Regulation of B cell functions by S-nitrosoglutathione in the EAE model

Complement receptors (CRs) play an integral role in innate immunity and also function to initiate and shape the adaptive immune response. Our earlier results showed that complement receptor type 1 (CR1, CD35) is a potent inhibitor of the B cell receptor- (BCR-) induced functions of human B lymphocytes. Here we show that this inhibition occurs already at the initial steps of B cell activation since ligation of CR1 reduces the BCR-induced phosphorylation of key signaling molecules such as Syk and mitogen activated protein kinases (MAPKs). Furthermore, our data give evidence that although B lymphocytes of active systemic lupus erythematosus (SLE) patients express lower level of CR1, the inhibitory capacity of this complement receptor is still maintained and its ligand-induced clustering results in significant inhibition of the main B cell functions, similar to that found in the case of healthy individuals. Since we have found that reduced CR1 expression of SLE patients does not affect the inhibitory capacity of the receptor, our results further support the therapeutical potential of CD35 targeting the decrease of B cell activation and autoantibody production in autoimmune patients.

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Identifying novel B-cell targets for chronic inflammatory autoimmune disease by screening of chemical probes in a patient-derived cell assay

10.1101/2020.01.08.898270 ◽

2020 ◽

Author(s):

Yvonne Sundström ◽

Ming-Mei Shang ◽

Sudeepta Kumar Panda ◽

Caroline Grönwall ◽

Fredrik Wermeling ◽

...

Keyword(s):

Autoimmune Disease ◽

B Cell ◽

Lupus Erythematosus ◽

Chemical Probes ◽

Cell Secretion ◽

Protein Targets ◽

Inflammatory Myositis ◽

Idiopathic Inflammatory Myositis ◽

Cell Functions ◽

Future Drug

SUMMARYB-cell secretion of autoantibodies drives autoimmune diseases, including systemic lupus erythematosus and idiopathic inflammatory myositis. Few therapies are presently available for treatment of these patients, often resulting in unsatisfactory effects and helping only some of patients. We developed a screening assay for evaluation of novel targets suspending B-cell maturation into antibody secreting cells, which could contribute to future drug development. The assay was employed for testing 43 high quality chemical probes and compounds inhibiting under-explored protein targets, using primary cells from patients with autoimmune disease. Probes inhibiting bromodomain family proteins and histone methyl transferases demonstrated abrogation of B-cell functions to a degree comparable to a positive control, the JAK inhibitor tofacitinib. Inhibition of each target rendered a specific functional cell and potential disease modifying effect, indicating specific epigenetic protein targets as potential new intervention points for future drug discovery and development efforts.

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Lymphocyte interleukin 2 production and responsiveness are altered in patients with primary myelodysplastic syndrome

Blood ◽

10.1182/blood.v70.2.494.bloodjournal702494 ◽

1987 ◽

Vol 70 (2) ◽

pp. 494-500

Author(s):

O Ayanlar-Batuman ◽

J Shevitz ◽

UC Traub ◽

S Murphy ◽

D Sajewski

Keyword(s):

T Cells ◽

B Cells ◽

Myelodysplastic Syndrome ◽

B Cell ◽

Interleukin 2 ◽

T Cell Proliferation ◽

Cell Functions ◽

Normal Limits ◽

Stimulatory Capacity

Immunoregulatory T and B cell functions in 15 patients with primary myelodysplastic syndrome (MDS) were studied by measuring the proliferative and the stimulatory capacity of T and B cells, respectively, in autologous (auto) and allogeneic (allo) mixed lymphocyte reaction (MLR). T cell proliferation in the auto MLR was 25% of the control (P less than .02), whereas proliferation in the allo MLR was normal. When control T cells were stimulated by MDS B cells, their proliferative response was only 57% of the control (P less than .01). The mechanism responsible for these abnormalities was studied by determining the capacity of MDS and normal T cells to produce interleukin 2 (IL 2) and to generate IL 2 receptors (IL 2R) following stimulation with control and MDS B cells. In the auto MLR of MDS patients, only 3% +/- 2% of T cells developed IL 2R positivity, whereas in control cultures 12% +/- 2% of T cells were positive, as determined by immunofluorescence, using a monoclonal antibody (MoAb) directed against the IL 2R, and FACS analysis. When MDS T cells were stimulated by control B cells, IL 2R generation and the production of IL 2 were within normal limits. In contrast, when control T cells were stimulated by MDS B cells or control B cells, the MDS B cells induced production of only 26% of IL 2 as compared with control B cells. In parallel experiments, IL 2R generation in control T cells stimulated by either MDS or control B cells was similar. We conclude that in the primary MDS, T and B cell interactions are impaired. Although MDS T cells develop normal quantities of IL 2R and produce normal amounts of IL 2 when stimulated by control B cells, they are markedly impaired when stimulated by self B cells. Similarly, MDS B cells can induce IL 2R generation in control T cells but not in MDS T cells. Myelodysplastic B cells are also defective in inducing IL 2 production by normal T cells in an allo MLR. These in vitro abnormalities strongly suggest that generation of lymphocytes with immunoregulatory functions is impaired in patients with MDS.

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Accounting for B cell behaviour and sampling bias yields a superior predictor of anti-PD-L1 response in bladder cancer

10.1101/2021.03.04.433370 ◽

2021 ◽

Author(s):

Ilya A Dyugay ◽

Daniil K Lukyanov ◽

Maria A Turchaninova ◽

Andrew R Zaretsky ◽

Oybek A Khalmurzaev ◽

...

Keyword(s):

Bladder Cancer ◽

T Cell ◽

B Cells ◽

B Cell ◽

Molecular Subtype ◽

Specific Antigen ◽

Therapy Response ◽

Prognostic Indicator ◽

Molecular Signature ◽

Cell Functions

Tumor-infiltrating B cells and intratumorally-produced immunoglobulins (IG) play important roles in the tumor microenvironment and response to immunotherapy. IgG antibodies produced by intratumoral B cells may drive antibody-dependent cellular cytotoxicity (ADCC) and enhance antigen presentation by dendritic cells. Furthermore, B cells are efficient antigen-specific antigen presenters that can essentially modulate the behaviour of helper T cells. Here we investigated the role of intratumoral IG isotype and clonality in bladder cancer. Our results show that the IgG1/IgA ratio offers a strong and independent prognostic indicator for the Basal squamous molecular subtype and for the whole ImVigor210 cohort in anti-PD-L1 immunotherapy. Our findings also indicate that effector B cell functions, rather than clonally-produced antibodies, are involved in the antitumor response. High IgG1/IgA ratio was associated with relative abundance of cytotoxic genes and prominence of the IL-21/IL-21R axis suggesting importance of T cell/B cell interaction. We integrated the B, NK, and T cell components, employing immFocus-like normalization to account for the stochastic nature of tumor tissue sampling. Using a random forest model with nested cross-validation, we developed a tumor RNA-Seq-based predictor of anti-PD-L1 therapy response in muscle-invasive urothelial carcinoma. The resulting PRIMUS (PRedIctive MolecUlar Signature) predictor achieves superior sensitivity compared to PD-L1 expression scores or existing gene signatures, allowing for reliable identification of responders even within the desert patient subcohort analyzed as a hold out set.

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Costimulation through the inducible costimulator ligand is essential for both T helper and B cell functions in T cell–dependent B cell responses

Nature Immunology ◽

10.1038/ni947 ◽

2003 ◽

Vol 4 (8) ◽

pp. 765-772 ◽

Cited By ~ 134

Author(s):

Tak W Mak ◽

Arda Shahinian ◽

Steve K Yoshinaga ◽

Andrew Wakeham ◽

Louis-Martin Boucher ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

T Helper ◽

Cell Functions ◽

Cell Responses ◽

Inducible Costimulator ◽

B Cell Responses

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Epratuzumab modulates B‐cell signaling without affecting B‐cell numbers or B‐cell functions in a mouse model with humanized CD22

European Journal of Immunology ◽

10.1002/eji.201646383 ◽

2016 ◽

Vol 46 (9) ◽

pp. 2260-2272 ◽

Cited By ~ 5

Author(s):

Lamia Özgör ◽

Carolin Brandl ◽

Anthony Shock ◽

Lars Nitschke

Keyword(s):

Mouse Model ◽

Cell Signaling ◽

B Cell ◽

Cell Numbers ◽

Cell Functions ◽

B Cell Signaling

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Immunomodulation of T and B cell functions in multiple myeloma patients treated with combined erythropoietin and α-interferon therapy

International Journal of Clinical & Laboratory Research ◽

10.1007/bf02592361 ◽

1995 ◽

Vol 25 (2) ◽

pp. 79-83 ◽

Cited By ~ 2

Author(s):

F. Silvestris ◽

L. Savino ◽

M. Tucci ◽

A. Vacca ◽

F. Dammacco

Keyword(s):

Multiple Myeloma ◽

B Cell ◽

Interferon Therapy ◽

Cell Functions

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B Cells Are Essential for Vaccination-Induced Resistance to Virulent Toxoplasma gondii

Infection and Immunity ◽

10.1128/iai.68.3.1026-1033.2000 ◽

2000 ◽

Vol 68 (3) ◽

pp. 1026-1033 ◽

Cited By ~ 131

Author(s):

Peter C. Sayles ◽

George W. Gibson ◽

Lawrence L. Johnson

Keyword(s):

B Cells ◽

Toxoplasma Gondii ◽

B Cell ◽

Induced Resistance ◽

Immune Serum ◽

Challenge Infection ◽

Host Cells ◽

Cell Functions ◽

Ifn Γ ◽

Deficient Mice

ABSTRACT T lymphocytes and gamma interferon (IFN-γ) are known mediators of immune resistance to Toxoplasma gondii infection, but whether B cells also play an important role is not clear. We have investigated this issue using B-cell-deficient (μMT) mice. If vaccinated with attenuated T. gondii tachyzoites, μMT mice are susceptible to a challenge intraperitoneal infection with highly virulent tachyzoites that similarly vaccinated B-cell-sufficient mice resist. Susceptibility is evidenced by increased numbers of parasites at the challenge infection site and by extensive mortality. The susceptibility of B-cell-deficient mice does not appear to be caused by deficient T-cell functions or diminished capacity of vaccinated and challenged B-cell-deficient mice to produce IFN-γ. Administration of Toxoplasma-immune serum, but not nonimmune serum, to vaccinated B-cell-deficient mice significantly prolongs their survival after challenge with virulent tachyzoites. Vaccinated mice lacking Fc receptors or the fifth component of complement resist a challenge infection, suggesting that neither Fc-receptor-dependent phagocytosis of antibody-coated tachyzoites nor antibody-dependent cellular cytotoxicity nor antibody-and-complement-dependent lysis of tachyzoites is a crucial mechanism of resistance. However, Toxoplasma-immune serum effectively inhibits the infection of host cells by tachyzoites in vitro. Together, the results support the hypothesis that B cells are required for vaccination-induced resistance to virulent tachyzoites in order to produce antibodies and that antibodies may function protectively in vivo by blocking infection of host cells by tachyzoites.

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Antibody Production and In Vitro Behavior of CD27-Defined B-Cell Subsets: Persistent Hepatitis C Virus Infection Changes the Rules

Journal of Virology ◽

10.1128/jvi.80.8.3923-3934.2006 ◽

2006 ◽

Vol 80 (8) ◽

pp. 3923-3934 ◽

Cited By ~ 56

Author(s):

Vito Racanelli ◽

Maria Antonia Frassanito ◽

Patrizia Leone ◽

Maria Galiano ◽

Valli De Re ◽

...

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

T Cell ◽

B Cells ◽

B Cell ◽

Feedback Inhibition ◽

Cell Subset ◽

Functional Program ◽

Cell Functions

ABSTRACT There is growing interest in the tendency of B cells to change their functional program in response to overwhelming antigen loading, perhaps by regulating specific parameters, such as efficiency of activation, proliferation rate, differentiation to antibody-secreting cells (ASC), and rate of cell death in culture. We show that individuals persistently infected with hepatitis C virus (HCV) carry high levels of circulating immunoglobulin G (IgG) and IgG-secreting cells (IgG-ASC). Thus, generalized polyclonal activation of B-cell functions may be supposed. While IgGs include virus-related and unrelated antibodies, IgG-ASC do not include HCV-specific plasma cells. Despite signs of widespread activation, B cells do not accumulate and memory B cells seem to be reduced in the blood of HCV-infected individuals. This apparent discrepancy may reflect the unconventional activation kinetics and functional responsiveness of the CD27+ B-cell subset in vitro. Following stimulation with T-cell-derived signals in the absence of B-cell receptor (BCR) engagement, CD27+ B cells do not expand but rapidly differentiate to secrete Ig and then undergo apoptosis. We propose that their enhanced sensitivity to BCR-independent noncognate T-cell help maintains a constant level of nonspecific serum antibodies and ASC and serves as a backup mechanism of feedback inhibition to prevent exaggerated B-cell responses that could be the cause of significant immunopathology.

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