scholarly journals Characterization of a rare IL-10–competent B-cell subset in humans that parallels mouse regulatory B10 cells

Blood ◽  
2011 ◽  
Vol 117 (2) ◽  
pp. 530-541 ◽  
Author(s):  
Yohei Iwata ◽  
Takashi Matsushita ◽  
Mayuka Horikawa ◽  
David J. DiLillo ◽  
Koichi Yanaba ◽  
...  
Keyword(s):  
B Cells ◽  
Autoimmune Disease ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Ex Vivo ◽  
Cell Subset ◽  
Cell Subpopulation ◽  
B10 Cells

Abstract Regulatory B cells control inflammation and autoimmunity in mice, including the recently identified IL-10–competent B10 cell subset that represents 1% to 3% of spleen B cells. In this study, a comparable IL-10–competent B10 cell subset was characterized in human blood. B10 cells were functionally identified by their ability to express cytoplasmic IL-10 after 5 hours of ex vivo stimulation, whereas progenitor B10 (B10pro) cells required 48 hours of in vitro stimulation before they acquired the ability to express IL-10. B10 and B10pro cells represented 0.6% and approximately 5% of blood B cells, respectively. Ex vivo B10 and B10pro cells were predominantly found within the CD24hiCD27+ B-cell subpopulation that was able to negatively regulate monocyte cytokine production through IL-10–dependent pathways during in vitro functional assays. Blood B10 cells were present in 91 patients with rheumatoid arthritis, systemic lupus erythematosus, primary Sjögren syndrome, autoimmune vesiculobullous skin disease, or multiple sclerosis, and were expanded in some cases as occurs in mice with autoimmune disease. Mean B10 + B10pro-cell frequencies were also significantly higher in patients with autoimmune disease compared with healthy controls. The characterization of human B10 cells will facilitate their identification and the study of their regulatory activities during human disease.

scholarly journals Ex vivo characterization and isolation of rare memory B cells with antigen tetramers

Blood ◽  
2011 ◽  
Vol 118 (2) ◽  
pp. 348-357 ◽  
Author(s):  
Bettina Franz ◽  
Kenneth F. May ◽  
Glenn Dranoff ◽  
Kai Wucherpfennig
Keyword(s):  
B Cells ◽  
B Cell ◽  
Single Cell ◽  
Ex Vivo ◽  
Cell Receptor ◽  
Memory B Cells ◽  
Cell Repertoire ◽  
Low Frequencies

Abstract Studying human antigen-specific memory B cells has been challenging because of low frequencies in peripheral blood, slow proliferation, and lack of antibody secretion. Therefore, most studies have relied on conversion of memory B cells into antibody-secreting cells by in vitro culture. To facilitate direct ex vivo isolation, we generated fluorescent antigen tetramers for characterization of memory B cells by using tetanus toxoid as a model antigen. Brightly labeled memory B cells were identified even 4 years after last immunization, despite low frequencies ranging from 0.01% to 0.11% of class-switched memory B cells. A direct comparison of monomeric to tetrameric antigen labeling demonstrated that a substantial fraction of the B-cell repertoire can be missed when monomeric antigens are used. The specificity of the method was confirmed by antibody reconstruction from single-cell sorted tetramer+ B cells with single-cell RT-PCR of the B-cell receptor. All antibodies bound to tetanus antigen with high affinity, ranging from 0.23 to 2.2 nM. Furthermore, sequence analysis identified related memory B cell and plasmablast clones isolated more than a year apart. Therefore, antigen tetramers enable specific and sensitive ex vivo characterization of rare memory B cells as well as the production of fully human antibodies.

scholarly journals Jo-1 autoantigen-specific B cells are skewed towards distinct functional B cell subsets in anti-synthetase syndrome patients

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Jennifer Young-Glazer ◽  
Alberto Cisneros ◽  
Erin M. Wilfong ◽  
Scott A. Smith ◽  
Leslie J. Crofford ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Biology ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
Cell Subset ◽  
Trna Synthetase ◽  
B Cell Subsets ◽  
Antibody Secreting Cells

Abstract Background Anti-Jo-1 autoantibodies which recognize histidyl-tRNA synthetase identify patients with the rare rheumatologic disease, anti-histidyl-tRNA synthetase syndrome (Jo-1 ARS), a phenotypically distinct subset of idiopathic inflammatory myopathies (IIM). Jo-1-binding B cells (JBCs) are implicated in disease pathogenesis, yet they have not been studied directly. We therefore aimed to characterize JBCs to better understand how they expand and function in Jo-1 ARS. Methods We enrolled 10 IIM patients diagnosed with Jo-1 ARS, 4 patients with non-Jo-1 IIM, and 8 age- and sex-matched healthy controls. We phenotypically characterized peripheral blood mononuclear cells (PBMCs) ex vivo using flow cytometry to define the B cell subsets in which JBCs reside. We further tested their ability to differentiate into antibody-secreting cells following stimulation in vitro. Results The majority of JBCs were IgM+ (not class-switched). Compared to non-JBCs in the same donors, JBCs contained a higher percentage of autoimmune-prone CD21lo cells and were increased in the CD21lo IgM+ IgD− CD27+ memory subset relative to healthy donor B cells. Whereas non-JBCs were present in the anergic BND B cell subset, JBCs were nearly absent from this compartment. JBCs were detected among plasmablasts in some donors, but a reduced frequency of JBCs differentiated into CD38hi24− plasmablasts compared to non-JBCs present in the same wells following in vitro stimulation. Conclusions JBCs are enriched for autoimmune-prone CD21lo B cells, some of which exhibit a memory phenotype in the peripheral repertoire of Jo-1 ARS patients. JBCs undergo limited class switch and show reduced capacity to differentiate into antibody-secreting cells. This suggests complex B cell biology exists beyond class-switched cells that differentiate to secrete anti-Jo-1 autoantibody (i.e., what is captured through serum autoantibody studies). New Jo-1 ARS therapies should thus ideally target non-class-switched JBCs in addition to those that have undergone IgG class-switching to most effectively block cross-talk with autoreactive T cells.

scholarly journals Interaction of helper T cells and Lyb5+ B cells responding to phosphorylcholine is MHC-restricted.

1984 ◽  
Vol 160 (1) ◽  
pp. 329-334 ◽  
Author(s):  
D E Mosier ◽  
A J Feeney
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Lines ◽  
Cell Subset ◽  
Keyhole Limpet Hemocyanin ◽  
Cell Subpopulation ◽  
Helper T Cell ◽  
T Cell Lines

The requirements for T cell/B cell interaction for the induction of primary in vitro antibody responses to phosphorylcholine (PC)-keyhole limpet hemocyanin (KLH) were examined. Long-term helper T cell lines derived from KLH-primed (CBA/N X BALB/c) F1 female mice (H-2k/d) were able to support a T15-idiotype dominant, IgM anti-PC response of BALB/c (H-2d) B cells and macrophages, but could not activate PC-specific responses by BALB.B (H-2b) B cells, even in the presence of irradiated H-2k/d antigen-presenting cells. Polyclonal IgM secretion in the same cultures did not appear to depend upon a major histocompatibility complex (MHC)-restricted T-B interaction. Since IgM anti-PC responses seem to be entirely derived from the Lyb5+ B cell subpopulation, we conclude that at least some Lyb5+ B cells can only be activated by MHC-restricted T-B interactions. We also found that xid B cells from (CBA/N X BALB/c) F1 male mice could be polyclonally activated by helper T cell lines by an apparently MHC-unrestricted interaction. Our data thus suggests that residence in the Lyb5- or Lyb5+ B cell subset does not determine the T:B interaction requirements for antibody synthesis.

scholarly journals POS0412 CD21-/LOW B-CELLS ARE INCREASED IN PATIENTS WITH ANKYLOSING SPONDYLITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 435.2-436
Author(s):  
R. Wilbrink ◽  
A. Spoorenberg ◽  
S. Arends ◽  
F. G. M. Kroese ◽  
G. M. Verstappen
Keyword(s):  
Ankylosing Spondylitis ◽  
B Cells ◽  
Autoimmune Disease ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Mononuclear Cells ◽  
Cell Subset ◽  
Memory B Cells ◽  
Clinical Parameters ◽  
Color Flow

Background:Ankylosing spondylitis (AS) is a chronic immune mediated inflammatory rheumatic disease, in which primarily the sacroiliac joints and the spine are affected. Extra-skeletal manifestations (ESM) include uveitis, psoriasis, inflammatory bowel disease and peripheral arthritis. In studies into the pathogenesis of AS, B-cells have received little attention most likely due to the lack of auto-antibodies1. A B-cell subset that has been particularly associated with autoreactivity is characterized by low expression of CD21. These CD21-/low B-cells are increased in systemic autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus and primary Sjögren syndrome (pSS)2. At least part of the CD21-/low B-cells are considered to represent anergic, autoreactive B-cells, that fail to become activated through conventional B-cell receptor and CD40 signaling2.Objectives:To phenotypically study the peripheral B-cell compartment in in the blood of AS patients compared to pSS patients, a typical B-cell-associated autoimmune disease, and healthy controls (HC). Special emphasis was given to the CD21-/low compartment.Methods:The proportions and phenotype of peripheral B-cells were assessed in cryopreserved peripheral blood mononuclear cells of 45 AS patients (62% male, mean age 49.2±13.2 years, mean ASDAS 2.5±1.0), 20 age-matched patients with pSS (20% male, mean age 50.6±12.0, median (IQR) ESSDAI 3±6.25) and 30 age- and sex-matched HCs, using 15-color flow-cytometry analysis. Differences between groups were tested using the Independent Samples t-test or Mann-Whitney U test depending on the distribution of variables. Associations between CD21-/low B-cells and clinical parameters were explored using the Pearson or Spearman correlation coefficient.Results:The percentage of total B-cells in AS patients did not differ from pSS patients and HCs. In AS patients, percentages of CD27+ memory B-cells and CD27-IgD+ naïve B-cells were also similar to HCs, whereas CD27+IgD- memory B-cells were significantly reduced in pSS patients, as expected. The proportions of CD27-CD38lowCD21-/low B-cells among total B-cells were significantly increased in both AS (median 6.4%, p<0.0001) and pSS patients (median 7.8%, p<0.0001) compared to HCs (median 4.9%). Interestingly, only in AS patients, expression of chemokine receptors CXCR3 and CXCR5 was significantly elevated on CD27-CD38lowCD21-/low B-cells compared to HCs (p<0.001 and p<0.01, respectively). In comparison to HCs the expression of the immune markers T-bet and CD11c by CD27-CD38lowCD21-/low B-cells was significantly lower in AS patients (p<0.01 and p<0.01, respectively). The distribution of IgM and IgD expression within the CD27-CD38lowCD21-/low B-cell population was similar between all three study groups. Regarding the association between CD27-CD38lowCD21-/low B-cells and clinical parameters in AS patients, we observed a positive correlation with age (r=0.347, p=0.02) and erythrocyte sedimentation rate (ρ=0.386, p=0.01). Furthermore, AS patients with ESM showed increased proportions of CD27-CD38lowCD21-/low B-cells compared to patients without ESM (p<0.05).Conclusion:In this cross-sectional study, we observed an increased proportion of circulating CD27-CD38lowCD21-/low B-cells in AS patients, similar as in patients with pSS, a typical B-cell-mediated autoimmune disease. The elevated expression of CXCR3 on CD27-CD38lowCD21-/low B-cells in AS patients is suggestive for active involvement in the inflammatory response. These findings are indicative of B-cell involvement in the pathogenesis of AS, against current dogma.References:[1]Ranganathan V et al. Nat Rev Rheumatol. 2017;13(6):359-367.[2]Thorarinsdottir K et al. Scand J Immunol. 2015;82(3):254-261.Disclosure of Interests:Rick Wilbrink: None declared, Anneke Spoorenberg: None declared, Suzanne Arends: None declared, Frans G.M. Kroese Speakers bureau: BMS, Roche, Janssen-Cilag, Consultant of: BMS, Grant/research support from: BMS, Gwenny M. Verstappen: None declared

scholarly journals Trypanosoma cruzi Induces Regulatory B Cell Alterations in Patients With Chronic Chagas Disease

2021 ◽  
Vol 11 ◽  
Author(s):  
Magalí C. Girard ◽  
Micaela S. Ossowski ◽  
Arturo Muñoz-Calderón ◽  
Marisa Fernández ◽  
Yolanda Hernández-Vásquez ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Chagas Disease ◽  
Ex Vivo ◽  
Production Capacity ◽  
Cell Phenotype ◽  
Regulatory B Cell ◽  
B10 Cells ◽  
Chronic Chagas Disease

The clinical evolution of patients with chronic Chagas disease (CCD) is mainly associated with an excessive inflammation and a defective immunomodulatory profile caused by the interaction between T. cruzi and the host. Regulatory B (Breg) cells exert immune suppression mostly through IL-10 production (B10 cells), but also through IL-10-independent mechanisms. Previously, we demonstrated that CCD patients with cardiomyopathy show changes in the ex vivo Breg cell phenotypic distribution although maintain IL-10 production capacity. Here, we sought to identify potential alterations on Breg cells upon in vitro stimulation. Isolated B cells from CCD patients with or without cardiomyopathy and non-infected (NI) donors were stimulated with T. cruzi lysate or CpG + CD40L, and characterized by flow cytometry based on the expression of CD24, CD27, CD38, and the regulatory molecules IL-10 and PD-L1. IL-10 and IL-17 secretion in the supernatant of B cells was evaluated by ELISA. Data showed that T. cruzi stimulation diminished the expression of CD24 and CD38 on CD27− B cells while reducing the percentage of CD24high inside CD27+ B cells. Furthermore, T. cruzi induced a regulatory B cell phenotype by increasing B10 cells and IL-10 secretion in all the groups. The innate-like B10 cells expansion observed in patients with cardiomyopathy would be associated with CD27− B10 cell subsets, while no predominant phenotype was found in the other groups. Patients with cardiomyopathy also displayed higher IL-17 secretion levels in T. cruzi–activated B cells. CpG + CD40L stimulation revealed that B cells from CCD patients and NI donors had the same ability to differentiate into B10 cells and secrete IL-10 in vitro. Additionally, CCD patients showed an increased frequency of CD24−CD27− B cells and a reduction in the percentage of CD24highCD27+ Breg cells, which appeared to be inversely correlated with the presence of T. cruzi DNA in blood. Finally, CCD patients exhibited a higher frequency of PD-L1+ B cells in T. cruzi–stimulated samples, suggesting that IL-10-independent mechanisms could also be tangled in the control of inflammation. Altogether, our results provide evidence about the potential role of Breg cells in the immune response developed against T. cruzi and its contribution to chronic Chagas cardiomyopathy.

scholarly journals Invariant NKT cells limit activation of autoreactive CD1d-positive B cells

2010 ◽  
Vol 207 (5) ◽  
pp. 943-952 ◽  
Author(s):  
Fredrik Wermeling ◽  
Sara M. Lind ◽  
Emilie Domange Jordö ◽  
Susanna L. Cardell ◽  
Mikael C.I. Karlsson
Keyword(s):  
B Cells ◽  
Autoimmune Disease ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
Cell Subset ◽  
Peripheral Tolerance ◽  
Inkt Cells ◽  
Autoantibody Production ◽  
Autoreactive B Cells

Faulty activation of autoreactive B cells is a hallmark of autoimmune diseases like systemic lupus erythematosus (SLE). An important feature restricting activation of autoreactive B cells is efficient removal of apoptotic material. Mounting evidence also connects a primary defect in invariant natural killer T (iNKT) cells to autoimmune disease development. However, exactly how this unconventional T cell subset is involved remains to be defined. Here, we identify a suppressive role for iNKT cells in a model where autoantibody production is triggered by an increased load of circulating apoptotic cells, resembling the situation in SLE patients. Absence or reduction of iNKT cells as well as absence of CD1d-expression on B cells, needed for direct iNKT–B cell interaction, leads to increased autoreactive B cell activation and symptoms of disease. The suppression mediated by the iNKT cells is observed before B cell entry into germinal centers and can be rescued by transferring iNKT cells to deficient mice. This links iNKT cells to handling of dying cells and identifies a novel peripheral tolerance checkpoint relevant for autoimmune disease. Thus, these observations connect two clinical observations in SLE patients previously considered to be unrelated and define a new target for immunotherapy.

scholarly journals Dual T cell– and B cell–intrinsic deficiency in humans with biallelic RLTPR mutations

2016 ◽  
Vol 213 (11) ◽  
pp. 2413-2435 ◽  
Author(s):  
Yi Wang ◽  
Cindy S. Ma ◽  
Yun Ling ◽  
Aziz Bousfiha ◽  
Yildiz Camcioglu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Ex Vivo ◽  
Cell Phenotype ◽  
Loss Of Function ◽  
Inborn Errors

Combined immunodeficiency (CID) refers to inborn errors of human T cells that also affect B cells because of the T cell deficit or an additional B cell–intrinsic deficit. In this study, we report six patients from three unrelated families with biallelic loss-of-function mutations in RLTPR, the mouse orthologue of which is essential for CD28 signaling. The patients have cutaneous and pulmonary allergy, as well as a variety of bacterial and fungal infectious diseases, including invasive tuberculosis and mucocutaneous candidiasis. Proportions of circulating regulatory T cells and memory CD4+ T cells are reduced. Their CD4+ T cells do not respond to CD28 stimulation. Their CD4+ T cells exhibit a "Th2" cell bias ex vivo and when cultured in vitro, contrasting with the paucity of "Th1," "Th17," and T follicular helper cells. The patients also display few memory B cells and poor antibody responses. This B cell phenotype does not result solely from the T cell deficiency, as the patients’ B cells fail to activate NF-κB upon B cell receptor (BCR) stimulation. Human RLTPR deficiency is a CID affecting at least the CD28-responsive pathway in T cells and the BCR-responsive pathway in B cells.

scholarly journals CD1c but neither CD1a nor CD1b molecules are expressed on normal, activated, and malignant human B cells: identification of a new B-cell subset

Blood ◽  
1988 ◽  
Vol 72 (1) ◽  
pp. 241-247 ◽  
Author(s):  
D Delia ◽  
G Cattoretti ◽  
N Polli ◽  
E Fontanella ◽  
A Aiello ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
De Novo ◽  
Cell Subset ◽  
Ultrastructural Level ◽  
Cytoplasmic Staining ◽  
Clear Cut ◽  
Hodgkin's Lymphomas

Abstract The CD1 cluster of monoclonal antibodies (MoAbs) CD1a, CD1b, and CD1c, identifies molecules that are differentially expressed on hematopoietic and nonhematopoietic tissues. Our earlier finding that the mantle zone (MZ) but not the germinal center (GC) of normal lymph nodes (LN) is CD1c+, CD1a-, and CD1b- prompted us to further investigate the expression of these molecules on normal, activated, and malignant B cells. We report that blood and spleen contain CD1c+ B cells that account for 49% +/- 20.4% (mean +/- SD) and 50.9% +/- 4.4% of the total B cell population, respectively. CD1a- and CD1b-specific MoAbs are unreactive with both B and T cells; these latter are CD1c- as well. When CD1c+ and CD1c- B cells are activated in vitro, the CD1c molecule is upregulated in the former subset and induced de novo in the latter. Conversely, activated blood T cells remain CD1c-. Neither CD1a nor CD1b molecules are detected on activated T and B lymphocytes. At ultrastructural level, the CD1c+ B cells exhibit distinctive features, namely, condensed chromatin with or without a nucleolus and a unique cluster of cytoplasmic vesicles and organelles; the number of nucleolated cells is higher in the spleen (95%) than in the tonsil (40%) or blood (5%). These findings further confirm the similarity between blood and MZ B cells. The CD1c expression assessed on 27 B-cell chronic lymphocytic leukemias (B-CLL) and 46 B non-Hodgkin's lymphomas (B-NHL) was detected on 41% and 32% of cases, respectively; the latter comprised four follicular and 11 diffuse histotypes. The Burkitt's lymphomas were CD1c-negative. The B-cell neoplasms were all CD1a- and, except for four with a weak cytoplasmic staining, all CD1b- as well. The clear-cut CD1c distribution in normal LN (MZ+, GC-) contrasted with the evidence that some B-NHL cells of GC origin (eg, follicular with predominantly small cleaved cells) were CD1c+. Overall, the finding that CD1c expression is restricted to a fraction of B cells present in lymphoid organs and in peripheral blood indicates that CD1c is a powerful marker for the identification and dissection of B-cell subsets whose functional properties can now be evaluated.

scholarly journals Proportions of B-cell subsets are altered in incomplete systemic lupus erythematosus and correlate with interferon score and IgG levels

Rheumatology ◽  
2020 ◽  
Vol 59 (9) ◽  
pp. 2616-2624
Author(s):  
Svenja Henning ◽  
Wietske M Lambers ◽  
Berber Doornbos-van der Meer ◽  
Wayel H Abdulahad ◽  
Frans G M Kroese ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Subset ◽  
Cross Sectional Study ◽  
Type I ◽  
Healthy Controls ◽  
Sectional Study ◽  
Cross Sectional ◽  
B Cell Subsets

Abstract Objectives Incomplete SLE (iSLE) patients display symptoms typical for SLE but have insufficient criteria to fulfil the diagnosis. Biomarkers are needed to identify iSLE patients that will progress to SLE. IFN type I activation, B-cell-activating factor (BAFF) and B-cell subset distortions play an important role in the pathogenesis of SLE. The aim of this cross-sectional study was to investigate whether B-cell subsets are altered in iSLE patients, and whether these alterations correlate with IFN scores and BAFF levels. Methods iSLE patients (n = 34), SLE patients (n = 41) with quiescent disease (SLEDAI ≤4) and healthy controls (n = 22) were included. Proportions of B-cell subsets were measured with flow cytometry, IFN scores with RT-PCR and BAFF levels with ELISA. Results Proportions of age-associated B-cells were elevated in iSLE patients compared with healthy controls and correlated with IgG levels. In iSLE patients, IFN scores and BAFF levels were significantly increased compared with healthy controls. Also, IFN scores correlated with proportions of switched memory B-cells, plasma cells and IgG levels, and correlated negatively with complement levels in iSLE patients. Conclusion In this cross-sectional study, distortions in B-cell subsets were observed in iSLE patients and were correlated with IFN scores and IgG levels. Since these factors play an important role in the pathogenesis of SLE, iSLE patients with these distortions, high IFN scores, and high levels of IgG and BAFF may be at risk for progression to SLE.

scholarly journals The KDM4A/KDM4C/NF-κB and WDR5 epigenetic cascade regulates the activation of B cells

2018 ◽  
Vol 46 (11) ◽  
pp. 5547-5560 ◽  
Author(s):  
Kuo-Hsuan Hung ◽  
Yong H Woo ◽  
I-Ying Lin ◽  
Chin-Hsiu Liu ◽  
Li-Chieh Wang ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
De Novo ◽  
Epigenetic Mechanism ◽  
B Cell Activation ◽  
Motif Analysis ◽  
Follicular Helper

Abstract T follicular helper (Tfh) cell-derived signals promote activation and proliferation of antigen-primed B cells. It remains unclear whether epigenetic regulation is involved in the B cell responses to Tfh cell-derived signals. Here, we demonstrate that Tfh cell-mimicking signals induce the expression of histone demethylases KDM4A and KDM4C, and the concomitant global down-regulation of their substrates, H3K9me3/me2, in B cells. Depletion of KDM4A and KDM4C potentiates B cell activation and proliferation in response to Tfh cell-derived signals. ChIP-seq and de novo motif analysis reveals NF-κB p65 as a binding partner of KDM4A and KDM4C. Their co-targeting to Wdr5, a MLL complex member promoting H3K4 methylation, up-regulates cell cycle inhibitors Cdkn2c and Cdkn3. Thus, Tfh cell-derived signals trigger KDM4A/KDM4C - WDR5 - Cdkn2c/Cdkn3 cascade in vitro, an epigenetic mechanism regulating proper proliferation of activated B cells. This pathway is dysregulated in B cells from systemic lupus erythematosus patients and may represent a pathological link.

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