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Article ; Online: Assessing DNA Damage Responses Using B Lymphocyte Cultures.

Johnston, Rachel / White, Lynn S / Bednarski, Jeffrey J

Methods in molecular biology (Clifton, N.J.)

2022 Volume 2444, Page(s) 69–80

Abstract: Development of B cells requires the programmed generation and repair of double-stranded DNA breaks in antigen receptor genes. Investigation of the cellular responses to these DNA breaks has established important insights into B cell development and, more ...

Abstract	Development of B cells requires the programmed generation and repair of double-stranded DNA breaks in antigen receptor genes. Investigation of the cellular responses to these DNA breaks has established important insights into B cell development and, more broadly, has provided fundamental advances into the molecular mechanisms of DNA damage response pathways. Abelson transformed pre-B cell lines and primary pre-B cell cultures are malleable experimental systems with diverse applications for studying DNA damage responses. This chapter describes methods for generating these cellular systems, inducing and quantifying DSBs, and assessing DNA damage programs.
MeSH term(s)	B-Lymphocytes ; DNA Breaks, Double-Stranded ; DNA Damage ; Humans ; Lymphoma, B-Cell ; Receptors, Antigen
Chemical Substances	Receptors, Antigen
Language	English
Publishing date	2022-03-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-2063-2_5
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Article ; Online: Immune Reconstitution in Pediatric Patients Following Hematopoietic Cell Transplant for Non-malignant Disorders.

Bhatt, Sima T / Bednarski, Jeffrey J

Frontiers in immunology

2020 Volume 11, Page(s) 1988

Abstract: Allogeneic hematopoietic cell transplant (HCT) is curative for pediatric patients with non-malignant hematopoietic disorders, including hemoglobinopathies, bone marrow failure syndromes, and primary immunodeficiencies. Early establishment of donor- ... ...

Abstract	Allogeneic hematopoietic cell transplant (HCT) is curative for pediatric patients with non-malignant hematopoietic disorders, including hemoglobinopathies, bone marrow failure syndromes, and primary immunodeficiencies. Early establishment of donor-derived innate and adaptive immunity following HCT is associated with improved overall survival, lower risk of infections and decreased incidence of graft failure. Immune reconstitution (IR) is impacted by numerous clinical variables including primary disease, donor characteristics, conditioning regimen, and graft versus host disease (GVHD). Recent advancements in HCT have been directed at reducing toxicity of conditioning therapy, expanding donor availability through use of alternative donor sources, and addressing morbidity from GVHD with novel graft manipulation. These novel transplant approaches impact the kinetics of immune recovery, which influence post-transplant outcomes. Here we review immune reconstitution in pediatric patients undergoing HCT for non-malignant disorders. We explore the transplant-associated factors that influence immunologic recovery and the disease-specific associations between IR and transplant outcomes.
MeSH term(s)	Age Factors ; Child ; Graft vs Host Disease/etiology ; Hematopoietic Stem Cell Transplantation/adverse effects ; Hematopoietic Stem Cell Transplantation/methods ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/metabolism ; Hemoglobinopathies/etiology ; Hemoglobinopathies/therapy ; Humans ; Immune Reconstitution ; Primary Immunodeficiency Diseases/etiology ; Primary Immunodeficiency Diseases/therapy ; Risk Factors ; Tissue Donors ; Transplantation Conditioning/adverse effects ; Transplantation Conditioning/methods ; Transplantation, Homologous ; Treatment Outcome
Language	English
Publishing date	2020-08-18
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2020.01988
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Article ; Online: Cutting Edge: The Tetraspanin CD53 Promotes CXCR4 Signaling and Bone Marrow Homing in B Cells.

Chakraborty, Mousumi / Greenberg, Zev J / Dong, Qian / Roundy, Nate / Bednarski, Jeffrey J / Paracatu, Luana Chiquetto / Duncavage, Eric / Li, Weikai / Schuettpelz, Laura G

Journal of immunology (Baltimore, Md. : 1950)

2024 Volume 212, Issue 7, Page(s) 1075–1080

Abstract: B cell trafficking involves the coordinated activity of multiple adhesive and cytokine-receptor interactions, and the players in this process are not fully understood. In this study, we identified the tetraspanin CD53 as a critical regulator of both ... ...

Abstract	B cell trafficking involves the coordinated activity of multiple adhesive and cytokine-receptor interactions, and the players in this process are not fully understood. In this study, we identified the tetraspanin CD53 as a critical regulator of both normal and malignant B cell trafficking. CXCL12 is a key chemokine in B cell homing to the bone marrow and secondary lymphoid organs, and both normal and malignant B cells from Cd53-/- mice have reduced migration toward CXCL12 in vitro, as well as impaired marrow homing in vivo. Using proximity ligation studies, we identified the CXCL12 receptor, CXCR4, as a novel, to our knowledge, CD53 binding partner. This interaction promotes receptor function, because Cd53-/- B cells display reduced signaling and internalization of CXCR4 in response to CXCL12. Together, our data suggest that CD53 interacts with CXCR4 on both normal and malignant B cells to promote CXCL12 signaling, receptor internalization, and marrow homing.
MeSH term(s)	Animals ; Mice ; Bone Marrow/metabolism ; B-Lymphocytes/metabolism ; Chemokine CXCL12/metabolism ; Signal Transduction ; Tetraspanins/metabolism ; Carrier Proteins/metabolism ; Receptors, CXCR4/metabolism ; Cell Movement/physiology ; Bone Marrow Cells/metabolism
Chemical Substances	Chemokine CXCL12 ; Tetraspanins ; Carrier Proteins ; Receptors, CXCR4
Language	English
Publishing date	2024-02-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.2300336
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Article ; Online: At the intersection of DNA damage and immune responses.

Bednarski, Jeffrey J / Sleckman, Barry P

Nature reviews. Immunology

2019 Volume 19, Issue 4, Page(s) 231–242

Abstract: DNA damage occurs on exposure to genotoxic agents and during physiological DNA transactions. DNA double-strand breaks (DSBs) are particularly dangerous lesions that activate DNA damage response (DDR) kinases, leading to initiation of a canonical DDR ( ... ...

Abstract	DNA damage occurs on exposure to genotoxic agents and during physiological DNA transactions. DNA double-strand breaks (DSBs) are particularly dangerous lesions that activate DNA damage response (DDR) kinases, leading to initiation of a canonical DDR (cDDR). This response includes activation of cell cycle checkpoints and engagement of pathways that repair the DNA DSBs to maintain genomic integrity. In adaptive immune cells, programmed DNA DSBs are generated at precise genomic locations during the assembly and diversification of lymphocyte antigen receptor genes. In innate immune cells, the production of genotoxic agents, such as reactive nitrogen molecules, in response to pathogens can also cause genomic DNA DSBs. These DSBs in adaptive and innate immune cells activate the cDDR. However, recent studies have demonstrated that they also activate non-canonical DDRs (ncDDRs) that regulate cell type-specific processes that are important for innate and adaptive immune responses. Here, we review these ncDDRs and discuss how they integrate with other signals during immune system development and function.
MeSH term(s)	Adaptive Immunity/immunology ; Animals ; Cell Cycle Checkpoints/immunology ; DNA/immunology ; DNA Breaks, Double-Stranded ; DNA Damage/immunology ; Humans ; Immunity, Innate/immunology
Chemical Substances	DNA (9007-49-2)
Language	English
Publishing date	2019-02-18
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2062776-2
ISSN	1474-1741 ; 1474-1733
ISSN (online)	1474-1741
ISSN	1474-1733
DOI	10.1038/s41577-019-0135-6
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Article ; Online: Pediatric Necrobiotic Xanthogranuloma as a Novel Phenotype of IKAROS Gain of Function.

Guess, Rachel / Harocopos, George / Bednarski, Jeffrey J / Hassmann, Lynn M / Bigley, Tarin M

Journal of clinical immunology

2023 Volume 44, Issue 1, Page(s) 19

MeSH term(s)	Child ; Humans ; Gain of Function Mutation ; Necrobiotic Xanthogranuloma ; Paraproteinemias
Chemical Substances	IKZF1 protein, human
Language	English
Publishing date	2023-12-22
Publishing country	Netherlands
Document type	Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	779361-3
ISSN	1573-2592 ; 0271-9142
ISSN (online)	1573-2592
ISSN	0271-9142
DOI	10.1007/s10875-023-01622-4
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Article ; Online: DNA damage signals inhibit neutrophil function.

Bednarski, Jeffrey J

Blood

2015 Volume 126, Issue 26, Page(s) 2773–2774

MeSH term(s)	Apoptosis/physiology ; Ataxia Telangiectasia Mutated Proteins/metabolism ; Enzyme Activation/physiology ; Humans ; Neutrophils/metabolism ; Respiratory Burst/physiology
Chemical Substances	Ataxia Telangiectasia Mutated Proteins (EC 2.7.11.1)
Language	English
Publishing date	2015-12-23
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2015-11-678672
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Article ; Online: Hematopoietic KIT D816Y mutation presenting as in utero aggressive systemic mastocytosis with response to midostaurin.

Voelker, Dayne / Bednarski, Jeffrey J / Nieman, Elizabeth / Carter, Melody C / Polk, Brooke

The journal of allergy and clinical immunology. In practice

2022 Volume 11, Issue 4, Page(s) 1323–1325.e1

MeSH term(s)	Humans ; Mastocytosis/drug therapy ; Mastocytosis/genetics ; Mastocytosis, Systemic/diagnosis ; Mastocytosis, Systemic/drug therapy ; Mastocytosis, Systemic/genetics ; Mutation/genetics ; Staurosporine/therapeutic use
Chemical Substances	midostaurin (ID912S5VON) ; Staurosporine (H88EPA0A3N) ; KIT protein, human (EC 2.7.10.1)
Language	English
Publishing date	2022-12-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Intramural
ZDB-ID	2843237-X
ISSN	2213-2201 ; 2213-2198
ISSN (online)	2213-2201
ISSN	2213-2198
DOI	10.1016/j.jaip.2022.12.016
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Article: Safety of Probiotics Among High-Risk Pediatric Hematopoietic Stem Cell Transplant Recipients.

Sadanand, Arhanti / Newland, Jason G / Bednarski, Jeffrey J

Infectious diseases and therapy

2019 Volume 8, Issue 2, Page(s) 301–306

Abstract: Introduction: Increased diversity of the intestinal microbiome has been significantly associated with lower mortality after hematopoietic stem cell transplant (HSCT). Probiotics, such as Lactobacillus species with defined probiotic potential, may have ... ...

Abstract	Introduction: Increased diversity of the intestinal microbiome has been significantly associated with lower mortality after hematopoietic stem cell transplant (HSCT). Probiotics, such as Lactobacillus species with defined probiotic potential, may have beneficial properties including restoration of commensal species to the intestinal tract, anti-microbial effects, and healing of the intestinal mucosa. However, the use of probiotics in immune-compromised patients raises concerns, specifically regarding the risk for possible Lactobacillus bacteremia. Risk of bacteremia is an even greater concern in HSCT patients with breakdown of mucosal barriers, specifically patients with Clostridium difficile infection (CDI) or gastrointestinal graft-versus-host disease (GVHD). Minimal data have been reported on the safety of probiotics in these high-risk HSCT populations. Methods: We performed a retrospective study of allogeneic HSCT recipients at our institution between 2011 and 2016, and identified 14 patients (median age 7 years) prescribed probiotics, 10 of whom received probiotics prior to day 100 after HSCT. Results: Eight of ten patients were diagnosed with acute GVHD, four of whom (40%) specifically had acute GVHD involving the gastrointestinal tract. Five patients (50%) on probiotics prior to day 100 were diagnosed with CDI (median onset at day 13 post-transplant). There were no cases of Lactobacillus bacteremia, including in patients with GVHD or CDI. Conclusion: This small case series supports the safe use of probiotics in a high-risk population of pediatric HSCT patients with compromised intestinal mucosal integrity. Further studies are needed to determine if probiotics have benefit in preventing and treating gastrointestinal GVHD or CDI.
Language	English
Publishing date	2019-04-15
Publishing country	New Zealand
Document type	Journal Article
ZDB-ID	2701611-0
ISSN	2193-6382 ; 2193-8229
ISSN (online)	2193-6382
ISSN	2193-8229
DOI	10.1007/s40121-019-0244-3
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Article ; Online: A Novel CYBB Variant Causing X-Linked Chronic Granulomatous Disease in a Patient with Empyema.

Kitcharoensakkul, Maleewan / Song, Zhimin / Bednarski, Jeffrey J / Dinauer, Mary

Journal of clinical immunology

2020 Volume 41, Issue 1, Page(s) 266–269

MeSH term(s)	Biomarkers ; Child, Preschool ; Empyema/complications ; Empyema/diagnosis ; Enzyme Activation ; Genetic Association Studies ; Genetic Predisposition to Disease ; Granulomatous Disease, Chronic/complications ; Granulomatous Disease, Chronic/diagnosis ; Granulomatous Disease, Chronic/genetics ; Granulomatous Disease, Chronic/therapy ; Humans ; Male ; Mutation ; NADPH Oxidase 2/genetics ; NADPH Oxidases/genetics ; NADPH Oxidases/metabolism ; Symptom Assessment ; Tomography, X-Ray Computed
Chemical Substances	Biomarkers ; CYBB protein, human (EC 1.6.3.-) ; NADPH Oxidase 2 (EC 1.6.3.-) ; NADPH Oxidases (EC 1.6.3.-)
Language	English
Publishing date	2020-10-22
Publishing country	Netherlands
Document type	Case Reports ; Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	779361-3
ISSN	1573-2592 ; 0271-9142
ISSN (online)	1573-2592
ISSN	0271-9142
DOI	10.1007/s10875-020-00897-1
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Article ; Online: Nuclease-independent functions of RAG1 direct distinct DNA damage responses in B cells.

Johnston, Rachel / Mathias, Brendan / Crowley, Stephanie J / Schmidt, Haley A / White, Lynn S / Mosammaparast, Nima / Green, Abby M / Bednarski, Jeffrey J

EMBO reports

2022 Volume 24, Issue 1, Page(s) e55429

Abstract: Developing B cells generate DNA double-stranded breaks (DSBs) to assemble immunoglobulin receptor (Ig) genes necessary for the expression of a mature B cell receptor. These physiologic DSBs are made by the RAG endonuclease, which is comprised of the RAG1 ...

Abstract	Developing B cells generate DNA double-stranded breaks (DSBs) to assemble immunoglobulin receptor (Ig) genes necessary for the expression of a mature B cell receptor. These physiologic DSBs are made by the RAG endonuclease, which is comprised of the RAG1 and RAG2 proteins. In pre-B cells, RAG-mediated DSBs activate the ATM kinase to coordinate canonical and non-canonical DNA damage responses (DDR) that trigger DSB repair and B cell developmental signals, respectively. Whether this broad cellular response is distinctive to RAG DSBs is poorly understood. To delineate the factors that direct DDR signaling in B cells, we express a tetracycline-inducible Cas9 nuclease in Rag1-deficient pre-B cells. Both RAG- and Cas9-mediated DSBs at Ig genes activate canonical DDR. In contrast, RAG DSBs, but not Cas9 DSBs, induce the non-canonical DDR-dependent developmental program. This unique response to RAG DSBs is, in part, regulated by non-core regions of RAG1. Thus, B cells trigger distinct cellular responses to RAG DSBs through unique properties of the RAG endonuclease that promotes activation of B cell developmental programs.
MeSH term(s)	Homeodomain Proteins/genetics ; Homeodomain Proteins/metabolism ; DNA Breaks, Double-Stranded ; B-Lymphocytes/metabolism ; Signal Transduction ; Precursor Cells, B-Lymphoid ; DNA Damage
Chemical Substances	Homeodomain Proteins
Language	English
Publishing date	2022-11-16
Publishing country	England
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2020896-0
ISSN	1469-3178 ; 1469-221X
ISSN (online)	1469-3178
ISSN	1469-221X
DOI	10.15252/embr.202255429
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