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  1. Article ; Online: NADPH oxidase exerts a B cell-intrinsic contribution to lupus risk by modulating endosomal TLR signals.

    Liu, Shuozhi / Lagos, Jonathan / Shumlak, Natali M / Largent, Andrea D / Lewis, Sebastien T E / Holder, Ursula / Du, Samuel W / Liu, Yifan / Hou, Baidong / Acharya, Mridu / Jackson, Shaun W

    The Journal of experimental medicine

    2024  Volume 221, Issue 4

    Abstract: Genome-wide association studies in systemic lupus erythematosus (SLE) have linked loss-of-function mutations in phagocytic NADPH oxidase complex (NOX2) genes, including NCF1 and NCF2, to disease pathogenesis. The prevailing model holds that reduced NOX2 ... ...

    Abstract Genome-wide association studies in systemic lupus erythematosus (SLE) have linked loss-of-function mutations in phagocytic NADPH oxidase complex (NOX2) genes, including NCF1 and NCF2, to disease pathogenesis. The prevailing model holds that reduced NOX2 activity promotes SLE via defective efferocytosis, the immunologically silent clearance of apoptotic cells. Here, we describe a parallel B cell-intrinsic mechanism contributing to breaks in tolerance. In keeping with an important role for B cell Toll-like receptor (TLR) pathways in lupus pathogenesis, NOX2-deficient B cells exhibit enhanced signaling downstream of endosomal TLRs, increased humoral responses to nucleic acid-containing antigens, and the propensity toward humoral autoimmunity. Mechanistically, TLR-dependent NOX2 activation promotes LC3-mediated maturation of TLR-containing endosomes, resulting in signal termination. CRISPR-mediated disruption of NCF1 confirmed a direct role for NOX2 in regulating endosomal TLR signaling in primary human B cells. Together, these data highlight a new B cell-specific mechanism contributing to autoimmune risk in NCF1 and NCF2 variant carriers.
    MeSH term(s) Humans ; NADPH Oxidases/genetics ; Genome-Wide Association Study ; Autoimmunity/genetics ; Endosomes ; Lupus Erythematosus, Systemic/genetics
    Chemical Substances NADPH Oxidases (EC 1.6.3.-)
    Language English
    Publishing date 2024-03-05
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218343-2
    ISSN 1540-9538 ; 0022-1007
    ISSN (online) 1540-9538
    ISSN 0022-1007
    DOI 10.1084/jem.20230774
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Cutting Edge: Systemic Autoimmunity in Murine STAT3 Gain-of-Function Syndrome Is Characterized by Effector T Cell Expansion in the Absence of Overt Regulatory T Cell Dysfunction.

    Woods, Jonathan / Pemberton, Sarah E / Largent, Andrea D / Chiang, Kristy / Liggitt, Denny / Oukka, Mohamed / Rawlings, David J / Jackson, Shaun W

    Journal of immunology (Baltimore, Md. : 1950)

    2022  Volume 209, Issue 6, Page(s) 1033–1038

    Abstract: Germline gain-of-function mutations in the transcriptional ... ...

    Abstract Germline gain-of-function mutations in the transcriptional factor
    MeSH term(s) Animals ; Autoimmunity ; CD8-Positive T-Lymphocytes/metabolism ; Cell Differentiation ; Gain of Function Mutation ; Gene Knock-In Techniques ; Humans ; Inflammation/pathology ; Mice ; Mice, Transgenic ; STAT3 Transcription Factor/genetics ; T-Lymphocytes, Regulatory ; Th17 Cells
    Chemical Substances STAT3 Transcription Factor ; STAT3 protein, human ; Stat3 protein, mouse
    Language English
    Publishing date 2022-08-22
    Publishing country United States
    Document type Journal Article
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.2100920
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Dysregulated IFN-γ signals promote autoimmunity in STAT1 gain-of-function syndrome.

    Largent, Andrea D / Lambert, Katharina / Chiang, Kristy / Shumlak, Natali / Liggitt, Denny / Oukka, Mohammed / Torgerson, Troy R / Buckner, Jane H / Allenspach, Eric J / Rawlings, David J / Jackson, Shaun W

    Science translational medicine

    2023  Volume 15, Issue 703, Page(s) eade7028

    Abstract: Heterozygous signal transducer and activator of transcription 1 ( ...

    Abstract Heterozygous signal transducer and activator of transcription 1 (
    MeSH term(s) Humans ; Child ; Mice ; Animals ; Autoimmunity/genetics ; Gain of Function Mutation ; Interferon-gamma/metabolism ; Syndrome ; Inflammation ; STAT1 Transcription Factor/genetics ; STAT1 Transcription Factor/metabolism
    Chemical Substances Interferon-gamma (82115-62-6) ; STAT1 Transcription Factor ; STAT1 protein, human
    Language English
    Publishing date 2023-07-05
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2518854-9
    ISSN 1946-6242 ; 1946-6234
    ISSN (online) 1946-6242
    ISSN 1946-6234
    DOI 10.1126/scitranslmed.ade7028
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Cutting Edge: A Threshold of B Cell Costimulatory Signals Is Required for Spontaneous Germinal Center Formation in Autoimmunity.

    Chiang, Kristy / Largent, Andrea D / Arkatkar, Tanvi / Thouvenel, Christopher D / Du, Samuel W / Shumlak, Natali / Woods, Jonathan / Li, Quan-Zhen / Liu, Yifan / Hou, Baidong / Rawlings, David J / Jackson, Shaun W

    Journal of immunology (Baltimore, Md. : 1950)

    2021  Volume 207, Issue 9, Page(s) 2217–2222

    Abstract: Cognate interactions between autoreactive B and T cells promote systemic lupus erythematosus pathogenesis by inter alia facilitating spontaneous germinal center (GC) formation. Whereas both myeloid and B cell APCs express B7 ligands (CD80 and CD86), the ... ...

    Abstract Cognate interactions between autoreactive B and T cells promote systemic lupus erythematosus pathogenesis by inter alia facilitating spontaneous germinal center (GC) formation. Whereas both myeloid and B cell APCs express B7 ligands (CD80 and CD86), the prevailing model holds that dendritic cell costimulation is sufficient for CD28-dependent T cell activation. In this study, we report that B cell-intrinsic CD80/CD86 deletion unexpectedly abrogates GCs in murine lupus. Interestingly, absent GCs differentially impacted serum autoantibodies. In keeping with distinct extrafollicular and GC activation pathways driving lupus autoantibodies, lack of GCs correlated with loss of RNA-associated autoantibodies but preserved anti-dsDNA and connective tissue autoantibody titers. Strikingly, even heterozygous B cell CD80/CD86 deletion was sufficient to prevent autoimmune GCs and RNA-associated autoantibodies. Together, these findings identify a key mechanism whereby B cells promote lupus pathogenesis by providing a threshold of costimulatory signals required for autoreactive T cell activation.
    MeSH term(s) Animals ; Autoantibodies/metabolism ; Autoimmunity ; B-Lymphocytes/immunology ; B7-1 Antigen/genetics ; B7-1 Antigen/metabolism ; B7-2 Antigen/genetics ; B7-2 Antigen/metabolism ; Cells, Cultured ; Disease Models, Animal ; Germinal Center/immunology ; Humans ; Lupus Erythematosus, Systemic/immunology ; Lupus Nephritis/immunology ; Lymphocyte Activation ; Mice ; Mice, Knockout ; Receptor Cross-Talk ; T-Lymphocytes, Helper-Inducer/immunology
    Chemical Substances Autoantibodies ; B7-1 Antigen ; B7-2 Antigen
    Language English
    Publishing date 2021-09-29
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.2100548
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Functional Characterization of CD11c

    Du, Samuel W / Arkatkar, Tanvi / Al Qureshah, Fahd / Jacobs, Holly M / Thouvenel, Christopher D / Chiang, Kristy / Largent, Andrea D / Li, Quan-Zhen / Hou, Baidong / Rawlings, David J / Jackson, Shaun W

    Journal of immunology (Baltimore, Md. : 1950)

    2019  Volume 203, Issue 11, Page(s) 2817–2826

    Abstract: Age-associated B cells (ABCs) are a unique subset of B cells defined by surface CD11b and CD11c expression. Although ABC expansion has been observed in both human and animal studies in the setting of advanced age, during humoral autoimmunity and ... ...

    Abstract Age-associated B cells (ABCs) are a unique subset of B cells defined by surface CD11b and CD11c expression. Although ABC expansion has been observed in both human and animal studies in the setting of advanced age, during humoral autoimmunity and following viral infection, the functional properties of this cellular subset remain incompletely defined. In the current study, we demonstrate that ABCs fulfill the criteria for memory B cells (MBCs), based on evidence of Ag-dependent expansion and persistence in a state poised for rapid differentiation into Ab-secreting plasma cells during secondary responses. First, we show that a majority of ABCs are not actively cycling but exhibit an extensive replication history consistent with prior Ag engagement. Second, despite unswitched surface IgM expression, ABCs show evidence of activation-induced cytidine deaminase (AID)-dependent somatic hypermutation. Third, BCRs cloned from sorted ABCs exhibit broad autoreactivity and polyreactivity. Although the overall level of ABC self-reactivity was not increased relative to naive B cells, ABCs lacked features of functional anergy characteristic of autoreactive B cells. Fourth, ABCs express MBC surface markers consistent with being poised for rapid plasma cell differentiation during recall responses. Finally, in a murine model of viral infection, adoptively transferred CD11c
    MeSH term(s) Aging/immunology ; Animals ; B-Lymphocytes/immunology ; CD11c Antigen/immunology ; Immunologic Memory/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout
    Chemical Substances CD11c Antigen
    Language English
    Publishing date 2019-10-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 3056-9
    ISSN 1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
    ISSN (online) 1550-6606
    ISSN 0022-1767 ; 1048-3233 ; 1047-7381
    DOI 10.4049/jimmunol.1900404
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: WT1 Is Necessary for the Proliferation and Migration of Cells of Renin Lineage Following Kidney Podocyte Depletion.

    Kaverina, Natalya V / Eng, Diana G / Largent, Andrea D / Daehn, Ilse / Chang, Anthony / Gross, Kenneth W / Pippin, Jeffrey W / Hohenstein, Peter / Shankland, Stuart J

    Stem cell reports

    2017  Volume 9, Issue 4, Page(s) 1152–1166

    Abstract: Wilms' tumor suppressor 1 (WT1) plays an important role in cell proliferation and mesenchymal-epithelial balance in normal development and disease. Here, we show that following podocyte depletion in three experimental models, and in patients with focal ... ...

    Abstract Wilms' tumor suppressor 1 (WT1) plays an important role in cell proliferation and mesenchymal-epithelial balance in normal development and disease. Here, we show that following podocyte depletion in three experimental models, and in patients with focal segmental glomerulosclerosis (FSGS) and membranous nephropathy, WT1 increased significantly in cells of renin lineage (CoRL). In an animal model of FSGS in RenWt1
    MeSH term(s) Animals ; Biomarkers ; Cell Lineage ; Cell Movement/genetics ; Cell Proliferation/genetics ; Disease Models, Animal ; Gene Deletion ; Kidney Function Tests ; Kidney Glomerulus/metabolism ; Kidney Glomerulus/pathology ; Mice ; Mice, Knockout ; Podocytes/cytology ; Podocytes/metabolism ; Renin/genetics ; Renin/metabolism ; WT1 Proteins/genetics ; WT1 Proteins/metabolism
    Chemical Substances Biomarkers ; WT1 Proteins ; Renin (EC 3.4.23.15)
    Language English
    Publishing date 2017-09-28
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2720528-9
    ISSN 2213-6711 ; 2213-6711
    ISSN (online) 2213-6711
    ISSN 2213-6711
    DOI 10.1016/j.stemcr.2017.08.020
    Database MEDical Literature Analysis and Retrieval System OnLINE

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