Immunodeficiency in Bloom’s Syndrome

Bloom’s syndrome (BS) is an autosomal recessive disease, caused by mutations in the BLM gene. This gene codes for BLM protein, which is a helicase involved in DNA repair. DNA repair is especially important for the development and maturation of the T and B cells. Since BLM is involved in DNA repair, we aimed to study if BLM deficiency affects T and B cell development and especially somatic hypermutation (SHM) and class switch recombination (CSR) processes. Clinical data of six BS patients was collected, and immunoglobulin serum levels were measured at different time points. In addition, we performed immune phenotyping of the B and T cells and analyzed the SHM and CSR in detail by analyzing IGHA and IGHG transcripts using next-generation sequencing. The serum immunoglobulin levels were relatively low, and patients had an increased number of infections. The absolute number of T, B, and NK cells were low but still in the normal range. Remarkably, all BS patients studied had a high percentage (20–80%) of CD4+ and CD8+ effector memory T cells. The process of SHM seems normal; however, the Ig subclass distribution was not normal, since the BS patients had more IGHG1 and IGHG3 transcripts. In conclusion, BS patients have low number of lymphocytes, but the immunodeficiency seems relatively mild since they have no severe or opportunistic infections. Most changes in the B cell development were seen in the CSR process; however, further studies are necessary to elucidate the exact role of BLM in CSR

Ataxia Talangiectasia and Bloom Syndrome : Medical and ethical dilemmas in two DNA repair disorders

Contains fulltext : 230643.pdf (Publisher’s version ) (Open Access)Radboud University, 05 maart 2021Promotor : Willemsen, M.A.A.P. Co-promotores : Weemaes, C.M.R., Burg, M. van der229 p

Regulatory T Cells in Development and Prediction of Necrotizing Enterocolitis in Preterm Neonates: A Scoping Review

Necrotizing enterocolitis (NEC) is a leading cause of mortality in premature infants. However, the pathophysiology and influence of regulatory T cells (Tregs) have not been sufficiently elucidated. We performed a scoping review to investigate current knowledge on the influence of Tregs in NEC, and to investigate the predictive value of Treg number in NEC development. Pubmed, Embase, Prospero and Cochrane Library were searched during December 2020. Primary research articles discussing Tregs and NEC development written in English were selected. Two reviewers screened title and abstract for relevance, after which full-text screening was performed. A total of 20 articles were selected-13 of the articles discussed studies performed in animal models, while 8 used human neonate data. One study discussed both animal and human data. It was shown that after NEC diagnosis or induction, Treg levels were decreased while Th17 levels were increased. No studies were found which investigated the predictive value of Treg number in NEC development. A reduced Treg level is found in animals and neonates with NEC. The question remains whether this effect is a factor on the causal pathway of NEC development or a bystander effect. Future research focusing on the pathophysiological timeline of NEC and the involvement of Tregs is required for better understanding of this disease.Developmen

Early diagnosis of ataxia telangiectasia in the neonatal phase: a parents' perspective.

Contains fulltext : 218859.pdf (Publisher’s version ) (Open Access)Ataxia telangiectasia (A-T) is a severe neurodegenerative disorder with variable immunodeficiency. Together with the Dutch A-T community, we investigated the opinion of A-T parents on an early A-T diagnosis in the asymptomatic phase of the disease. During an annual national meeting for A-T patients and families, the topic of an early A-T diagnosis was discussed in relation to the recent introduction of neonatal screening for severe combined immunodeficiency (SCID) in the Netherlands. Based on the discussion, individual arguments were identified and processed into a questionnaire, which was sent out to 64 A-T parents (32 families). Arguments included were insecurity to diagnosis, possible medical advantages, appropriate genetic counseling and family planning, loss of "golden" year(s), and early cancer screening for parents. The response rate was 55% (n = 35 parents). Twenty-six (74%) parents felt that the advantages of an early diagnosis outweighed the disadvantages, five parents thought that the disadvantages would outweigh the advantages (14%), and four parents did not indicate a preference.Conclusion: The majority of parents of a child with A-T would have preferred an early diagnosis during the asymptomatic phase of the disease, because the uncertainty during the diagnostic process had had a major impact on their lives. In addition, the knowledge of being carriers of an ATM gene mutation influenced decisions about family planning. Parents who opposed against an early diagnosis emphasized the joy of having a seemingly healthy child until diagnosis.What is Known:* Ataxia telangiectasia (A-T) is a devastating DNA repair disorder with a huge impact on quality of life of patients and their parents.* Patients with A-T may incidentally be identified at birth as the consequence of neonatal screening for severe combined immunodeficiency (SCID).What is New:* The majority of Dutch parents of A-T patients (74%) would have preferred an early diagnosis of their child in the asymptomatic phase of the disease.* Major arguments for an early A-T diagnosis were (1) the experienced insecurity in diagnostic trajectories and its impact on families and (2) the knowledge of being ATM mutation carriers when deciding about family planning. An argument against an early diagnosis is losing the joy of having a seemingly healthy child until diagnosis.01 februari 202

Telangiectasias: Small lesions referring to serious disorders

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Epigenetic immune cell counting to analyze potential biomarkers in preterm infants: a proof of principle in necrotizing enterocolitis

Epigenetic immune cell counting is a DNA (de)methylation-based technique which can be used to quantify lymphocyte subsets on dried blood spots (DBS). The foregoing techniques allow for a retrospective investigation of immune cell profiles in newborns. In this study, we used this technique for determining lymphocyte subcounts as a potential biomarker for necrotizing enterocolitis (NEC). We investigated whether this technique can be implemented in the field of neonatology, by testing whether regulatory T cell (Treg) levels are pre-existently low in preterms with NEC. Newborn screening (NBS) cards from 32 preterms with NEC and 32 age- and weight-matched preterm controls, and 60 healthy term newborns, were analyzed. Relative and absolute cell counts were determined for CD3+, CD4+, CD8+, Th17, and Treg T cells. For both relative and absolute cell counts of CD3+, CD4+, CD8+, and Th17 T cells, significant differences were found between healthy term controls and both preterm groups, but not between preterm groups. For Tregs, no significant differences were found in either relative or absolute counts between any of the newborn groups. This study demonstrates the principle of epigenetic immune cell counting to analyze lymphocyte subsets in preterm neonates.Transplantation and immunomodulatio

Dilemma of Reporting Incidental Findings in Newborn Screening Programs for SCID: Parents' Perspective on Ataxia Telangiectasia

Background: Ataxia Telangiectasia (A-T) is a severe DNA repair disorder that leads to a broad range of symptoms including neurodegeneration and a variable immunodeficiency. A-T is one of the incidental findings that accompanies newborn screening (NBS) for severe combined immunodeficiency (SCID), leading to an early diagnosis of A-T at birth in a pre-symptomatic stage. While some countries embrace all incidental findings, the current policy in the Netherlands on reporting untreatable incidental findings is more conservative. We present parents' perspectives and considerations on the various advantages vs. disadvantages of early and late diagnosis of A-T. Methods: A questionnaire was developed and sent to 4,000 parents of healthy newborns who participated in the Dutch SONNET-study (implementation pilot for newborn screening for SCID). The questionnaire consisted of open-ended and scale questions on advantages and disadvantages of early and late diagnosis of A-T. To address potential bias, demographic characteristics of the study sample were compared to a reference population. Results: A total of 664 of 4,000 parents sent back the questionnaire (response rate 16.6%). The vast majority of parents (81.9%) favored early diagnosis of A-T over late diagnosis. Main arguments were to avoid a long period of uncertainty prior to diagnosis and to ensure the most optimal clinical care and guidance from the onset of symptoms. Parents who favored late diagnosis of A-T stated that early diagnosis would not lead to improved quality of life and preferred to enjoy the asymptomatic "golden years" with their child. The majority of parents (81.1%) stated that they would participate in newborn screening for A-T if a test was available. Conclusions: Reporting untreatable incidental findings remains a disputed topic worldwide. Although the current policy in the Netherlands is not to report untreatable incidental findings, unless the health advantage is clear, the majority of parents of healthy newborns are in favor of an early A-T diagnosis in the pre-symptomatic phase of the disorder. Our results as well as other studies that showed support for the screening of untreatable disorders may serve as valuable tools to inform policymakers in their considerations about NBS for untreatable disorders.Transplantation and immunomodulatio

Telangiectasias in Ataxia Telangiectasia: Clinical significance, role of ATM deficiency and potential pathophysiological mechanisms

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