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Article ; Online: Characterization of Definitive Regulatory B Cell Subsets by Cell Surface Phenotype, Function and Context.

Neu, Savannah D / Dittel, Bonnie N

2021 Volume 12, Page(s) 787464

Abstract: Regulatory B cell or "Breg" is a broad term that represents the anti-inflammatory activity ... of B cells, but does not describe their individual phenotypes, specific mechanisms of regulation or relevant ... disease contexts. Thus, given the variety of B cell regulatory mechanisms reported in human disease and ...

Abstract	Regulatory B cell or "Breg" is a broad term that represents the anti-inflammatory activity of B cells, but does not describe their individual phenotypes, specific mechanisms of regulation or relevant disease contexts. Thus, given the variety of B cell regulatory mechanisms reported in human disease and their animal models, a more thorough and comprehensive identification strategy is needed for tracking and comparing B cell subsets between research groups and in clinical settings. This review summarizes the discovery process and mechanism of action for well-defined regulatory B cell subsets with an emphasis on the mouse model of multiple sclerosis experimental autoimmune encephalomyelitis. We discuss the importance of conducting thorough B cell phenotyping along with mechanistic studies prior to defining a particular subset of B cells as Breg. Since virtually all B cell subsets can exert regulatory activity, it is timely for their definitive identification across studies.
MeSH term(s)	Animals ; B-Lymphocyte Subsets/immunology ; B-Lymphocyte Subsets/metabolism ; B-Lymphocytes, Regulatory/immunology ; B-Lymphocytes, Regulatory/metabolism ; Encephalomyelitis, Autoimmune, Experimental/blood ; Encephalomyelitis, Autoimmune, Experimental/immunology ; Humans ; Immunophenotyping ; Multiple Sclerosis/blood ; Multiple Sclerosis/immunology
Language	English
Publishing date	2021-12-20
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; 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.2021.787464
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: B Cell Subsets and Mechanisms Involved in Immune Regulation in Health and Disease.

Dittel, Bonnie N / Rojas, Olga L

Journal of molecular biology

2020 Volume 433, Issue 1, Page(s) 166710

MeSH term(s)	Animals ; B-Lymphocyte Subsets/immunology ; B-Lymphocyte Subsets/metabolism ; Biomarkers ; Cytokines/metabolism ; Disease Susceptibility ; Homeostasis ; Humans ; Immunomodulation
Chemical Substances	Biomarkers ; Cytokines
Language	English
Publishing date	2020-11-12
Publishing country	England
Document type	Editorial
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2020.11.009
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Article ; Online: T Cell-Specific STAT1 Expression Promotes Lytic Replication and Supports the Establishment of Gammaherpesvirus Latent Reservoir in Splenic B Cells.

Sylvester, P A / Jondle, C N / Schmalzriedt, D L / Dittel, B N / Tarakanova, V L

mBio

2022 Volume 13, Issue 4, Page(s) e0210722

Abstract: ... rodents, and are associated with cancers, including B cell lymphomas. While type I and II interferon (IFN ... gammaherpesviruses, manipulates and usurps B cell differentiation to establish a lifelong latent reservoir in B ... cells. Specifically, germinal center B cells host the majority of latent MHV68 reservoir in the lymphoid organs ...

Abstract	Gammaherpesviruses establish lifelong infections in most vertebrate species, including humans and rodents, and are associated with cancers, including B cell lymphomas. While type I and II interferon (IFN) systems of the host are critical for the control of acute and chronic gammaherpesvirus infection, the cell type-specific role(s) of IFN signaling during infection is poorly understood and is often masked by the profoundly altered viral pathogenesis in the hosts with global IFN deficiencies. STAT1 is a critical effector of all classical IFN responses along with its involvement in other cytokine signaling pathways. In this study, we defined the effect of T cell-specific STAT1 deficiency on the viral and host parameters of infection with murine gammaherpesvirus 68 (MHV68). MHV68 is a natural rodent pathogen that, similar to human gammaherpesviruses, manipulates and usurps B cell differentiation to establish a lifelong latent reservoir in B cells. Specifically, germinal center B cells host the majority of latent MHV68 reservoir in the lymphoid organs, particularly at the peak of viral latency. Unexpectedly, T cell-specific STAT1 expression, while limiting the overall expansion of the germinal center B cell population during chronic infection, rendered these B cells more effective at hosting the latent virus reservoir. Further, T cell-specific STAT1 expression in a wild type host limited circulating levels of IFNγ, with corresponding increases in lytic MHV68 replication and viral reactivation. Thus, our study unveils an unexpected proviral role of T cell-specific STAT1 expression during gammaherpesvirus infection of a natural intact host.
MeSH term(s)	Animals ; Gammaherpesvirinae/genetics ; Herpesviridae Infections ; Host-Pathogen Interactions ; Humans ; Interferons/metabolism ; Mice ; Mice, Inbred C57BL ; Rhadinovirus ; STAT1 Transcription Factor/genetics ; STAT1 Transcription Factor/metabolism ; T-Lymphocytes/metabolism ; Virus Latency/physiology
Chemical Substances	STAT1 Transcription Factor ; STAT1 protein, human ; Stat1 protein, mouse ; Interferons (9008-11-1)
Language	English
Publishing date	2022-08-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2557172-2
ISSN	2150-7511 ; 2161-2129
ISSN (online)	2150-7511
ISSN	2161-2129
DOI	10.1128/mbio.02107-22
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Article ; Online: Characterization of the Cell Surface Phenotype and Regulatory Activity of B-Cell IgD Low (BD

Khalil, Mohamed / Ray, Avijit / Dittel, Bonnie N

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

2021 Volume 2270, Page(s) 217–231

Abstract: B-cell IgD Low (BD ...

Abstract	B-cell IgD Low (BD
MeSH term(s)	Animals ; B-Lymphocytes, Regulatory/immunology ; B-Lymphocytes, Regulatory/metabolism ; CD4-Positive T-Lymphocytes/immunology ; Female ; Flow Cytometry/methods ; Forkhead Transcription Factors/metabolism ; Immune Tolerance ; Immunoglobulin D/immunology ; Immunoglobulin D/isolation & purification ; Immunoglobulin D/metabolism ; Interleukin-2 Receptor alpha Subunit/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Phenotype ; Receptors, Tumor Necrosis Factor/metabolism ; Spleen/cytology ; T-Lymphocytes, Regulatory/immunology
Chemical Substances	Forkhead Transcription Factors ; Immunoglobulin D ; Interleukin-2 Receptor alpha Subunit ; Receptors, Tumor Necrosis Factor
Language	English
Publishing date	2021-01-07
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	10.1007/978-1-0716-1237-8_12
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Article ; Online: Comparison of the Efficacy and Safety of Anti-CD20 B Cells Depleting Drugs in Multiple Sclerosis.

Cotchett, Kelly R / Dittel, Bonnie N / Obeidat, Ahmed Z

Multiple sclerosis and related disorders

2021 Volume 49, Page(s) 102787

Abstract: ... These monoclonal antibodies deplete B cells by targeting the cell surface protein CD20. This review highlights ...

Abstract	Rituximab, ocrelizumab, ofatumumab and ublituximab are disease modifying therapies (DMT) currently used in the treatment of multiple sclerosis (MS) or are in advanced stages of clinical trials. These monoclonal antibodies deplete B cells by targeting the cell surface protein CD20. This review highlights the similarities and major differences between the four agents. We summarize data from various clinical trials of each of these therapeutics and discuss their efficacy and safety. Additional considerations regarding the route of administration and cost are presented. Among the four therapeutics, only ocrelizumab is approved for primary progressive (PP) MS. Infusion/injection related reactions (IRRs) are the most common adverse events associated with all four therapeutics. In phase III trials of ocrelizumab and ofatumumab, the incidence of IRRs was lower with ofatumumab. Ofatumumab is unique among the four therapeutics due to its availability as a subcutaneous injection (SQ). Although SQ administration may be appealing for some patients it may raise concerns regarding medication compliance among physicians. Phase II trials studying ublituximab for the treatment of RMS yielded promising results. Phase III trials are currently comparing the efficacy of ublituximab to teriflunomide.
MeSH term(s)	Antigens, CD20 ; B-Lymphocytes ; Humans ; Multiple Sclerosis/drug therapy ; Pharmaceutical Preparations ; Rituximab
Chemical Substances	Antigens, CD20 ; Pharmaceutical Preparations ; Rituximab (4F4X42SYQ6)
Language	English
Publishing date	2021-01-22
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2645330-7
ISSN	2211-0356 ; 2211-0348
ISSN (online)	2211-0356
ISSN	2211-0348
DOI	10.1016/j.msard.2021.102787
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Article ; Online: Discovery and Function of B-Cell IgD Low (BD

Khalil, Mohamed I / Gurski, Cody J / Dittel, Landon J / Neu, Savannah D / Dittel, Bonnie N

Journal of molecular biology

2020 Volume 433, Issue 1, Page(s) 166584

Abstract: It is now appreciated that in addition to their role in humoral immunity, B cells also exert ... regulatory mechanisms that lead to attenuation of inflammatory responses. The concept of B-cell regulation ... became well recognized when mice deficient in B cells due to genetic disruption were shown to be ...

Abstract	It is now appreciated that in addition to their role in humoral immunity, B cells also exert regulatory mechanisms that lead to attenuation of inflammatory responses. The concept of B-cell regulation became well recognized when mice deficient in B cells due to genetic disruption were shown to be refractory to recovery from the signs of experimental autoimmune encephalomyelitis (EAE), the mouse model of multiple sclerosis. This seminal study spurred the search for B-cell regulatory phenotypes and mechanisms of action. Our approach was to utilize differential B-cell depletion with anti-CD20 to retain B cells whose presence were required to achieve EAE recovery. Utilizing flow cytometry, adoptive cell therapy and genetic approaches, we discovered a new B-cell subset that, upon adoptive transfer into B cell-deficient mice, was sufficient to promote EAE recovery. This B-cell subset is IgM
MeSH term(s)	Animals ; Antibody Formation/immunology ; Autoimmunity ; B-Lymphocyte Subsets/immunology ; B-Lymphocyte Subsets/metabolism ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; Glucocorticoids/pharmacology ; Homeostasis ; Humans ; Immune Tolerance ; Immunoglobulin D/immunology ; Immunomodulation ; Lymphocyte Depletion ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/metabolism
Chemical Substances	Glucocorticoids ; Immunoglobulin D
Language	English
Publishing date	2020-06-29
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80229-3
ISSN	1089-8638 ; 0022-2836
ISSN (online)	1089-8638
ISSN	0022-2836
DOI	10.1016/j.jmb.2020.06.023
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Article ; Online: Targeting transmembrane-domain-less MOG expression to platelets prevents disease development in experimental autoimmune encephalomyelitis.

Cai, Yuanhua / Schroeder, Jocelyn A / Jing, Weiqing / Gurski, Cody / Williams, Calvin B / Wang, Shaoyuan / Dittel, Bonnie N / Shi, Qizhen

Frontiers in immunology

2022 Volume 13, Page(s) 1029356

Abstract: Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system with no cure yet. Here, we report genetic engineering of hematopoietic stem cells (HSCs) to express myelin oligodendrocyte glycoprotein (MOG), specifically ...

Abstract	Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system with no cure yet. Here, we report genetic engineering of hematopoietic stem cells (HSCs) to express myelin oligodendrocyte glycoprotein (MOG), specifically in platelets, as a means of intervention to induce immune tolerance in experimental autoimmune encephalomyelitis (EAE), the mouse model of MS. The platelet-specific αIIb promoter was used to drive either a full-length or truncated MOG expression cassette. Platelet-MOG expression was introduced by lentivirus transduction of HSCs followed by transplantation. MOG protein was detected on the cell surface of platelets only in full-length MOG-transduced recipients, but MOG was detected in transmembrane-domain-less MOG
MeSH term(s)	Mice ; Animals ; Myelin-Oligodendrocyte Glycoprotein ; Encephalomyelitis, Autoimmune, Experimental ; Multiple Sclerosis ; Immune Tolerance ; Central Nervous System
Chemical Substances	Myelin-Oligodendrocyte Glycoprotein
Language	English
Publishing date	2022-10-27
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; 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.2022.1029356
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Article: Mechanisms of Regulatory B cell Function in Autoimmune and Inflammatory Diseases beyond IL-10.

Ray, Avijit / Dittel, Bonnie N

Journal of clinical medicine

2017 Volume 6, Issue 1

Abstract: ... production B cells play prominent roles in immune regulation. While B cell-derived IL-10 has garnered much ... attention, B cells also effectively regulate inflammation by a variety of IL-10-independent mechanisms. B ... called regulatory B cells (Breg), no definitive phenotype has emerged for B cells with regulatory ...

Abstract	In the past two decades it has become clear that in addition to antigen presentation and antibody production B cells play prominent roles in immune regulation. While B cell-derived IL-10 has garnered much attention, B cells also effectively regulate inflammation by a variety of IL-10-independent mechanisms. B cell regulation has been studied in both autoimmune and inflammatory diseases. While collectively called regulatory B cells (Breg), no definitive phenotype has emerged for B cells with regulatory potential. This has made their study challenging and thus unique B cell regulatory mechanisms have emerged in a disease-dependent manner. Thus to harness the therapeutic potential of Breg, further studies are needed to understand how they emerge and are induced to evoke their regulatory activities.
Language	English
Publishing date	2017-01-23
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2662592-1
ISSN	2077-0383
ISSN	2077-0383
DOI	10.3390/jcm6010012
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Article ; Online: Conserved Gammaherpesvirus Protein Kinase Counters the Antiviral Effects of Myeloid Cell-Specific STAT1 Expression To Promote the Establishment of Splenic B Cell Latency.

Sylvester, P A / Jondle, C N / Stoltz, K P / Lanham, J / Dittel, B N / Tarakanova, V L

Journal of virology

2021 Volume 95, Issue 17, Page(s) e0085921

Abstract: Gammaherpesviruses establish lifelong infections and are associated with B cell lymphomas. Murine ... of the virus to B cells, where physiological B cell differentiation is usurped to ensure the establishment ... reservoir in splenic B cells. All gammaherpesviruses encode a conserved protein kinase that antagonizes type ...

Abstract	Gammaherpesviruses establish lifelong infections and are associated with B cell lymphomas. Murine gammaherpesvirus 68 (MHV68) infects epithelial and myeloid cells during acute infection, with subsequent passage of the virus to B cells, where physiological B cell differentiation is usurped to ensure the establishment of a chronic latent reservoir. Interferons (IFNs) represent a major antiviral defense system that engages the transcriptional factor STAT1 to attenuate diverse acute and chronic viral infections, including those of gammaherpesviruses. Correspondingly, global deficiency of type I or type II IFN signaling profoundly increases the pathogenesis of acute and chronic gammaherpesvirus infection, compromises host survival, and impedes mechanistic understanding of cell type-specific role of IFN signaling. Here, we demonstrate that myeloid-specific STAT1 expression attenuates acute and persistent MHV68 replication in the lungs and suppresses viral reactivation from peritoneal cells, without any effect on the establishment of viral latent reservoir in splenic B cells. All gammaherpesviruses encode a conserved protein kinase that antagonizes type I IFN signaling
MeSH term(s)	Animals ; Antiviral Agents/pharmacology ; B-Lymphocytes/virology ; Gammaherpesvirinae/enzymology ; Herpesviridae Infections/virology ; Host-Pathogen Interactions ; Interferons/metabolism ; Lymphocyte Activation ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myeloid Cells/metabolism ; Protein Kinases/genetics ; Protein Kinases/metabolism ; STAT1 Transcription Factor/physiology ; Spleen/virology ; Viral Proteins/genetics ; Viral Proteins/metabolism ; Virus Activation ; Virus Latency
Chemical Substances	Antiviral Agents ; STAT1 Transcription Factor ; Stat1 protein, mouse ; Viral Proteins ; Interferons (9008-11-1) ; Protein Kinases (EC 2.7.-)
Language	English
Publishing date	2021-08-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.00859-21
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Article: Direct suppression of autoreactive lymphocytes in the central nervous system via the CB2 receptor.

Dittel, B N

British journal of pharmacology

2007 Volume 153, Issue 2, Page(s) 271–276

Abstract: The cannabinoid system is now recognized as a regulator of both the nervous and immune systems. Although marijuana has been used for centuries for the treatment of a variety of disorders, its therapeutic mechanisms are only now being understood. The best- ...

Abstract	The cannabinoid system is now recognized as a regulator of both the nervous and immune systems. Although marijuana has been used for centuries for the treatment of a variety of disorders, its therapeutic mechanisms are only now being understood. The best-studied plant cannabinoid, delta9-tetrahydrocannabinol (THC), produced by Cannabis sativa and found in marijuana, has shown evidence of being immunosuppressive in both in vivo and in vitro. Since THC binds to at least two receptors that are differentially expressed by the immune and nervous systems, it has not been possible to clearly discriminate the biological effects it exerts in the two systems. In addition, endogenous cannabinoids have also been described that bind to both receptors and exert both neuronal and immune modulatory activity. The generation of mice deficient in specific cannabinoid receptors has facilitated studies to discriminate cannabinoid-specific functions. This review focuses on the function of the cannabinoid receptor 2 (CB2), primarily expressed in the immune system, in regulating T cell effector functions associated with autoimmune inflammation in the central nervous system (CNS).
MeSH term(s)	Animals ; Autoimmune Diseases/immunology ; Cannabinoid Receptor Modulators/physiology ; Central Nervous System/drug effects ; Central Nervous System/immunology ; Encephalomyelitis, Autoimmune, Experimental/immunology ; Encephalomyelitis, Autoimmune, Experimental/physiopathology ; Humans ; Immune System/physiology ; Lymphocytes/drug effects ; Lymphocytes/immunology ; Receptor, Cannabinoid, CB2/drug effects ; Receptor, Cannabinoid, CB2/immunology
Chemical Substances	Cannabinoid Receptor Modulators ; Receptor, Cannabinoid, CB2
Language	English
Publishing date	2007-10-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1038/sj.bjp.0707493
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