Hui-Chen Hsu

University of Alabama at Birmingham, Birmingham, Alabama, United States

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Publications (75)444.8 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Transient thymic involution is frequently found during inflammation, yet the mode of action of inflammatory cytokines is not well defined. Here we report that interleukin-23 (IL-23) production by the thymic dendritic cells (DCs) promotes apoptosis of the CD4(hi)CD8(hi) double-positive (DP) thymocytes. A deficiency in IL-23 signalling interferes with negative selection in the male D(b)/H-Y T-cell receptor (TCR) transgenic mice. IL-23 plus TCR signalling results in significant upregulation of IL-23 receptor (IL-23R) expressed predominantly on CD4(hi)CD8(hi)CD3(+)αβTCR(+) DP thymocytes, and leads to RORγt-dependent apoptosis. These results extend the action of IL-23 beyond its peripheral effects to a unique role in TCR-mediated negative selection including elimination of natural T regulatory cells in the thymus.
    Nature Communications 07/2014; 5:4259. · 10.74 Impact Factor
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    ABSTRACT: Objective: Follicular regulatory T (Tfr) cells act as the regulatory counterpart of follicular T helper (Tfh) cells to suppress germinal center (GC) B cell differentiation. We recently identified that interleukin 21 (IL-21) promoted Tfh differentiation in autoimmune BXD2 mice that develop spontaneous GCs. The objective of this study was to determine the modulatory effects of IL-21 on Tfr and the Tfr/Tfh balance in BXD2 mice. Methods: The percentage and phenotype of Tfr were determined in BXD2 and BXD2-Il21(-/-) mice. The effects of IL-21 on Tfr and the ratio of Tfr/Tfh were evaluated. Sorted Tfr cells from BXD2-Il21(-/-) mice were co-cultured with Tfh and B cells, or transferred into BXD2 mice to determine their function. Results: GC B cells and Tfh cells were significantly reduced, but the percentage of Tfr cells was 2-fold higher in BXD2-Il21(-/-) mice than in WT-BXD2. Adenovirus-IL-21 administration to BXD2-Il21(-/-) mice decreased Tfr and the ratio of Tfr/Tfh but increased GC B cells in the spleen. rmIL-21 suppressed Foxp3 and significantly reduced Tgfb1, Il2 and Gitr but enhanced Il21, Il6, Pd1, Cxcr5 and Icos in Tfr cells. IL-21 also counteracted Tfr-mediated inhibition of antibody secretion in the Tfh-B cell co-culture system. Transfer of Tfr cells into young BXD2 mice reduced GC size and decreased autoantibody-producing B cells. Conclusion: High levels of IL-21 selectively enhanced Tfh differentiation but inhibited Tfr commitment and their suppressive function on Tfh and B cells, suggesting that IL-21 skews the balance from Tfr to Tfh to promote autoreactive GC reactions in BXD2 mice. © 2014 American College of Rheumatology.
    Arthritis & rheumatology (Hoboken, N.J.). 06/2014;
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    ABSTRACT: The breakdown in tolerance of autoreactive B cells in the lupus-prone NZM2410-derived B6.Sle1.Sle2.Sle3 (TC) mice results in the secretion of autoantibodies. TC dendritic cells (DCs) enhance B cell proliferation and antibody secretion in a cytokine-dependent manner. However, the specific cytokine milieu by which TC DCs activate B cells was not known. In this study, we compared TC and C57BL/6 (B6) control for the distribution of DC subsets and for their production of cytokines affecting B cell responses. We show that TC DCs enhanced B cell proliferation through the production of IL-6 and IFN-γ, while antibody secretion was only dependent on IL-6. Pre-disease TC mice showed an expanded PDCA1+ cells prior to disease onset that was localized to the marginal zone and further expanded with age. The presence of PDCA1+ cells in the marginal zone correlated with a Type I Interferon (IFN) signature in marginal zone B cells, and this response was higher in TC than B6 mice. In vivo administration of anti-chromatin immune complexes upregulated IL-6 and IFN-γ production by splenic DCs from TC but not B6 mice. The production of BAFF and APRIL was decreased upon TC DC stimulation both in vitro and in vivo, indicating that these B cell survival factors do not play a role in B cell modulation by TC DCs. Finally, TC B cells were defective at downregulating IL-6 expression in response to anti-inflammatory apoptotic cell exposure. Overall, these results show that the TC autoimmune genetic background induces the production of B cell-modulating inflammatory cytokines by DCs, which are regulated by the microenvironment as well as the interplay between DC.
    PLoS ONE 01/2014; 9(8):e102151. · 3.53 Impact Factor
  • Jun Li, Hui-Chen Hsu, John D Mountz
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    ABSTRACT: The synovial tissue of Rheumatoid Arthritis (RA) patients is enriched with macrophages and T lymphocytes which are two central players in the pathogenesis of RA. Interaction between myeloid cells and T cells are essential for the initiation and progression of the inflammatory processes in the synovium. With the rapid evolution of our understanding of how these two cell types are involved in the regulation of immune responses, RA is emerging as an ideal disease model for investigating the cell-cell interactions and consequently introducing novel biologic agents that are designed to disrupt these processes. This review will discuss the bidirectional interaction between the IL-23(+) inflammatory macrophages and IL-17(+) GM-CSF(+) CD4 T cells in rheumatic diseases as well as potential antirheumatic strategies via apoptosis induction in this context.
    Journal of orthopedics & rheumatology. 11/2013; 1(1):4.
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    ABSTRACT: Germinal centers (GCs) provide a microenvironment that promotes and regulates the interactions of B cells with follicular Th (TFH) cells. In this study, we show that there are significantly higher frequencies of CXCR5(+)ICOS(+) TFH cells in autoimmune BXD2 mice, and these cells express both IL-21R and IL-17RA. Although IL-17 and IL-21 are both important for the formation of spontaneous GCs and development of pathogenic autoantibodies, IL-21, but not IL-17, is required for the proper development of TFH cells in BXD2 mice. The total numbers of TFH cells and their ability to induce B cell responses in vitro were not affected by a deficiency of IL-17RA in BXD2-Il17ra(-/-) mice, the majority of CXCR5(+) TFH cells from BXD2-Il17ra(-/-) mice were, however, not localized in the GC light zone (LZ). Interruption of IL-17 signaling, either acutely by AdIL-17R:Fc or chronically by Il17ra(-/-), disrupted TFH-B interactions and abrogated the generation of autoantibody-forming B cells in BXD2 mice. IL-17 upregulated the expression of regulator of G-protein signaling 16 (RGS16) to promote the ability of TFH to form conjugates with B cells, which was abolished in TFH cells from BXD2-Rgs16(-/-) mice. The results suggests that IL-17 is an extrinsic stop signal that it acts on postdifferentiated IL-17RA(+) TFH to enable its interaction with responder B cells in the LZ niche. These data suggest a novel concept that TFH differentiation and its stabilization in the LZ are two separate checkpoints and that IL-21 and IL-17 act at each checkpoint to enable pathogenic GC development.
    The Journal of Immunology 07/2013; · 5.52 Impact Factor
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    ABSTRACT: Objective. Regulator of G-protein Signaling (RGS) proteins inhibit chemokine signaling by desensitizing G-protein coupled receptor signals. The mechanisms by which RGS13 promotes the generation of pathogenic autoantibodies in germinal centers (GC) were determined using BXD2-Rgs13(-/-) mice. Methods. Confocal and light microscopy imaging was used to determine the location of cells that express RGS13 and activation-induced cytidine deaminase (AID) in the spleen and the number of plasmablasts. The levels of GC and plasma cell program transcripts in GC B cells were determined by quantitative real-time PCR. Differential IL-17-mediated expression of Rgs13 in GC versus non-GC B cells was analyzed using A20 versus 70Z/3 B cells. Results. In spleens of BXD2 mice, RGS13 was mainly expressed by GC B cells and was stimulated by IL-17 but not IL-21. IL-17 upregulated Rgs13 in A20 GC but not 70Z/3 non-GC B cells. BXD2-Rgs13(-/-) mice exhibited smaller GCs, lower AID levels, suggesting lower somatic hypermutation and affinity maturation. There were, however, increased IgM(bright) plasmablasts, upregulation of plasma program genes Irf4, Blimp1, Xbp1 and pCREB target genes Fosb and Obf1, with down-regulation of GC program genes Aicda, Pax5 and Bach2 in GC B cells of BXD2-Rgs13(-/-) mice. BXD2-Rgs13(-/-) mice showed lower titers of IgG autoantibodies and IgG deposits in the glomeruli, suggesting reduced autoantibody pathogenicity. Conclusion. RGS13 deficiency is associated with reduction in GC program genes and exit of less pathogenic IgM plasmablasts in BXD2 mice. Prolonged GC program, mediated by upregulation RGS13, enhanced AID expression and enabled generation of pathogenic autoantibodies in autoreactive GCs. © 2013 American College of Rheumatology.
    Arthritis & Rheumatology 07/2013; · 7.48 Impact Factor
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    ABSTRACT: Objective. Bidirectional GM-CSF(+) T cell and IRF-5(+) macrophage (Mφ) interactions play a major role in autoimmunity. In the absence of SHP-1, GM-CSF-stimulated cells are resistant to death receptor-mediated apoptosis. The objective of this study is to determine whether TRA-8, an anti-death receptor 5 (DR5) agonistic antibody, can eliminate inflammatory Mφs and CD4 T cells in the SHP-1-defective condition. Methods. A ubiquitous Cre (Ubc.Cre) human/mouse (hu/mo) DR5 transgenic (Tg) mouse was crossed with SHP-1-defective viable motheaten (me(v) /me(v) ) mice. TRA-8 was administered weekly for up to 4 weeks. The clinical scores, histopathologic severity, and MØ and CD4 T cell phenotypes were evaluated. The effect of TRA-8 in depleting inflammatory MØ and CD4 T cells was also evaluated using human rheumatoid arthritis (RA) synovial fluid. Results. Inflammatory MØ (IL-23(+) IRF5(+) ) and CD4 T (IL-17(+) GM-CSF(+) ) cells were elevated in me(v) /me(v) mice. In DR5 Tg me(v) /me(v) mice, DR5 expression was upregulated in these two cell populations. TRA-8 treatment depleted these cells and resulted in a significant reduction of autoantibodies and inflammation. In human RA synovial cells, the expression of IRF5 and DR5 was negatively correlated with PTPN6. TRA-8, but not TRAIL, suppressed RA inflammatory MØ and Th17 cells in the low SHP-1 condition. Conclusion. In contrast with TRAIL, which lacks the capability to counteract the survival signal in the absence of SHP-1, TRA-8 eliminated both M1 MØ and pathogenic CD4 T cells in a SHP-1-independent manner. The present study suggests that TRA-8 can deplete inflammatory cells resulting from an overactive GM-CSF/IRF-5 axis. © 2013 American College of Rheumatology.
    Arthritis & Rheumatology 07/2013; · 7.48 Impact Factor
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    ABSTRACT: Given the protective roles of 25-hydroxyvitamin D (25[OH]D or vitamin D) in musculoskeletal health and the potential beneficial effects of vitamin D supplementation in reducing the risk of various chronic diseases, intensive repletion of vitamin D has been widely advocated. Of note, CD8 T cells have the highest levels of the vitamin D receptor compared with other major immune cells. The effects of vitamin D on CD8 T cells during aging, however, remain unclear. This study determined the relationship between vitamin D levels and CD8 T-cell status in 34 healthy female subjects (all >60 years old). The CD8 T cell phenotype was defined by the surface expression of CD28 and CD95. The low-25(OH)D serum groups (≤30 ng/ml) had higher percentages of CD28(+)CD95(-)CD8(+) (naïve) T cells and lower percentages of CD28(+)CD95(+)CD8(+) (effector) T cells. By contrast, subjects with high levels of 25(OH)D had very low percentages of naïve CD8 T cells but very high percentages of effector CD8 T cells. There was a significant inverse correlation between 25(OH)D levels and the frequency of naïve CD8 T cells. The results show that higher levels of vitamin D are correlated with decreased frequencies of naïve CD8 T cells during early aging, suggesting that higher levels of 25(OH)D accelerate CD8 T-cell senescence. These results warrant the further evaluation of the effects of vitamin D supplementation in immune aging.
    Advances in Aging Research 05/2013; 2(2):72-80.
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    ABSTRACT: Marginal zone macrophages (MZMs) act as a barrier to entry of circulating apoptotic debris into the follicles of secondary lymphoid organs. In autoimmune BXD2 mice, there is a progressive reduction in the function and numbers of MZMs. Absence of MZMs results in retention of apoptotic cell (AC) debris within the marginal zone (MZ) and increased loading of AC Ags on MZ B cells and MZ-precursor (MZ-P) B cells. The MZ-P B cells are capable of translocating the AC Ags to the follicular zone and stimulating T cells. Both MZMs and MZ-P B cells from BXD2 mice express low levels of tolerogenic signals and high levels of inflammatory signals. Thus, the current study suggests a multifaceted mechanism in which MZMs maintain tolerance to apoptotic autoantigens and suppress their translocation to follicles. Lack of clearance of apoptotic debris by MZMs drives follicular Ag-transportation by MZ-P B cells to stimulate an autoimmune response.
    The Journal of Immunology 03/2013; · 5.52 Impact Factor
  • Jun Li, Hui-Chen Hsu, John D Mountz
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    ABSTRACT: Macrophages play a central role in the pathogenesis of rheumatoid arthritis (RA). There is an imbalance of inflammatory and antiinflammatory macrophages in RA synovium. Although the polarization and heterogeneity of macrophages in RA have not been fully uncovered, the identity of macrophages in RA can potentially be defined by their products, including the co-stimulatory molecules, scavenger receptors, different cytokines/chemokines and receptors, and transcription factors. In the last decade, efforts to understand the polarization, apoptosis regulation, and novel signaling pathways in macrophages, as well as how distinct activated macrophages influence disease progression, have led to strategies that target macrophages with varied specificity and selectivity. Major targets that are related to macrophage development and apoptosis include TNF-α, IL-1, IL-6, GM-CSF, M-CSF, death receptor 5 (DR5), Fas, and others, as listed in Table 1. Combined data from clinical, preclinical, and animal studies of inhibitors of these targets have provided valuable insights into their roles in the disease progression and, subsequently, have led to the evolving therapeutic paradigms in RA. In this review, we propose that reestablishment of macrophage equilibrium by inhibiting the development of, and/or eliminating, the proinflammatory macrophages will be an effective therapeutic approach for RA and other autoimmune diseases.
    Current Rheumatology Reports 08/2012; 14(5):445-54.
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    John D Mountz, Jun Li, Hui-Chen Hsu
    Arthritis & Rheumatology 12/2011; 64(3):609-12. · 7.48 Impact Factor
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    ABSTRACT: To determine the therapeutic efficacy and immunomodulatory effect of an anti-human death receptor 5 (DR5) antibody, TRA-8, in eliminating macrophage subsets in a mouse model of type II collagen-induced arthritis (CIA). A human/mouse-chimeric DR5-transgenic mouse, under the regulation of a mouse 3-kb promoter and a loxP-flanked STOP cassette, was generated and crossed with an ubiquitous Cre (Ubc.Cre) mouse and a lysozyme M-Cre (LysM.Cre)-transgenic mouse to achieve inducible or macrophage-specific expression. Chicken type II collagen was used to induce CIA in mice, which were then treated with an anti-human DR5 antibody, TRA-8. Clinical scores, histopathologic severity, macrophage apoptosis and depletion, and T cell subset development were evaluated. In human/mouse DR5-transgenic Ubc.Cre mice with CIA, transgenic DR5 was most highly expressed on CD11b+ macrophages, with lower expression on CD4+ T cells. In human/mouse DR5-transgenic LysM.Cre mice, transgenic DR5 was restrictively expressed on macrophages. Both in vivo near-infrared imaging of caspase activity and TUNEL staining demonstrated that TRA-8 rapidly induced apoptosis of macrophages in inflamed synovium. Depletion of pathogenic macrophages by TRA-8 led to significantly reduced clinical scores for arthritis; decreased macrophage infiltration, synovial hyperplasia, osteoclast formation, joint destruction, cathepsin activity, and inflammatory cytokine expression in joints; reduced numbers of Th17 cells; and an increased number of Treg cells in draining lymph nodes. The anti-human DR5 antibody TRA-8 was efficacious in reducing the severity of arthritis via targeted depletion of macrophages and immunomodulation. Our data provide preclinical evidence that TRA-8 is a potential novel biologic agent for rheumatoid arthritis therapy.
    Arthritis & Rheumatology 10/2011; 64(4):1098-109. · 7.48 Impact Factor
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    ABSTRACT: BE-3-3-3-3 (1,15-(ethylamino)4,8,12-triazapentadecane) is a bis(ethyl)polyamine analogue under investigation as a therapeutic agent for breast cancer. Since estradiol (E(2)) is a critical regulatory molecule in the growth of breast cancer, we examined the effect of BE-3-3-3-3 on estrogen receptor α (ERα) positive MCF-7 cells in the presence and absence of E(2). In the presence of E(2), a concentration-dependent decrease in DNA synthesis was observed using [(3)H]-thymidine incorporation assay. In the absence of E(2), low concentrations (2.5-10 μM) of BE-3-3-3-3 increased [(3)H]-thymidine incorporation at 24 and 48 h. BE-3-3-3-3 induced the expression of early response genes, c-myc and c-fos, in the absence of E(2), but not in its presence, as determined by real-time quantitative polymerase chain reaction (qPCR). BE-3-3-3-3 had no significant effect on these genes in an ERα-negative cell line, MDA-MB-231. Chromatin immunoprecipitation assay demonstrated enhanced promoter occupation by either E(2) or BE-3-3-3-3 of an estrogen-responsive gene pS2/Tff1 by ERα and its co-activator, steroid receptor co-activator 3 (SRC-3). Confocal microscopy of BE-3-3-3-3-treated cells revealed membrane localization of ERα, similar to that induced by E(2). The failure of BE-3-3-3-3 to inhibit cell proliferation was associated with autophagic vacuole formation, and the induction of Beclin 1 and MAP LC3 II. These results indicate a differential effect of BE-3-3-3-3 on MCF-7 cells in the absence and presence of E(2), and suggest that pre-clinical and clinical development of polyamine analogues might require special precautions and selection of sensitive subpopulation of patients.
    Amino Acids 08/2011; 42(2-3):899-911. · 3.91 Impact Factor
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    ABSTRACT: The pathogenesis of systemic lupus erythematosus (SLE) is multifactorial and multi-genetic. Chronic inflammation associated with lupus is thought to be due to loss of self-tolerance due to molecular mimicry, environment trigger, hormonal factors or apoptosis defects. Defects in apoptosis will be the focus of this chapter. Defects in apoptosis can lead to abnormal clonal deletion of autoreactive cells or failure to downmodulate an inflammatory response. Although the Fas death domain family of molecules are the primary pathway for elimination of inflammatory cells, defects in these death domain molecules are rarely observed in lupus and lupus-like syndromes. Patients with autoimmune-lymphoproliferative (ALPS) syndrome disease have defects in Fas, and we have reported one patient with SLE that exhibits a mutation of Fas ligand. Other death domain family molecules such as death receptor 3 (DR3), DR4, DRS, Fas ligand 2 (FasL2) have not been studied in SLE. Also, there are signaling pathways for apoptosis including Fas-associated protein with death domain (FADD), tumor necrosis factor receptor-1 associated death domain (TRADD), FADD-like interleukin-113 converting enzyme (FLICE) which are important in apoptosis signaling. The bc1-2 family modulate apoptosis, and have been reported to be abnormal in human autoimmune disease. Soluble inhibitors of Fas apoptosis including a soluble form of Fas which lacks the transmembrane exon are elevated in SLE patients. Different genetic and environmental factors are proposed to interfere with apoptosis and clearance of inflammatory cells at several levels leading to the cellular defects of T cell dysfunction and B cell hyperactivity observed in patients with SLE.
    07/2011: pages 181-212;
  • Hui-Chen Hsu, John D Mountz
    Arthritis & Rheumatology 06/2011; · 7.48 Impact Factor
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    ABSTRACT: To investigate the role of CD86(high) marginal zone (MZ) precursor B cells in type I interferon (IFN)-induced T cell-dependent responses in autoimmune BXD2 mice. Confocal microscopic imaging was used to determine the location of plasmacytoid dendritic cells (DCs), MZ precursor B cells, and CD4 T cells in the spleens of BXD2 and BXD2-Ifnar(-/-) mice. Immunohistochemical staining was used to determine IgG(bright) cells in the spleens of BXD2 and BXD2-Ifnar(-/-) mice. Enzyme-linked immunosorbent assay was used to determine serum levels of IFNα and autoantibodies, and 4-hydroxy-3-nitrophenylacetyl hapten (NP)-chicken γ-globulin (CGG) (NP-CGG)- or NP-Ficoll-induced anti-NP2 antibody titers. Real-time quantitative polymerase chain reaction was used to determine the levels of type I IFN transcripts. T cell proliferation was measured using (3) H-thymidine. The expression of CD86 and CD80 was determined by fluorescence-activated cell sorting analysis. The deletion of type I IFN receptor abrogated the development of IgG(bright) cells and suppressed a T cell-dependent antibody response. Type I IFN signaling was associated with the expression of CD86, but not CD80, on follicular, MZ, and MZ precursor B cells. However, MZ precursor B cells demonstrated the highest expression of CD86 and the highest capacity for T cell costimulation with intact type I IFN receptor. This effect was blocked by an antibody that neutralizes CD86. In IFN receptor-intact BXD2 mouse spleens, MZ precursor B cells clustered at the T cell-B cell border. CD86 deletion suppressed germinal center formation, autoantibody production, and development of autoimmune diseases in BXD2 mice. Type I IFN can promote autoimmune responses in BXD2 mice through up-regulation of CD86(high) expression on MZ precursor B cells and trafficking of MZ precursor B cells to the T cell-B cell border to provide costimulation of CD4 T cells.
    Arthritis & Rheumatology 01/2011; 63(4):1054-64. · 7.48 Impact Factor
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    ABSTRACT: Chemotaxis is essential for shaping immune responses and chemokine-receptor antagonists are now being evaluated as therapies for various inflammatory and autoimmune diseases. However, the dysregulation of chemotaxis in autoimmune disease may involve both promotion and inhibition of B-cell migration. This review focuses on the disparate mechanisms by which two inflammatory cytokines that have been associated with autoimmune disease, namely interferon-alpha (IFN-alpha) and interleukin-17 (IL-17), may regulate B-cell migratory responses. Chemotactic responses play a key role in orchestrating the cell-cell interactions in the germinal centers (GCs). This process involves active shuttling of the antigen-carrying B cells between the marginal zone and the GCs. We have shown that in autoimmune BXD2 mice, the migration of marginal zone precursor B cells is promoted by high levels of IFN-alpha produced by plasmacytoid dendritic cells in the marginal sinus that antagonize the activity of the S1P(1) chemokine receptor. In contrast, within the GCs, interleukin-17A (IL-17A) upregulates the expression of regulators of G protein signaling (RGS) in B cells to desensitize the G protein-coupled receptor (GPCR) signaling pathway of CXCL12 and CXCL13 chemokines. This promotes a prolonged stable interaction of B and T cells in the GC that induces high levels of activation-induced cytidine deaminase (AICDA) thereby enabling development of pathogenic autoantibody-producing B cells.
    Discovery medicine 01/2011; 11(56):76-85. · 2.97 Impact Factor
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    ABSTRACT: To determine whether functional suppression of the catalytic domain of activation-induced cytidine deaminase (AID) can suppress the hyperreactive germinal center (GC) responses in BXD2 mice. We generated transgenic BXD2 mice expressing a dominant-negative (DN) form of Aicda at the somatic hypermutation site (BXD2-Aicda-DN-transgenic mice). Real-time quantitative reverse transcriptase-polymerase chain reaction was used to determine the expression of Aicda and DNA damage/repair genes. Enzyme-linked immunosorbent assay was used to measure serum levels of autoantibodies and immune complexes (ICs). Development of GCs and antibody-containing ICs as well as numbers of proliferative and apoptotic cells were determined using flow cytometry and/or immunohistochemical analyses. Development of arthritis and kidney disease was evaluated histologically in 6-8-month-old mice. Suppression of the somatic hypermutation function of AID resulted in a significant decrease in autoantibody production without affecting the expression of DNA damage-related genes in GC B cells of BXD2-Aicda-DN-transgenic mice. There was decreased proliferation, increased apoptosis, increased expression of caspase 9 messenger RNA in GC B cells, and lower numbers of GCs in the spleens of BXD2-Aicda-DN-transgenic mice. Decreased GC response was associated with lower levels of IgG-containing ICs. Anti-IgM- and anti-CD40 plus anti-Ig-induced B cell proliferative responses were decreased in BXD2-Aicda-DN-transgenic mice. Inhibition of the AID somatic hypermutation function in BXD2 mice suppressed development of spontaneous GCs, generation of autoantibody-producing B cells, and autoimmunity in BXD2 mice. Suppression of AID catalytic function to limit selection-based survival of GC B cells could become a novel therapy for the treatment of autoimmune disease.
    Arthritis & Rheumatology 01/2011; 63(7):2038-48. · 7.48 Impact Factor
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    Hui-Chen Hsu, John D Mountz
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    ABSTRACT: Although the phenotype of T-cell senescence has been extensively investigated, few studies have analyzed the factors that promote the generation and maintenance of naïve and memory T cells that exist throughout the lifespan of the individuals. Unlike senescent T cells, naïve and memory T cells are able to participate in useful immune responses as well as respond to new activation. Hormones such as leptin, ghrelin, insulin-like growth factor 1, IGFBP3, and cytokines, including IL-7, regulate both thymopoiesis and maintenance of naïve T cells in the periphery. Although chronic viruses such as cytomegalovirus (CMV) are thought to drive T-cell senescence, other microbes may be important for the maintenance of nonsenescent T cells. Microbiota of the gut can induce metabolic syndrome as well as modulate T-cell development into specific subpopulations of effector cells. Finally, T-cell generation, maintenance, and apoptosis depend upon pathways of energy utilization within the T cells, which parallel those that regulate overall metabolism. Therefore, better understanding of metabolic syndrome, T-cell metabolism, hormones, and microbiota may lead to new insights into the maintenance of proper immune responses in old age.
    Current opinion in immunology 08/2010; 22(4):541-8. · 10.88 Impact Factor
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    ABSTRACT: We previously identified that autoreactive B cells from BXD2 mice can be targeted by IL-17, leading to upregulation of the expression of regulators of G-protein signaling (Rgs) genes that facilitated the development of spontaneous germinal centers. Little is known about the signaling pathway used by IL-17 to upregulate RGS. In the current study, we found that IL-17 rapidly activates the canonical NF-kappaB signaling pathway and that BXD2 B cells exhibit higher basal and activated phosphorylated p65 levels than B6 or BXD2-Il17ra(-/-) B cells. Inhibition of p65 phosphorylation downregulated RGS16 expression and abrogated the IL-17-induced chemotactic arrest of B cells in response to CXCL12. Knockdown of TNFR-associated factor 6 or NF-kappaB activator 1 in 70Z/3 pre-B cells led to decreased Rgs16 expression, indicating that both of these two genes are involved in IL-17-mediated activation of NF-kappaB signaling in B cells. These findings identify the signaling pathway regulated by IL-17 to contribute to the development of spontaneous germinal centers in autoimmune BXD2 mice.
    The Journal of Immunology 02/2010; 184(5):2289-96. · 5.52 Impact Factor

Publication Stats

2k Citations
444.80 Total Impact Points

Institutions

  • 1997–2014
    • University of Alabama at Birmingham
      • • Division of Clinical Immunology and Rheumatology
      • • Department of Medicine
      Birmingham, Alabama, United States
  • 2004
    • The Jackson Laboratory
      Bar Harbor, Maine, United States