The immunological epigenetic landscape of the human life trajectory

Adaptive immunity changes over an individual's lifetime, maturing by adulthood and diminishing with old age. Epigenetic mechanisms involving DNA and histone methylation form the molecular basis of immunological memory during lymphocyte development. Monocytes alter their function to convey immune tolerance, yet the epigenetic influences at play remain to be fully understood in the context of lifespan. This study of a healthy genetically homogenous cohort of children, adults and seniors sought to decipher the epigenetic dynamics in B-lymphocytes and monocytes. Variable global cytosine methylation within retro-transposable LINE-1 repeats was noted in monocytes compared to B-lymphocytes across age groups. The expression of the human leukocyte antigen (HLA)-DQ alpha chain gene HLA-DQA1*01 revealed significantly reduced levels in monocytes in all ages relative to B-lymphocytes, as well as between lifespan groups. High melting point analysis and bisulfite sequencing of the HLA-DQA1*01 promoter in monocytes highlighted variable cytosine methylation in children and seniors but greater stability at this locus in adults. Further epigenetic evaluation revealed higher histone lysine 27 trimethylation in monocytes from this adult group. Chromatin immunoprecipitation and RNA pulldown demonstrated association with a novel lncRNA TINA with structurally conserved similarities to the previously recognized epigenetic modifier PARTICLE. Seeking to interpret the epigenetic immunological landscape across three representative age groups, this study focused on HLA-DQA1*01 to expose cytosine and histone methylation alterations and their association with the non-coding transcriptome. Such insights unveil previously unknown complex epigenetic layers, orchestrating the strength and weakening of adaptive immunity with the progression of life

Prenatal origin of childhood AML occurs less frequently than in childhood ALL

Background While there is enough convincing evidence in childhood acute lymphoblastic leukemia (ALL), the data on the pre-natal origin in childhood acute myeloid leukemia (AML) are less comprehensive. Our study aimed to screen Guthrie cards (neonatal blood spots) of non-infant childhood AML and ALL patients for the presence of their respective leukemic markers. Methods We analysed Guthrie cards of 12 ALL patients aged 2–6 years using immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements (n = 15) and/or intronic breakpoints of TEL/AML1 fusion gene (n = 3). In AML patients (n = 13, age 1–14 years) PML/RARalpha (n = 4), CBFbeta/MYH11 (n = 3), AML1/ETO (n = 2), MLL/AF6 (n = 1), MLL/AF9 (n = 1) and MLL/AF10 (n = 1) fusion genes and/or internal tandem duplication of FLT3 gene (FLT3/ITD) (n = 2) were used as clonotypic markers. Assay sensitivity determined using serial dilutions of patient DNA into the DNA of a healthy donor allowed us to detect the pre-leukemic clone in Guthrie card providing 1–3 positive cells were present in the neonatal blood spot. Results In 3 patients with ALL (25%) we reproducibly detected their leukemic markers (Ig/TCR n = 2; TEL/AML1 n = 1) in the Guthrie card. We did not find patient-specific molecular markers in any patient with AML. Conclusion In the largest cohort examined so far we used identical approach for the backtracking of non-infant childhood ALL and AML. Our data suggest that either the prenatal origin of AML is less frequent or the load of pre-leukemic cells is significantly lower at birth in AML compared to ALL cases

FERRY: access control and quota management service

Fermilab developed the Frontier Experiments RegistRY (FERRY) service that provides a centralized repository for access control and job management attributes such as batch and storage access policies, quotas, batch priorities and NIS attributes for cluster configuration. This paper describes the FERRY architecture, deployment and integration with services that consume the stored information. The Grid community has developed several access control management services over the last decade. Over time, services for Fermilab experiments have required the collection and management of more access control and quota attributes. At the same time, various services used for this purpose, namely VOMS-Admin, GUMS and VULCAN, are being abandoned by the community. FERRY has multiple goals: maintaining a central repository for currently scattered information related to users' attributes, providing a Restful API that allows uniform data retrieval by services, and providing a replacement service for all the abandoned grid services. FERRY is integrated with the ServiceNow (SNOW) ticketing service and uses it as its user interface. In addition to the standard workflows for request approval and task creation, SNOW invokes orchestration that automates access to FERRY API. Our expectation is that FERRY will drastically improve user experience as well as decrease effort required by service administrators

FERRY: access control and quota management service

Fermilab developed the Frontier Experiments RegistRY (FERRY) service that provides a centralized repository for access control and job management attributes such as batch and storage access policies, quotas, batch priorities and NIS attributes for cluster configuration. This paper describes the FERRY architecture, deployment and integration with services that consume the stored information. The Grid community has developed several access control management services over the last decade. Over time, services for Fermilab experiments have required the collection and management of more access control and quota attributes. At the same time, various services used for this purpose, namely VOMS-Admin, GUMS and VULCAN, are being abandoned by the community. FERRY has multiple goals: maintaining a central repository for currently scattered information related to users' attributes, providing a Restful API that allows uniform data retrieval by services, and providing a replacement service for all the abandoned grid services. FERRY is integrated with the ServiceNow (SNOW) ticketing service and uses it as its user interface. In addition to the standard workflows for request approval and task creation, SNOW invokes orchestration that automates access to FERRY API. Our expectation is that FERRY will drastically improve user experience as well as decrease effort required by service administrators

The TREC/KREC Assay for the Diagnosis and Monitoring of Patients with DiGeorge Syndrome

<div><p></p><p>DiGeorge syndrome (DGS) presents with a wide spectrum of thymic pathologies. Nationwide neonatal screening programs of lymphocyte production using T-cell recombination excision circles (TREC) have repeatedly identified patients with DGS. We tested what proportion of DGS patients could be identified at birth by combined TREC and kappa-deleting element recombination circle (KREC) screening. Furthermore, we followed TREC/KREC levels in peripheral blood (PB) to monitor postnatal changes in lymphocyte production.</p><p>Methods</p><p>TREC/KREC copies were assessed by quantitative PCR (qPCR) and were related to the albumin control gene in dry blood spots (DBSs) from control (n = 56), severe immunodeficiency syndrome (SCID, n = 10) and DGS (n = 13) newborns. PB was evaluated in DGS children (n = 32), in diagnostic samples from SCID babies (n = 5) and in 91 controls.</p><p>Results</p><p>All but one DGS patient had TREC levels in the normal range at birth, albeit quantitative TREC values were significantly lower in the DGS cohort. One patient had slightly reduced KREC at birth. Postnatal DGS samples revealed reduced TREC numbers in 5 of 32 (16%) patients, whereas KREC copy numbers were similar to controls. Both TREC and KREC levels showed a more pronounced decrease with age in DGS patients than in controls (p<0.0001 for both in a linear model). DGS patients had higher percentages of NK cells at the expense of T cells (p<0.0001). The patients with reduced TREC levels had repeated infections in infancy and developed allergy and/or autoimmunity, but they were not strikingly different from other patients. In 12 DGS patients with paired DBS and blood samples, the TREC/KREC levels were mostly stable or increased and showed similar kinetics in respective patients.</p><p>Conclusions</p><p>The combined TREC/KREC approach with correction via control gene identified 1 of 13 (8%) of DiGeorge syndrome patients at birth in our cohort. The majority of patients had TREC/KREC levels in the normal range.</p></div