the screening program. 8/9 (89%) of term infants with abnormal TREC results received BCG vaccination within the first 6 days of life when TREC and ALC were low. No patients developed BCG complications after a median follow-up of 17 months.ConclusionNewborn screening for SCID can be implemented while continuing routine BCG vaccination at birth. Patients with transient TCL and no underlying primary immunodeficiency are able to tolerate BCG vaccination.

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“…A type of blood formulation called DBS has been used for newborn screening. The application of DBS for quantification includes amino acids and acylcarnitines [ 53 ], LSD enzymes [ 52 , 54 , 56 ], T cell receptor excision circle (TREC), and survival motor neuron (SMN) [ 57 , 58 ]. As the target biomarker (metabolites, enzyme activity, genome, etc.)…”

Section: Diagnosis and Screeningmentioning

confidence: 99%

Lysosomal Acid Lipase Deficiency: Genetics, Screening, and Preclinical Study

Mashima

Takada

2022

IJMS

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Lysosomal acid lipase (LAL) is a lysosomal enzyme essential for the degradation of cholesteryl esters through the endocytic pathway. Deficiency of the LAL enzyme encoded by the LIPA gene leads to LAL deficiency (LAL-D) (OMIM 278000), one of the lysosomal storage disorders involving 50–60 genes. Among the two disease subtypes, the severe disease subtype of LAL-D is known as Wolman disease, with typical manifestations involving hepatomegaly, splenomegaly, vomiting, diarrhea, and hematopoietic abnormalities, such as anemia. In contrast, the mild disease subtype of this disorder is known as cholesteryl ester storage disease, with hypercholesterolemia, hypertriglyceridemia, and high-density lipoprotein disappearance. The prevalence of LAL-D is rare, but several treatment options, including enzyme replacement therapy, are available. Accordingly, a number of screening methodologies have been developed for this disorder. This review summarizes the current discussion on LAL-D, covering genetics, screening, and the tertiary structure of human LAL enzyme and preclinical study for the future development of a novel therapy.

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Characterization of Infants with Idiopathic Transient and Persistent T Cell Lymphopenia Identified by Newborn Screening—a Single-Center Experience in New York State

Cited by 10 publications

References 50 publications

Blood levels of T-Cell Receptor Excision Circles (TRECs) provide an index of exposure to traumatic stress in mice and humans

Blood levels of T-Cell Receptor Excision Circles (TRECs) provide an index of exposure to traumatic stress in mice and humans

Implementation of Universal Newborn Screening for Severe Combined Immunodeficiency in Singapore While Continuing Routine Bacille-Calmette-Guerin Vaccination Given at Birth

Lysosomal Acid Lipase Deficiency: Genetics, Screening, and Preclinical Study

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