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Article ; Online: B cells in systemic lupus erythematosus.

Szelinski, Franziska / Lino, Andreia C / Dörner, Thomas

2021 Volume 34, Issue 2, Page(s) 125–132

Abstract: Purpose of review: New insight into altered B cell distribution including newly identified subsets and abnormalities in systemic lupus erythematosus (SLE) as well as their role in immune protection are summarized in this review.: Recent findings: SLE ...

Abstract	Purpose of review: New insight into altered B cell distribution including newly identified subsets and abnormalities in systemic lupus erythematosus (SLE) as well as their role in immune protection are summarized in this review. Recent findings: SLE carries characteristic B cell abnormalities, which offer new insights into B cell differentiation and their disturbances including discoveries of pathogenic B cell subsets and intrinsic B cell abnormalities. A recent study in SLE found that antigen-experienced B cell subsets lacking expression of CD27 and IgD defined by their lack of CXCR5 and CD19low expression are expanded in SLE and represent plasmablasts likely escaping proper selection. In terms of therapeutic targeting with broader coverage than rituximab, second-generation anti-CD20, anti-CD38 and CD19-CART treatment experiences have advanced our understanding recently. However, the key role of qualitative and quantitative B cell requirements in connection with T cells became apparent during SARS-Cov2 infection and vaccination, especially in patients with gradual B cell impairments by rituximab, mycophenolate mofetil and cyclophosphamide. Summary: Identification and characterization relevant B cell subsets together with altered regulatory mechanisms in SLE facilitates new approaches in targeting pathogenic B cells but require consideration of preservation of protection.
MeSH term(s)	B-Lymphocytes ; COVID-19 ; Humans ; Lupus Erythematosus, Systemic ; RNA, Viral ; SARS-CoV-2
Chemical Substances	RNA, Viral
Language	English
Publishing date	2021-12-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1045317-9
ISSN	1531-6963 ; 1040-8711
ISSN (online)	1531-6963
ISSN	1040-8711
DOI	10.1097/BOR.0000000000000865
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Article ; Online: Purification and Immunophenotypic Characterization of Murine Plasma Cells.

Dang, Van Duc / Fillatreau, Simon / Lino, Andreia C

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

2021 Volume 2270, Page(s) 47–59

Abstract: B cells are primarily known for their capacity to differentiate into antibody-secreting cells (ASCs). ASCs are usually viewed as terminally differentiated cells sharing a unique phenotype. However, it lately became evident that ASCs exist in a variety of ...

Abstract	B cells are primarily known for their capacity to differentiate into antibody-secreting cells (ASCs). ASCs are usually viewed as terminally differentiated cells sharing a unique phenotype. However, it lately became evident that ASCs exist in a variety of subsets differing by their lifespan, anatomic location, and immunological function. Thus, ASCs can exist as long-lived plasma cells (LLPC) that can persist for years in a nonproliferating state within particular niches in the bone marrow (BM), or as short-lived plasma cells (SLPC) that are primarily found in secondary lymphoid organs or inflamed tissues and wane upon the termination of the associated immune response. Another layer of ASC diversity was uncovered with the discovery of their capacity to produce various pro- or anti-inflammatory cytokines. Notably, a subset of natural regulatory plasma cells characterized by the distinctive expression of the inhibitory receptor lymphocyte activation gene (LAG)-3 and a unique capacity to produce interleukin (IL)-10 upon stimulation was recently identified. Here, we describe how to immunophenotypically characterize murine plasma cells as well as how to isolate them using cell sorting, with a special focus on these recently described natural regulatory plasma cells.
MeSH term(s)	Animals ; Antibody-Producing Cells/immunology ; B-Lymphocytes/immunology ; Bone Marrow/immunology ; Bone Marrow Cells/cytology ; Cytokines/metabolism ; Flow Cytometry/methods ; Immunity, Humoral/immunology ; Immunologic Memory/immunology ; Immunophenotyping/methods ; Mice ; Mice, Inbred C57BL ; Plasma Cells/immunology ; Spleen/cytology
Chemical Substances	Cytokines
Language	English
Publishing date	2021-01-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-1237-8_3
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: B- and Plasma Cell Subsets in Autoimmune Diseases: Translational Perspectives.

Dang, Van Duc / Stefanski, Ana-Luisa / Lino, Andreia C / Dörner, Thomas

The Journal of investigative dermatology

2021 Volume 142, Issue 3 Pt B, Page(s) 811–822

Abstract: B lymphocytes play a central role in immunity owing to their unique antibody-producing capacity that provides protection against certain infections and during vaccination. In autoimmune diseases, B cells can gain pathogenic relevance through autoantibody ...

Abstract	B lymphocytes play a central role in immunity owing to their unique antibody-producing capacity that provides protection against certain infections and during vaccination. In autoimmune diseases, B cells can gain pathogenic relevance through autoantibody production, antigen presentation, and proinflammatory cytokine secretion. Recent data indicate that B and plasma cells can function as regulators through the production of immunoregulatory cytokines and/or employing checkpoint molecules. In this study, we review the key findings that define subsets of B and plasma cells with pathogenic and protective functions in autoimmunity. In addition to harsh B-cell depletion, we discuss the strategies that have the potential to reinstall the balance of pathogenic and protective B cells with the potential of more specific and personalized therapies.
MeSH term(s)	Autoimmune Diseases ; Autoimmunity ; B-Lymphocytes ; Cytokines ; Humans ; Plasma Cells
Chemical Substances	Cytokines
Language	English
Publishing date	2021-12-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	80136-7
ISSN	1523-1747 ; 0022-202X
ISSN (online)	1523-1747
ISSN	0022-202X
DOI	10.1016/j.jid.2021.05.038
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Article ; Online: Exploring the Role of Microbiota in the Limiting of B1 and MZ B-Cell Numbers by Naturally Secreted Immunoglobulins.

Mohr, Elodie / Lino, Andreia C

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

2017 Volume 1643, Page(s) 85–103

Abstract: Immunoglobulins (Igs)-or antibodies (Ab)-are important to combat foreign pathogens but also to the immune system homeostasis. We developed the ... ...

Abstract	Immunoglobulins (Igs)-or antibodies (Ab)-are important to combat foreign pathogens but also to the immune system homeostasis. We developed the AID
MeSH term(s)	Animals ; B-Lymphocyte Subsets/immunology ; B-Lymphocyte Subsets/metabolism ; Bone Marrow Transplantation ; Enzyme-Linked Immunosorbent Assay ; Flow Cytometry ; Genotype ; Immunoglobulin M/immunology ; Immunoglobulins/genetics ; Immunoglobulins/immunology ; Immunohistochemistry ; Mice ; Mice, Knockout ; Microbiota/immunology ; Microscopy, Confocal ; Transplantation Chimera
Chemical Substances	Immunoglobulin M ; Immunoglobulins
Language	English
Publishing date	2017
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-7180-0_7
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Article ; Online: B cell subset distribution in human bone marrow is stable and similar in left and right femur: An instructive case.

Wiedemann, Annika / Lino, Andreia C / Dörner, Thomas

PloS one

2019 Volume 14, Issue 2, Page(s) e0212525

Abstract: The bone marrow (BM) is, in addition to being the site of B cell development, a tissue that harbors long-lived plasma cells (PC), the cells that protect the body against foreign antigens by continuous production of antibodies. Nothing is known about the ... ...

Abstract	The bone marrow (BM) is, in addition to being the site of B cell development, a tissue that harbors long-lived plasma cells (PC), the cells that protect the body against foreign antigens by continuous production of antibodies. Nothing is known about the long-term stability and functionality of both B cells and PC in the BM at the individual donor level since repeated sampling possibilities outside of oncology are scarce. Here, we had the opportunity to obtain BM samples from a patient undergoing bilateral total hip arthroplasty half a year apart. We observed that the frequencies of the analyzed B cell and PC subsets were similar despite a time of six months in between and sampling on left and right side of the body. Additionally, B cell receptor stimulation led to comparable results. Our data suggest that composition and functionality of B cells are stable in the BM of adults at the individual donor level.
MeSH term(s)	Arthroplasty, Replacement, Hip ; B-Lymphocyte Subsets/cytology ; B-Lymphocyte Subsets/immunology ; Bone Marrow Cells/cytology ; Bone Marrow Cells/immunology ; Female ; Femur/cytology ; Humans ; Middle Aged ; Osteoarthritis, Hip/surgery ; Plasma Cells/cytology ; Plasma Cells/immunology ; Time Factors
Language	English
Publishing date	2019-02-22
Publishing country	United States
Document type	Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0212525
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Therapeutic implications of the anergic/postactivated status of B cells in systemic lupus erythematosus.

Dörner, Thomas / Szelinski, Franziska / Lino, Andreia C / Lipsky, Peter E

RMD open

2020 Volume 6, Issue 2

Abstract: Systemic lupus erythematosus (SLE) is characterised by numerous abnormalities in B lineage cells, including increased CD27++ plasmablasts/plasma cells, atypical CD27-IgD- B cells with increased CD95, spleen tyrosine kinase (Syk)++, CXCR5- and CXCR5+ ... ...

Abstract	Systemic lupus erythematosus (SLE) is characterised by numerous abnormalities in B lineage cells, including increased CD27++ plasmablasts/plasma cells, atypical CD27-IgD- B cells with increased CD95, spleen tyrosine kinase (Syk)++, CXCR5- and CXCR5+ subsets and anergic CD11c+Tbet+ age-associated B cells. Most findings, together with preclinical lupus models, support the concept of B cell hyperactivity in SLE. However, it remains largely unknown whether these specific B cell subsets have pathogenic consequences and whether they provide relevant therapeutic targets. Recent findings indicate a global distortion of B cell functional capability, in which the entire repertoire of naïve and memory B cells in SLE exhibits an anergic or postactivated (APA) functional phenotype. The APA status of SLE B cells has some similarities to the functional derangement of lupus T cells. APA B cells are characterised by reduced global cytokine production, diminished B cell receptor (BCR) signalling with decreased Syk and Bruton's tyrosine kinase phosphorylation related to repeated in vivo BCR stimulation as well as hyporesponsiveness to toll-like receptor 9 engagement, but intact CD40 signalling. This APA status was related to constitutive co-localisation of CD22 linked to phosphatase SHP-1 and increased overall protein phosphatase activities. Notably, CD40 co-stimulation could revert this APA status and restore BCR signalling, downregulate protein tyrosine phosphatase transcription and promote B cell proliferation and differentiation. The APA status and their potential rescue by bystander help conveyed through CD40 stimulation not only provides insights into possible mechanisms of escape of autoreactive clones from negative selection but also into novel ways to target B cells therapeutically.
MeSH term(s)	Animals ; B-Lymphocytes/immunology ; B-Lymphocytes/metabolism ; Biomarkers ; CD40 Antigens/metabolism ; Cell Differentiation/immunology ; Clonal Anergy/immunology ; Disease Susceptibility ; Gene Expression Profiling ; Gene Expression Regulation ; Humans ; Lupus Erythematosus, Systemic/etiology ; Lupus Erythematosus, Systemic/metabolism ; Lupus Erythematosus, Systemic/therapy ; Lymphocyte Activation/immunology ; Receptors, Antigen, B-Cell/metabolism ; Signal Transduction ; Toll-Like Receptor 9/metabolism
Chemical Substances	Biomarkers ; CD40 Antigens ; Receptors, Antigen, B-Cell ; Toll-Like Receptor 9
Language	English
Publishing date	2020-07-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2812592-7
ISSN	2056-5933 ; 2056-5933
ISSN (online)	2056-5933
ISSN	2056-5933
DOI	10.1136/rmdopen-2020-001258
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Article: Efficient CRISPR-Cas9-mediated mutagenesis in primary human B cells for identifying plasma cell regulators.

Le, Tuan Anh / Chu, Van Trung / Lino, Andreia C / Schrezenmeier, Eva / Kressler, Christopher / Hamo, Dania / Rajewsky, Klaus / Dörner, Thomas / Dang, Van Duc

Molecular therapy. Nucleic acids

2022 Volume 30, Page(s) 621–632

Abstract: Human B lymphocytes are attractive targets for immunotherapies in autoantibody-mediated diseases. Gene editing technologies could provide a powerful tool to determine gene regulatory networks regulating B cell differentiation into plasma cells, and ... ...

Abstract	Human B lymphocytes are attractive targets for immunotherapies in autoantibody-mediated diseases. Gene editing technologies could provide a powerful tool to determine gene regulatory networks regulating B cell differentiation into plasma cells, and identify novel therapeutic targets for prevention and treatment of autoimmune disorders. Here, we describe a new approach that uses CRISPR-Cas9 technology to target genes in primary human B cells
Language	English
Publishing date	2022-11-21
Publishing country	United States
Document type	Journal Article
ZDB-ID	2662631-7
ISSN	2162-2531
ISSN	2162-2531
DOI	10.1016/j.omtn.2022.11.016
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Article ; Online: EZH2 Inhibition in B Cell Subsets: Comment on the Article by Rohraff et al.

Schrezenmeier, Eva / Lino, Andreia C / Alexander, Tobias / Dörner, Thomas

Arthritis & rheumatology (Hoboken, N.J.)

2019 Volume 72, Issue 2, Page(s) 371–373

MeSH term(s)	Animals ; B-Lymphocyte Subsets ; B-Lymphocytes ; Enhancer of Zeste Homolog 2 Protein ; Mice ; Mice, Inbred MRL lpr
Chemical Substances	Enhancer of Zeste Homolog 2 Protein (EC 2.1.1.43)
Language	English
Publishing date	2019-12-29
Publishing country	United States
Document type	Letter ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	2756371-6
ISSN	2326-5205 ; 2326-5191
ISSN (online)	2326-5205
ISSN	2326-5191
DOI	10.1002/art.41133
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Article ; Online: Enhanced Programmed Death 1 and Diminished Programmed Death Ligand 1 Up-Regulation Capacity of Post-Activated Lupus B Cells.

Stefanski, Ana-Luisa / Wiedemann, Annika / Reiter, Karin / Hiepe, Falk / Lino, Andreia C / Dörner, Thomas

Arthritis & rheumatology (Hoboken, N.J.)

2019 Volume 71, Issue 9, Page(s) 1539–1544

Abstract: Objective: To assess the expression of programmed death 1 (PD-1), PD ligand 1 (PD-L1), and PD-L2 by B cells from patients with systemic lupus erythematosus (SLE) at baseline and after in vitro stimulation and to analyze their functional relationship to ... ...

Abstract	Objective: To assess the expression of programmed death 1 (PD-1), PD ligand 1 (PD-L1), and PD-L2 by B cells from patients with systemic lupus erythematosus (SLE) at baseline and after in vitro stimulation and to analyze their functional relationship to B cell proliferation. Methods: Peripheral blood mononuclear cells obtained from 29 SLE patients and 27 healthy donors were stimulated with interleukin-2 (IL-2)/IL-10, anti-B cell receptor (anti-BCR), CpG, and CD40L alone or in combination. Expression of PD-1, PD-L1, and PD-L2 on defined B cell subsets as well as on CD3+ T cells was analyzed by flow cytometry at baseline and after 48 hours of stimulation. Additionally, after 48 hours of stimulation, CD71 was evaluated as a proliferation marker on CD19+CD20+ B cells. Results: Increased PD-1 expression was characteristic of unstimulated lupus B cells and T cells. Upon stimulation of B cells with IL-2/IL-10, anti-BCR, CpG, and CD40L for 48 hours, the capacity of SLE B cells to up-regulate PD-L1 expression was substantially diminished (P = 0.0006) along with reduced B cell proliferation (P = 0.0039). Reduced PD-L1 expression was inversely correlated with the presence of the interferon signature (r = -0.8571, P < 0.0001) and the clinical SLE Disease Activity Index score (r = -0.5696, P = 0.0087). Conclusion: Post-activated, hyporesponsive lupus B cells are characterized by a phenotype of increased PD-1, functionally diminished PD-L1 up-regulation capacity, and reduced proliferation upon stimulation.
MeSH term(s)	B-Lymphocytes/metabolism ; B7-H1 Antigen/physiology ; Cell Proliferation ; Flow Cytometry ; Humans ; Leukocytes, Mononuclear/metabolism ; Lupus Erythematosus, Systemic/blood ; Lymphocyte Activation ; Programmed Cell Death 1 Receptor/physiology ; Up-Regulation
Chemical Substances	B7-H1 Antigen ; CD274 protein, human ; PDCD1 protein, human ; Programmed Cell Death 1 Receptor
Language	English
Publishing date	2019-08-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2756371-6
ISSN	2326-5205 ; 2326-5191
ISSN (online)	2326-5205
ISSN	2326-5191
DOI	10.1002/art.40897
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Zs.A 24: Show issues

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Article ; Online: Persistent but atypical germinal center reaction among 3

Stefanski, Ana-Luisa / Rincon-Arevalo, Hector / Schrezenmeier, Eva / Karberg, Kirsten / Szelinski, Franziska / Ritter, Jacob / Chen, Yidan / Meisel, Christian / Jahrsdörfer, Bernd / Ludwig, Carolin / Schrezenmeier, Hubert / Lino, Andreia C / Dörner, Thomas

Frontiers in immunology

2022 Volume 13, Page(s) 943476

Abstract: Background: Durable vaccine-mediated immunity relies on the generation of long-lived plasma cells and memory B cells (MBCs), differentiating upon germinal center (GC) reactions. SARS-CoV-2 mRNA vaccination induces a strong GC response in healthy ... ...

Abstract	Background: Durable vaccine-mediated immunity relies on the generation of long-lived plasma cells and memory B cells (MBCs), differentiating upon germinal center (GC) reactions. SARS-CoV-2 mRNA vaccination induces a strong GC response in healthy volunteers (HC), but limited data is available about response longevity upon rituximab treatment. Methods: We evaluated humoral and cellular responses upon 3rd vaccination in seven patients with rheumatoid arthritis (RA) who initially mounted anti-spike SARS-CoV-2 IgG antibodies after primary 2x vaccination and got re-exposed to rituximab (RTX) 1-2 months after the second vaccination. Ten patients with RA on other therapies and ten HC represented the control groups. As control for known long-lived induced immunity, we analyzed humoral and cellular tetanus toxoid (TT) immune responses in steady-state. Results: After 3 Summary: On the basis of pre-existing affinity matured MBCs within primary immunisation, RTX re-exposed patients revealed a persistent but atypical GC immune response accompanied by boosted spike-specific memory CD4 T cells upon SARS-CoV-2 recall vaccination.
MeSH term(s)	Antibodies, Viral ; Arthritis, Rheumatoid ; COVID-19 ; COVID-19 Vaccines ; Germinal Center ; Humans ; Immunoglobulin A ; Immunoglobulin G ; Rituximab ; SARS-CoV-2 ; Vaccination
Chemical Substances	Antibodies, Viral ; COVID-19 Vaccines ; Immunoglobulin A ; Immunoglobulin G ; Rituximab (4F4X42SYQ6)
Language	English
Publishing date	2022-08-10
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.2022.943476
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