B-cell activation in cats with feline infectious peritonitis (FIP) by FIP-virus-induced B-cell differentiation/survival factors

Cell division is an essential component of B cell differentiation to antibody-secreting plasma cells, with critical reprogramming occurring during the initial stages of B cell activation. However, a complete understanding of the factors that coordinate early reprogramming events in vivo remain to be determined. In this study, we examined the initial reprogramming by IRF4 in activated B cells using an adoptive transfer system and mice with a B cell-specific deletion of IRF4. IRF4-deficient B cells responding to influenza, NP-Ficoll and LPS divided, but stalled during the proliferative response. Gene expression profiling of IRF4-deficient B cells at discrete divisions revealed IRF4 was critical for inducing MYC target genes, oxidative phosphorylation, and glycolysis. Moreover, IRF4-deficient B cells maintained an inflammatory gene expression signature. Complementary chromatin accessibility analyses established a hierarchy of IRF4 activity and identified networks of dysregulated transcription factor families in IRF4-deficient B cells, including E-box binding bHLH family members. Indeed, B cells lacking IRF4 failed to fully induce Myc after stimulation and displayed aberrant cell cycle distribution. Furthermore, IRF4-deficient B cells showed reduced mTORC1 activity and failed to initiate the B cell-activation unfolded protein response and grow in cell size. Myc overexpression in IRF4-deficient was sufficient to overcome the cell growth defect. Together, these data reveal an IRF4-MYC-mTORC1 relationship critical for controlling cell growth and the proliferative response during B cell differentiation.

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Differentiation, functions, and roles of T follicular regulatory cells in autoimmune diseases

Inflammation and Regeneration ◽

10.1186/s41232-021-00164-9 ◽

2021 ◽

Vol 41 (1) ◽

Author(s):

He Hao ◽

Shingo Nakayamada ◽

Yoshiya Tanaka

Keyword(s):

Cell Differentiation ◽

Autoimmune Diseases ◽

B Cell ◽

Cell Activation ◽

B Cell Differentiation ◽

B Cell Activation ◽

Regulatory Cells ◽

Autoantibody Production ◽

Follicular Helper ◽

Autoantibody Response

AbstractT follicular helper cells participate in stimulating germinal center (GC) formation and supporting B cell differentiation and autoantibody production. However, T follicular regulatory (Tfr) cells suppress B cell activation. Since changes in the number and functions of Tfr cells lead to dysregulated GC reaction and autoantibody response, targeting Tfr cells may benefit the treatment of autoimmune diseases. Differentiation of Tfr cells is a multistage and multifactorial process with various positive and negative regulators. Therefore, understanding the signals regulating Tfr cell generation is crucial for the development of targeted therapies. In this review, we discuss recent studies that have elucidated the roles of Tfr cells in autoimmune diseases and investigated the modulators of Tfr cell differentiation. Additionally, potential immunotherapies targeting Tfr cells are highlighted.

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STAT3 phosphorylation mediates the stimulatory effects of interferon alpha on B cell differentiation and activation in SLE

Rheumatology ◽

10.1093/rheumatology/kez354 ◽

2019 ◽

Cited By ~ 1

Author(s):

Aurélie De Groof ◽

Julie Ducreux ◽

Floor Aleva ◽

Andrew J Long ◽

Alina Ferster ◽

...

Keyword(s):

Cell Differentiation ◽

B Cells ◽

B Cell ◽

Cell Activation ◽

Mononuclear Cells ◽

Type I ◽

B Cell Differentiation ◽

B Cell Activation ◽

Loss Of Function ◽

Stat3 Phosphorylation

Abstract Objective Type I IFNs play a well-known role in the pathogenesis of SLE, through activation of CD4 T and antigen-presenting cells. Here, we investigated the effects of IFN alpha (IFNα) on SLE B cell activation and differentiation. Methods Peripheral blood mononuclear cells (PBMCs) and purified total or naïve B cells were obtained from healthy controls and SLE patients. The effects of IFNα on B cell differentiation were studied by flow cytometry. The role of STAT3 in B cell responses to IFNα was studied using pharmacological inhibitors and PBMCs from STAT3-deficient individuals. Results Incubation of normal PBMCs with IFNα induces a B cell differentiation pattern as observed spontaneously in SLE PBMCs. IFNα displays direct stimulatory effects on purified naïve B cells from healthy individuals, as evidenced by a significant induction of cell surface CD38 and CD95 in the presence of the cytokine. In purified naïve B cells, IFNα also induces STAT3 phosphorylation. IFNα-induced naïve B cell differentiation in total PBMCs is significantly inhibited in the presence of STAT3 inhibitors, or in PBMCs from individuals with STAT3 loss of function mutations. Spontaneous levels of STAT3, but not STAT1, phosphorylation are significantly higher in total B cells from SLE patients compared with controls. Pharmacological STAT3 inhibition in SLE PBMCs inhibits naïve B cell activation and differentiation. Conclusion IFNα displays direct stimulatory effects on B cell differentiation and activation in SLE. STAT3 phosphorylation mediates the effects of IFNα stimulation in naïve B cells, an observation that opens new therapeutic perspectives in SLE.

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Murine B cell differentiation lineages.

Journal of Experimental Medicine ◽

10.1084/jem.159.4.1169 ◽

1984 ◽

Vol 159 (4) ◽

pp. 1169-1188 ◽

Cited By ~ 90

Author(s):

R R Hardy ◽

K Hayakawa ◽

D R Parks ◽

L A Herzenberg ◽

L A Herzenberg

Keyword(s):

Cell Differentiation ◽

B Cells ◽

B Cell ◽

Cell Activation ◽

Specific Antigen ◽

Intermediate Stage ◽

The Other ◽

Similar Proportion ◽

B Cell Differentiation ◽

B Cell Activation

Subpopulations of mouse B cells express different amounts of two antigens (BLA-1 and BLA-2) recognized by rat monoclonal antibodies (53-10.1 and 30-E2). Two-color immunofluorescence analysis on the fluorescence-activated cell sorter (FACS) shows that the 53-10.1 monoclonal antibody reacts with a similar proportion of splenic B cells from normal and CBA/N (xid) mice, whereas 30-E2 reacts with most CBA/N B cells but with only a fraction of normal B cells. Data from three- and four-color immunofluorescence analyses with xid, athymic (nude), and normal mice suggest that the order in which these antigens are lost during B cell differentiation distinguishes two B cell lineages: immature B cells express both antigens, intermediate-stage B cells of one or the other lineage express only BLA-1 or only BLA-2, respectively, and mature resting B cells express neither. CBA/N mice lack one of the putative intermediate populations (BLA-1+,2-); thus, this population apparently gives rise to the predominant mature B cell population, which is present in normal adult spleen and lymph node but is missing in CBA/N. The other putative intermediate population (BLA-1-,2+) is decreased by two- to threefold in spleens from nude mice compared with strain-matched controls. Both BLA-1 and BLA-2 antigens rapidly reappear after specific (antigen) or nonspecific (lipopolysaccharide) B cell activation. IgM plaque-forming cells (PFC) derived from such activated cells continue to express both antigens while IgG PFC express only BLA-1.

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Hyaluronate-CD44 Interactions Can Induce Murine B-Cell Activation

Blood ◽

10.1182/blood.v89.8.2901 ◽

1997 ◽

Vol 89 (8) ◽

pp. 2901-2908 ◽

Cited By ~ 71

Author(s):

Asimah Rafi ◽

Mitzi Nagarkatti ◽

Prakash S. Nagarkatti

Keyword(s):

T Cells ◽

B Cells ◽

B Cell ◽

Cell Activation ◽

Critical Role ◽

Surface Glycoprotein ◽

B Cell Differentiation ◽

B Cell Activation ◽

Cell Surface Glycoprotein ◽

Immunodeficient Mice

Abstract CD44 is a widely distributed cell surface glycoprotein whose principal ligand has been identified as hyaluronic acid (HA), a major component of the extracellular matrix (ECM). Recent studies have demonstrated that activation through CD44 leads to induction of effector function in T cells and macrophages. In the current study, we investigated whether HA or monoclonal antibodies (MoAbs) against CD44 would induce a proliferative response in mouse lymphocytes. Spleen cells from normal and nude, but not severe combined immunodeficient mice, exhibited strong proliferative responsiveness to stimulation with soluble HA or anti-CD44 MoAbs. Furthermore, purified B cells, but not T cells, were found to respond to HA. HA was unable to stimulate T cells even in the presence of antigen presenting cells (APC) and was unable to act as a costimulus in the presence of mitogenic or submitogenic concentrations of anti-CD3 MoAbs. In contrast, stimulation of B cells with HA in vitro, led to B-cell differentiation as measured by production of IgM antibodies in addition to increased expression of CD44 and decreased levels of CD45R. The fact that the B cells were responding directly to HA through its binding to CD44 and not to any contaminants or endotoxins was demonstrated by the fact that F(ab)2 fragments of anti-CD44 MoAbs or soluble CD44 fusion proteins could significantly inhibit the HA-induced proliferation of B cells. Also, HA-induced proliferation of B cells was not affected by the addition of polymixin B, and B cells from lipopolysaccharide (LPS)-unresponsive C3H/HeJ strain responded strongly to stimulation with HA. Furthermore, HA, but not chondroitin-sulfate, another major component of the ECM, induced B-cell activation. It was also noted that injection of HA intraperitoneally, triggered splenic B cell proliferation in vivo. Together, the current study demonstrates that interaction between HA and CD44 can regulate murine B-cell effector functions and that such interactions may play a critical role during normal or autoimmune responsiveness of B cells.

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