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Article ; Online: Noncanonical B Cells: Characteristics of Uncharacteristic B Cells.

Haas, Karen M

Journal of immunology (Baltimore, Md. : 1950)

2023 Volume 211, Issue 9, Page(s) 1257–1265

Abstract: B lymphocytes were originally described as a cell type uniquely capable of secreting Abs ... investigators made great strides in delineating steps in the conventional pathway that B cells follow to produce ... high-affinity Abs. These studies revealed generalized, or canonical, features of B cells that include ...

Abstract	B lymphocytes were originally described as a cell type uniquely capable of secreting Abs. The importance of T cell help in Ab production was revealed soon afterward. Following these seminal findings, investigators made great strides in delineating steps in the conventional pathway that B cells follow to produce high-affinity Abs. These studies revealed generalized, or canonical, features of B cells that include their developmental origin and paths to maturation, activation, and differentiation into Ab-producing and memory cells. However, along the way, examples of nonconventional B cell populations with unique origins, age-dependent development, tissue localization, and effector functions have been revealed. In this brief review, features of B-1a, B-1b, marginal zone, regulatory, killer, NK-like, age-associated, and atypical B cells are discussed. Emerging work on these noncanonical B cells and functions, along with the study of their significance for human health and disease, represents an exciting frontier in B cell biology.
MeSH term(s)	Humans ; B-Lymphocytes ; T-Lymphocytes/metabolism ; Lymphoid Tissue
Language	English
Publishing date	2023-10-16
Publishing country	United States
Document type	Review ; Journal Article ; Research Support, N.I.H., Extramural
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.2200944
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Article ; Online: Health Outcomes of Infants with Vitamin B

Mütze, Ulrike / Walter, Magdalena / Keller, Mareike / Gramer, Gwendolyn / Garbade, Sven F / Gleich, Florian / Haas, Dorothea / Posset, Roland / Grünert, Sarah C / Hennermann, Julia B / Thimm, Eva / Fang-Hoffmann, Junmin / Syrbe, Steffen / Okun, Jürgen G / Hoffmann, Georg F / Kölker, Stefan

The Journal of pediatrics

2021 Volume 235, Page(s) 42–48

Abstract: Objective: To evaluate the clinical outcomes at age 1.5 ± 0.5 years of infants with vitamin B ... B: Results: In 285 862 newborns screened between 2016 and 2019, the estimated birth prevalence ... of vitamin B: Conclusions: Neonatal vitamin B ...

Abstract	Objective: To evaluate the clinical outcomes at age 1.5 ± 0.5 years of infants with vitamin B Study design: Prospective multicenter observational study on health outcomes of 31 infants with vitamin B Results: In 285 862 newborns screened between 2016 and 2019, the estimated birth prevalence of vitamin B Conclusions: Neonatal vitamin B
MeSH term(s)	Adolescent ; Child, Preschool ; Female ; Humans ; Infant ; Infant, Newborn ; Neonatal Screening ; Outcome Assessment, Health Care ; Pregnancy ; Prospective Studies ; Vitamin B 12 ; Vitamin B 12 Deficiency/diagnosis ; Vitamin B 12 Deficiency/drug therapy ; Vitamin B 12 Deficiency/epidemiology ; Vitamins
Chemical Substances	Vitamins ; Vitamin B 12 (P6YC3EG204)
Language	English
Publishing date	2021-02-11
Publishing country	United States
Document type	Journal Article ; Comment
ZDB-ID	3102-1
ISSN	1097-6833 ; 0022-3476
ISSN (online)	1097-6833
ISSN	0022-3476
DOI	10.1016/j.jpeds.2021.02.009
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Article ; Online: Newly emerging type B insulin resistance (TBIR) during treatment with eculizumab for AQP4-IgG-positive neuromyelitis optica spectrum disorder (NMOSD): fatal outcome.

Doubrovinskaja, S / Korporal-Kuhnke, M / Jarius, S / Haas, J / Wildemann, B

Journal of neurology

2023 Volume 271, Issue 5, Page(s) 2866–2870

Abstract: ... insulin resistance (IR) in patients with NMOSD has been suggested. Type B IR (TBIR) is a rare autoimmune condition ...

Abstract	Background: Aquaporin-4 immunoglobulin G (AQP4-IgG) antibody-positive neuromyelitis optica spectrum disorders (NMOSD) are frequently associated with other autoimmune disorders, including systemic lupus erythematosus (SLE). Eculizumab (ECU) is a highly effective long-term treatment for NMOSD. However, ECU is known to increase significantly the risk of infection with encapsulated bacteria and sepsis. Recently, increased insulin resistance (IR) in patients with NMOSD has been suggested. Type B IR (TBIR) is a rare autoimmune condition often accompanying or preceding SLE. TBIR has not yet been reported in NMOSD. Objective: To report an ECU-treated patient with AQP4-IgG-positive NMOSD who developed fatal septic complications after the emergence of TBIR. Methods: Description of the clinical course over a period of 8 years. Results: A female patient was diagnosed with NMOSD at the age of 16 years. A variety of disease-modifying drugs failed to achieve sufficient disease control, resulting in severe tetraparesis. Treatment with ECU was started 6 years after NMOSD diagnosis and stabilized the disease. The patient developed TBIR 8 months after initiation of ECU therapy. Following high-dose intravenous methylprednisolone therapy for a clinical relapse and three further courses of ECU, the patient was admitted with severe pneumonia caused by the encapsulated bacterium Klebsiella pneumoniae and hypoglycemia. Despite multimodal therapy, the patient died from sepsis-related multiorgan failure 18 months after initiation of ECU. Conclusions: TBIR should be considered as differential diagnosis in patients with NMOSD presenting with disturbed glucose metabolism, irrespective of the presence of SLE. More real-world data are needed on the risk/benefit ratio of ECU treatment in patients who have co-existing autoimmune comorbidities that may compromise immune function. Strategies to mitigate the risk of serious infection in patients treated with ECU are discussed.
MeSH term(s)	Humans ; Neuromyelitis Optica/drug therapy ; Neuromyelitis Optica/immunology ; Female ; Antibodies, Monoclonal, Humanized/administration & dosage ; Antibodies, Monoclonal, Humanized/pharmacology ; Aquaporin 4/immunology ; Insulin Resistance/physiology ; Fatal Outcome ; Immunoglobulin G/blood ; Adolescent ; Autoantibodies/blood ; Complement Inactivating Agents/administration & dosage
Chemical Substances	Antibodies, Monoclonal, Humanized ; eculizumab (A3ULP0F556) ; Aquaporin 4 ; AQP4 protein, human ; Immunoglobulin G ; Autoantibodies ; Complement Inactivating Agents
Language	English
Publishing date	2023-11-14
Publishing country	Germany
Document type	Case Reports ; Journal Article ; Letter
ZDB-ID	187050-6
ISSN	1432-1459 ; 0340-5354 ; 0012-1037 ; 0939-1517 ; 1619-800X
ISSN (online)	1432-1459
ISSN	0340-5354 ; 0012-1037 ; 0939-1517 ; 1619-800X
DOI	10.1007/s00415-023-12071-9
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Article ; Online: Small-molecule SUMO inhibition for biomarker-informed B-cell lymphoma therapy.

Demel, Uta M / Wirth, Matthias / Yousefian, Schayan / Zhang, Le / Isaakidis, Konstandina / Dönig, Judith / Böger, Marlitt / Singh, Nikita / Köse, Hazal / Haas, Simon / Müller, Stefan / Schick, Markus / Keller, Ulrich

Haematologica

2023 Volume 108, Issue 2, Page(s) 555–567

Abstract: ... prognosis in aggressive B-cell lymphoma (BCL) and other malignancies. Recently developed small-molecule ... and specific immunity in vivo. Specifically, SUMOi increased the number of memory B cells as well ... causing massive remodeling of the normal B-cell and T-cell compartment. ...

Abstract	Aberrant activity of the SUMOylation pathway has been associated with MYC overexpression and poor prognosis in aggressive B-cell lymphoma (BCL) and other malignancies. Recently developed small-molecule inhibitors of SUMOylation (SUMOi) target the heterodimeric E1 SUMO activation complex (SAE1/UBA2). Here, we report that activated MYC signaling is an actionable molecular vulnerability in vitro and in a preclinical murine in vivo model of MYC-driven BCL. While SUMOi conferred direct effects on MYC-driven lymphoma cells, SUMO inhibition also resulted in substantial remodeling of various subsets of the innate and specific immunity in vivo. Specifically, SUMOi increased the number of memory B cells as well as cytotoxic and memory T cells, subsets that are attributed a key role within a coordinated anti-tumor immune response. In summary, our data constitute pharmacologic SUMOi as a powerful therapy in a subset of BCL causing massive remodeling of the normal B-cell and T-cell compartment.
MeSH term(s)	Humans ; Mice ; Animals ; Proto-Oncogene Proteins c-myc/metabolism ; Signal Transduction ; Lymphoma/drug therapy ; Lymphoma, B-Cell/drug therapy ; Biomarkers ; Ubiquitin-Activating Enzymes/metabolism
Chemical Substances	Proto-Oncogene Proteins c-myc ; Biomarkers ; UBA2 protein, human ; Ubiquitin-Activating Enzymes (EC 6.2.1.45)
Language	English
Publishing date	2023-02-01
Publishing country	Italy
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2022.280995
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Article ; Online: The cytochrome b

Misslinger, Matthias / Gsaller, Fabio / Hortschansky, Peter / Müller, Christoph / Bracher, Franz / Bromley, Michael J / Haas, Hubertus

Metallomics : integrated biometal science

2017 Volume 9, Issue 11, Page(s) 1655–1665

Abstract: ... transferring mechanisms, heme-independent P450 reductase (CPR) and the heme-dependent cytochrome b ...

Abstract	Cytochrome P450 enzymes (P450) play essential roles in redox metabolism in all domains of life including detoxification reactions and sterol biosynthesis. The activity of P450s is fuelled by two electron-transferring mechanisms, heme-independent P450 reductase (CPR) and the heme-dependent cytochrome b
MeSH term(s)	Antifungal Agents/pharmacology ; Aspergillus fumigatus/genetics ; Aspergillus fumigatus/growth & development ; Aspergillus fumigatus/metabolism ; Cytochrome-B(5) Reductase/metabolism ; Cytochromes b5/genetics ; Cytochromes b5/metabolism ; Drug Resistance, Fungal/drug effects ; Drug Resistance, Fungal/genetics ; Ergosterol/biosynthesis ; Fungal Proteins/genetics ; Fungal Proteins/metabolism ; Gene Deletion ; Gene Expression Regulation, Fungal ; Iron/metabolism ; Sterol 14-Demethylase/metabolism ; Voriconazole/pharmacology
Chemical Substances	Antifungal Agents ; Fungal Proteins ; Cytochromes b5 (9035-39-6) ; Iron (E1UOL152H7) ; Sterol 14-Demethylase (EC 1.14.14.154) ; Cytochrome-B(5) Reductase (EC 1.6.2.2) ; Voriconazole (JFU09I87TR) ; Ergosterol (Z30RAY509F)
Language	English
Publishing date	2017-10-26
Publishing country	England
Document type	Journal Article
ZDB-ID	2474317-3
ISSN	1756-591X ; 1756-5901
ISSN (online)	1756-591X
ISSN	1756-5901
DOI	10.1039/c7mt00110j
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Article ; Online: Doxorubicin induces cardiotoxicity in a pluripotent stem cell model of aggressive B cell lymphoma cancer patients.

Basic research in cardiology

2022 Volume 117, Issue 1, Page(s) 13

Abstract: ... of anthracycline-induced cardiotoxicity (ACT) from patients with an aggressive form of B-cell lymphoma and ...

Abstract	Cancer therapies with anthracyclines have been shown to induce cardiovascular complications. The aims of this study were to establish an in vitro induced pluripotent stem cell model (iPSC) of anthracycline-induced cardiotoxicity (ACT) from patients with an aggressive form of B-cell lymphoma and to examine whether doxorubicin (DOX)-treated ACT-iPSC cardiomyocytes (CM) can recapitulate the clinical features exhibited by patients, and thus help uncover a DOX-dependent pathomechanism. ACT-iPSC CM generated from individuals with CD20
MeSH term(s)	Cardiotoxicity/metabolism ; Cardiotoxicity/pathology ; Doxorubicin/metabolism ; Doxorubicin/toxicity ; Heart Diseases/metabolism ; Heart Failure/metabolism ; Humans ; Induced Pluripotent Stem Cells/metabolism ; Lymphoma, B-Cell/metabolism ; Lymphoma, B-Cell/pathology ; Myocytes, Cardiac/metabolism ; Neoplasms/metabolism
Chemical Substances	Doxorubicin (80168379AG)
Language	English
Publishing date	2022-03-08
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	189755-x
ISSN	1435-1803 ; 0300-8428 ; 0175-9418
ISSN (online)	1435-1803
ISSN	0300-8428 ; 0175-9418
DOI	10.1007/s00395-022-00918-7
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Article ; Online: Final step of B-cell differentiation into plasmablasts; the right time to activate plasma cell PIM2 kinase.

Haas, Marion / Fest, Thierry

Immunology letters

2023 Volume 258, Page(s) 45–50

Abstract: The differentiation of B cells into antibody-secreting plasma cells is a complex process ... of antibody production. During the final stage of differentiation, B cells undergo significant expansion ... of the serine/threonine kinase PIM2 in B cell differentiation, from commitment stage to plasmablast and maintenance of expression ...

Abstract	The differentiation of B cells into antibody-secreting plasma cells is a complex process that involves extensive changes in morphology, lifespan, and cellular metabolism to support the high rates of antibody production. During the final stage of differentiation, B cells undergo significant expansion of their endoplasmic reticulum and mitochondria, which induces cellular stress and may lead to cell death in absence of effective inhibition of the apoptotic pathway. These changes are tightly regulated at transcriptional and epigenetic levels, as well as at post-translational level, with protein modifications playing a critical role in the process of cellular modification and adaptation. Our recent research has highlighted the pivotal role of the serine/threonine kinase PIM2 in B cell differentiation, from commitment stage to plasmablast and maintenance of expression in mature plasma cells. PIM2 has been shown to promote cell cycle progression during the final stage of differentiation and to inhibit Caspase 3 activation, raising the threshold for apoptosis. In this review, we examine the key molecular mechanisms controlled by PIM2 that contribute to plasma cell development and maintenance.
MeSH term(s)	Plasma Cells ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins/metabolism ; Protein Serine-Threonine Kinases/metabolism ; B-Lymphocytes/metabolism ; Cell Differentiation ; Apoptosis
Chemical Substances	Proto-Oncogene Proteins ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2023-05-18
Publishing country	Netherlands
Document type	Review ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	445150-8
ISSN	1879-0542 ; 0165-2478
ISSN (online)	1879-0542
ISSN	0165-2478
DOI	10.1016/j.imlet.2023.05.006
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Article ; Online: Phase II study of nivolumab and salvage nivolumab/ipilimumab in treatment-naïve patients with advanced non-clear cell renal cell carcinoma (HCRN GU16-260-Cohort B).

Journal for immunotherapy of cancer

2023 Volume 11, Issue 3

Abstract: ... prolonged SD) were potentially eligible to receive salvage nivolumab/ipilimumab (Part B). Patients were ... to Part B for correlative studies.: Results: 35 patients with nccRCC were enrolled: 19 (54%) had ... ipilimumab (Part B), but 15 patients did not enroll due to grade 2-3 toxicity (6) on nivolumab, symptomatic ...

Abstract	Background: To determine the efficacy and toxicity of nivolumab monotherapy in treatment-naïve patients with non-clear cell renal cell carcinoma (nccRCC) and the efficacy of nivolumab/ipilimumab salvage therapy in patients with tumors unresponsive to initial nivolumab monotherapy. Methods: Eligible patients with treatment-naïve nccRCC received nivolumab until progressive disease (PD), toxicity, or completion of 96 weeks of treatment (Part A). Patients with PD prior to, or stable disease (SD) at 48 weeks (prolonged SD) were potentially eligible to receive salvage nivolumab/ipilimumab (Part B). Patients were required to submit tissue from a metastatic lesion obtained within 12 months prior to study entry and prior to Part B for correlative studies. Results: 35 patients with nccRCC were enrolled: 19 (54%) had papillary, 6 (17%) had chromophobe and 10 (29%) had unclassified histology. At median follow-up of 22.9 months, RECIST-defined objective response rate (ORR) was 5 of 35 (14.3% 95% CI 4.8% to 30.3%) (complete response (CR) 2 (5.7%) and partial response (PR) 3 (8.6%)). ORR by histology was: papillary-1/19 (5%); chromophobe-1/6 (17%); and unclassified-3/10 (30%). Nine patients (26%) had tumors with sarcomatoid features with 3 (33%) (2 unclassified and 1 papillary) responding. ORR was 0/18, 3/11 (27%) and 2/6 (33%) for patients with tumor progammed death ligand 1 (PD-L1) expression of <5%, ≥5% or not measured, respectively. Median progression-free survival was 4.0 (2.7-4.3) months. Two of five responders have progressed. Thirty-two patients had PD or prolonged SD and therefore, were potentially eligible for salvage nivolumab/ipilimumab (Part B), but 15 patients did not enroll due to grade 2-3 toxicity (6) on nivolumab, symptomatic disease progression (5), or other reasons including no biopsy tissue (4). In the 17 Part B patients, there was one PR (6%) (unclassified/non-sarcomatoid). Grade Conclusions: Nivolumab monotherapy has limited activity in treatment-naïve nccRCC with most responses (4 of 5) seen in patients with sarcomatoid and/or unclassified tumors. Toxicity is consistent with prior nivolumab studies. Salvage treatment with nivolumab/ipilimumab was provided in half of these patients with minimal activity. Trial registration number: NCT03117309.
MeSH term(s)	Humans ; Nivolumab/pharmacology ; Nivolumab/therapeutic use ; Carcinoma, Renal Cell/drug therapy ; Carcinoma, Renal Cell/pathology ; Ipilimumab/adverse effects ; Salvage Therapy ; Soft Tissue Neoplasms ; Sarcoma
Chemical Substances	Nivolumab (31YO63LBSN) ; Ipilimumab
Language	English
Publishing date	2023-03-22
Publishing country	England
Document type	Clinical Trial, Phase II ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2022-004780
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Article ; Online: The Choroid Plexus Is Permissive for a Preactivated Antigen-Experienced Memory B-Cell Subset in Multiple Sclerosis.

Haas, Jürgen / Rudolph, Henriette / Costa, Leonardo / Faller, Simon / Libicher, Saskia / Würthwein, Cornelia / Jarius, Sven / Ishikawa, Hiroshi / Stump-Guthier, Carolin / Tenenbaum, Tobias / Schwerk, Christian / Schroten, Horst / Wildemann, Brigitte

Frontiers in immunology

2021 Volume 11, Page(s) 618544

Abstract: The role of B cells in multiple sclerosis (MS) is increasingly recognized. B cells undergo ... compartmentalized redistribution in blood and cerebrospinal fluid (CSF) during active MS, whereby memory B ... cells accumulate in the CSF. While B-cell trafficking across the blood-brain barrier has been intensely ...

Abstract	The role of B cells in multiple sclerosis (MS) is increasingly recognized. B cells undergo compartmentalized redistribution in blood and cerebrospinal fluid (CSF) during active MS, whereby memory B cells accumulate in the CSF. While B-cell trafficking across the blood-brain barrier has been intensely investigated, cellular diapedesis through the blood-CSF barrier (BCSFB) is incompletely understood. To investigate how B cells interact with the choroid plexus to transmigrate into the CSF we isolated circulating B cells from healthy donors (HC) and MS patients, utilized an inverted cell culture filter system of human choroid plexus papilloma (HIBCPP) cells to determine transmigration rates of B-cell subsets, immunofluorescence, and electron microscopy to analyze migration routes, and qRT-PCR to determine cytokines/chemokines mediating B-cell diapedesis. We also screened the transcriptome of intrathecal B cells from MS patients. We found, that spontaneous transmigration of HC- and MS-derived B cells was scant, yet increased significantly in response to B-cell specific chemokines CXCL-12/CXCL-13, was further boosted upon pre-activation and occurred
MeSH term(s)	Adult ; B-Lymphocyte Subsets/immunology ; Blood-Brain Barrier/immunology ; Cells, Cultured ; Chemotaxis, Leukocyte/immunology ; Choroid Plexus/immunology ; Female ; Humans ; Immunologic Memory/immunology ; Male ; Multiple Sclerosis, Relapsing-Remitting/immunology ; Transendothelial and Transepithelial Migration/physiology
Language	English
Publishing date	2021-01-26
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2020.618544
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Article ; Online: Linear B-cell epitopes used in a synthetic foot-and-mouth disease vaccine and for differentiation between infected and vaccinated cattle

Wiesmüller, K. H. / Höhlich, B. / Pfaff, Eberhard / Haas, Bernd / Moss, A. / Gerner, W. / Jung, G. / Saalmüller, Armin

2023

Keywords	Text ; ddc:630
Language	English
Publishing date	2023-03-30
Publishing country	de
Document type	Article ; Online
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