Publications by authors named "Laurie S Davis"

34 Publications

Foxo3 Promotes Apoptosis of B Cell Receptor-Stimulated Immature B Cells, Thus Limiting the Window for Receptor Editing.

J Immunol 2018 08 27;201(3):940-949. Epub 2018 Jun 27.

Rheumatic Diseases Division, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390;

Central tolerance checkpoints are critical for the elimination of autoreactive B cells and the prevention of autoimmunity. When autoreactive B cells encounter their Ag at the immature B cell stage, BCR cross-linking induces receptor editing, followed by apoptosis if edited cells remain autoreactive. Although the transcription factor Foxo1 is known to promote receptor editing, the role of the related factor Foxo3 in central B cell tolerance is poorly understood. We find that BCR-stimulated immature B cells from Foxo3-deficient mice demonstrate reduced apoptosis compared with wild type cells. Despite this, Foxo3 mice do not develop increased autoantibodies. This suggests that the increased survival of Foxo3 immature B cells allows additional rounds of receptor editing, resulting in more cells "redeeming" themselves by becoming nonautoreactive. Indeed, increased Igλ usage and increased recombining sequence recombination among Igλ-expressing cells were observed in Foxo3 mice, indicative of increased receptor editing. We also observed that deletion of high-affinity autoreactive cells was intact in the absence of Foxo3 in the anti-hen egg lysozyme (HEL)/membrane-bound HEL model. However, Foxo3 levels in B cells from systemic lupus erythematosus (SLE) patients were inversely correlated with disease activity and reduced in patients with elevated anti-dsDNA Abs. Although this is likely due in part to increased B cell activation in these SLE patients, it is also possible that low-affinity B cells that remain autoreactive after editing may survive inappropriately in the absence of Foxo3 and become activated to secrete autoantibodies in the context of other SLE-associated defects.
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http://dx.doi.org/10.4049/jimmunol.1701070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6057821PMC
August 2018

Flora-ishing guts assist cancer immunotherapies.

Authors:
Laurie S Davis

Sci Immunol 2018 02;3(20)

Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA. Email:

Gut bacteria influence patient response to cancer therapy.
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http://dx.doi.org/10.1126/sciimmunol.aat0813DOI Listing
February 2018

The yin and yang of cytokine priming on the macrophage epigenome.

Authors:
Laurie S Davis

Sci Immunol 2017 11;2(17)

Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA. Email:

TNF and type I interferons alter TLR4 responses by reprogramming the macrophage genome.
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http://dx.doi.org/10.1126/sciimmunol.aaq0016DOI Listing
November 2017

In SLE genetics, white does not equal black, 1+1 does not equal 2.

Authors:
Laurie S Davis

Sci Immunol 2017 Aug;2(14)

Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA. Email:

A transancestral SLE study examining the relationship between genetic load and disease risk.
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http://dx.doi.org/10.1126/sciimmunol.aao3114DOI Listing
August 2017

A of hope for autoimmunity.

Authors:
Laurie S Davis

Sci Immunol 2017 May 5;2(11). Epub 2017 May 5.

Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX 75390, USA. Email:

The long noncoding RNA modifies chromatin accessibility to reduce T regulatory cell differentiation and function.
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http://dx.doi.org/10.1126/sciimmunol.aan5142DOI Listing
May 2017

Transcriptional profiling of leukocytes from rheumatoid arthritis patients before and after anti-tumor necrosis factor therapy: A comparison of anti-nuclear antibody positive and negative subsets.

Exp Ther Med 2017 May 24;13(5):2183-2192. Epub 2017 Mar 24.

Rheumatic Diseases Division, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8884, USA.

Anti-nuclear antibodies (ANAs) may be induced in patients with rheumatoid arthritis (RA) receiving anti-tumor necrosis factor (TNF) therapy with TNF inhibitors (TNFi), etanercept, infliximab or adalimumab. In the present study, 11 patients who were TNFi drug naive were started on TNFi at a time of high disease activity. Of these, all cases were positive for rheumatoid factor and 9 cases tested were positive for anti-citrullinated peptide (anti-CCP) antibodies prior to TNFi treatment. Peripheral blood mononuclear cells (PBMCs) and serum were collected from all patients before and after TNFi therapy. Serum was assayed for ANAs over time. Total cellular RNA was extracted from PBMCs and assessed using Illumina arrays. Gene expression profiles were examined for alterations in key effector pathways. After 3 or more months on TNFi, 6 patients converted to ANA-positivity. Analysis of transcripts from patients with RA who converted to ANA-positivity after 3 months on TNFi identified complex gene expression profiles that reflected a reduction in cell adhesion, cell stress and lipid metabolism transcripts. In summary, unique transcriptional profiles in PBMCs from patients with RA were observed after TNFi therapy. This pilot study suggests that transcriptional profiling is a precise method of measuring the impact of TNFi therapies and reveals novel pathways that likely influence the immune response.
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http://dx.doi.org/10.3892/etm.2017.4265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5443193PMC
May 2017

Pathways leading to an immunological disease: systemic lupus erythematosus.

Rheumatology (Oxford) 2017 04;56(suppl_1):i55-i66

The Rheumatic Diseases Division, Department of Internal Medicine, UT Southwestern Medical Center at Dallas, TX, USA.

SLE is a chronic autoimmune disease caused by perturbations of the immune system. The clinical presentation is heterogeneous, largely because of the multiple genetic and environmental factors that contribute to disease initiation and progression. Over the last 60 years, there have been a number of significant leaps in our understanding of the immunological mechanisms driving disease processes. We now know that multiple leucocyte subsets, together with inflammatory cytokines, chemokines and regulatory mediators that are normally involved in host protection from invading pathogens, contribute to the inflammatory events leading to tissue destruction and organ failure. In this broad overview, we discuss the main pathways involved in SLE and highlight new findings. We describe the immunological changes that characterize this form of autoimmunity. The major leucocytes that are essential for disease progression are discussed, together with key mediators that propagate the immune response and drive the inflammatory response in SLE.
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http://dx.doi.org/10.1093/rheumatology/kew427DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5410978PMC
April 2017

Research and therapeutics-traditional and emerging therapies in systemic lupus erythematosus.

Rheumatology (Oxford) 2017 04;56(suppl_1):i100-i113

Rheumatic Diseases Division, Department of Internal Medicine, University of Texas Southwestern Medical Center.

This review summarizes traditional and emerging therapies for SLE. Evidence suggests that the heterogeneity of SLE is a crucial aspect contributing to the failure of large clinical trials for new targeted therapies. A clearer understanding of the mechanisms driving disease pathogenesis combined with recent advances in medical science are predicted to enable accelerated progress towards improved SLE diagnosis and personalized approaches to treatment.
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http://dx.doi.org/10.1093/rheumatology/kew417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850311PMC
April 2017

Type I interferon as a biomarker in autoimmunity and viral infection: a leukocyte subset-specific analysis unveils hidden diagnostic options.

J Mol Med (Berl) 2017 07 29;95(7):753-765. Epub 2017 Mar 29.

Department of Rheumatology and Clinical Immunology, Charité Universitätsmedizin Berlin, Chariteplatz 1, 10117, Berlin, Germany.

Interferon alpha and its surrogates, including IP-10 and SIGLEC1, paralleled changes of disease activity in systemic lupus erythematosus (SLE). However, the whole blood interferon signature (WBIFNS)-the current standard for type I IFN assessment in SLE-does not correlate with SLE disease activity in individual patients over time. The underlying causes for this apparent contradiction have not been convincingly demonstrated. Using a multicenter dataset of gene expression data from leukocyte subsets in SLE, we identify distinctive subset-specific contributions to the WBIFNS. In a subsequent analysis, the effects of type I interferon on cellular blood composition in patients with SLE and hepatitis B were also studied over time. We found that type I interferon mediates significant alterations in whole blood composition, including a neutropenia and relative lymphocytosis. Given different effects of type 1 interferon on different leukocyte subsets, these shifts confound measurement of a type 1 interferon signature in whole blood. To minimize and overcome these limitations of the WBIFNS, we suggest to measure IFN-induced transcripts or proteins in a specific leukocyte subset to improve clinical impact of interferon biomarkers.

Key Messages: Myeloid cells contribute more to the WBIFNS in SLE than their lymphocytic counterpart. Very similar leukocyte subsets reveal distinctive IFN signatures. IFN alpha mixes up composition of blood and leads to a preferential neutropenia, yielding relative lymphocytosis.
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http://dx.doi.org/10.1007/s00109-017-1515-7DOI Listing
July 2017

Heightened cleavage of Axl receptor tyrosine kinase by ADAM metalloproteases may contribute to disease pathogenesis in SLE.

Clin Immunol 2016 08 27;169:58-68. Epub 2016 May 27.

The Department of Internal Medicine, Rheumatic Diseases Division, University of Texas Southwestern Medical Center, Dallas, TX 75390, United States; The Department of Biomedical Engineering, University of Houston, Houston, TX 77204-5060, United States. Electronic address:

Systemic lupus erythematosus (SLE) is characterized by antibody-mediated chronic inflammation in the kidney, lung, skin, and other organs to cause inflammation and damage. Several inflammatory pathways are dysregulated in SLE, and understanding these pathways may improve diagnosis and treatment. In one such pathway, Axl tyrosine kinase receptor responds to Gas6 ligand to block inflammation in leukocytes. A soluble form of the Axl receptor ectodomain (sAxl) is elevated in serum from patients with SLE and lupus-prone mice. We hypothesized that sAxl in SLE serum originates from the surface of leukocytes and that the loss of leukocyte Axl contributes to the disease. We determined that macrophages and B cells are a source of sAxl in SLE and in lupus-prone mice. Shedding of the Axl ectodomain from the leukocytes of lupus-prone mice is mediated by the matrix metalloproteases ADAM10 and TACE (ADAM17). Loss of Axl from lupus-prone macrophages renders them unresponsive to Gas6-induced anti-inflammatory signaling in vitro. This phenotype is rescued by combined ADAM10/TACE inhibition. Mice with Axl-deficient macrophages develop worse disease than controls when challenged with anti-glomerular basement membrane (anti-GBM) sera in an induced model of nephritis. ADAM10 and TACE also mediate human SLE PBMC Axl cleavage. Collectively, these studies indicate that increased metalloprotease-mediated cleavage of leukocyte Axl may contribute to end organ disease in lupus. They further suggest dual ADAM10/TACE inhibition as a potential therapeutic modality in SLE.
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http://dx.doi.org/10.1016/j.clim.2016.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5193537PMC
August 2016

Blockade of CD354 (TREM-1) Ameliorates Anti-GBM-Induced Nephritis.

Inflammation 2016 Jun;39(3):1169-76

Division of Rheumatology, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Bldg Y, Flr 8, Room 206 (Y8.206), Dallas, TX, 75390-8884, USA.

CD354, Triggering Receptor of Myeloid Cells-1 (TREM-1), is a potent amplifier of myeloid immune responses. Our goal was to determine the expression and function of TREM-1 in immune-mediated nephritis. An anti-glomerular basement membrane antibody (anti-GBM)-induced nephritis model was employed, where mice were sensitized with rabbit IgG followed by anti-GBM serum to induce disease. Anti-GBM-treated 129x1/svJ mice developed severe nephritis whereas C57BL/6 (B6) mice were resistant to disease. Anti-GBM disease resulted in elevated renal TREM-1 messenger RNA (mRNA) and protein levels and increased urine TREM-1 levels in 129x1/svJ. TREM-1 blockade with an inhibitory peptide, LP17, inhibited proteinuria and renal disease as measured by glomerulonephritis class, severity of tubulointerstitial disease, crescent formation, and inflammatory cell infiltrates. In sum, TREM-1 is upregulated in renal inflammation and plays a vital role in driving disease. Thus, TREM-1 blockade emerges as a potential therapeutic avenue for immune-mediated renal diseases such as lupus nephritis.
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http://dx.doi.org/10.1007/s10753-016-0351-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4883274PMC
June 2016

Autoreactive CD19+CD20- Plasma Cells Contribute to Disease Severity of Experimental Autoimmune Encephalomyelitis.

J Immunol 2016 Feb 13;196(4):1541-9. Epub 2016 Jan 13.

Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas TX 75390; Department of Immunology, University of Texas Southwestern Medical Center, Dallas TX 75390

The contribution of autoantibody-producing plasma cells in multiple sclerosis (MS) remains unclear. Anti-CD20 B cell depletion effectively reduces disease activity in MS patients, but it has a minimal effect on circulating autoantibodies and oligoclonal bands in the cerebrospinal fluid. Recently we reported that MEDI551, an anti-CD19 mAb, therapeutically ameliorates experimental autoimmune encephalomyelitis (EAE), the mouse model of MS. MEDI551 potently inhibits pathogenic adaptive immune responses, including depleting autoantibody-producing plasma cells. In the present study, we demonstrated that CD19 mAb treatment ameliorates EAE more effectively than does CD20 mAb. Myelin oligodendrocyte glycoprotein-specific Abs and short-lived and long-lived autoantibody-secreting cells were nearly undetectable in the CD19 mAb-treated mice, but they remained detectable in the CD20 mAb-treated mice. Interestingly, residual disease severity in the CD20 mAb-treated animals positively correlated with the frequency of treatment-resistant plasma cells in the bone marrow. Of note, treatment-resistant plasma cells contained a substantial proportion of CD19(+)CD20(-) plasma cells, which would have otherwise been targeted by CD19 mAb. These data suggested that CD19(+)CD20(-) plasma cells spared by anti-CD20 therapy likely contribute to residual EAE severity by producing autoreactive Abs. In patients with MS, we also identified a population of CD19(+)CD20(-) B cells in the cerebrospinal fluid that would be resistant to CD20 mAb treatment.
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http://dx.doi.org/10.4049/jimmunol.1501376DOI Listing
February 2016

Green Tea Epigallocatechin-3-Gallate Suppresses Autoimmune Arthritis Through Indoleamine-2,3-Dioxygenase Expressing Dendritic Cells and the Nuclear Factor, Erythroid 2-Like 2 Antioxidant Pathway.

J Inflamm (Lond) 2015 15;12:53. Epub 2015 Sep 15.

Division of Rheumatology, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Bldg Y, Flr 8, Room 206 (Y8.206), Dallas, TX 75390-8884 USA.

Background: The activity of one of the major catechins in Green Tea, the polyphenol (-)-epigallocatechin-3-gallate (EGCG), has been shown to have a variety of health benefits. Recent studies suggest that EGCG can modulate both the innate and adaptive arms of the immune system. The goal of the current studies was to examine the immunomodulatory effects and mechanisms of action of EGCG on experimental arthritis in mice.

Methods: EGCG (10 mg/kg) was administered by oral gavage after CIA induction, while control mice were administered phosphate buffered saline (PBS). Disease mechanisms were studied in both groups of mice. Phenotypes were examined using repeated measure analysis of variance (ANOVA) and data from in vitro and ex vivo experiments were analyzed for significance using the Mann-Whitney U test.

Results: EGCG treatment ameliorated clinical symptoms and reduced histological scores in arthritic mice. Serum type-II collagen-specific immunoglobulin (Ig) IgG2a antibodies were significantly lower in EGCG-fed mice compared to PBS-treated mice. EGCG significantly suppressed T cell proliferation and relative frequencies of CD4 T cells, CD8 T cells and B cell subsets including marginal zone B cells, T1 and T2 transitional B cells, while increasing the frequency of CD4(+) Foxp3(+) regulatory T cells (Tregs) and indoleamine-2,3-dioxygenase (IDO) expression by CD11b(+) dendritic cells (DC). Splenic CD11b(+) DC from EGCG fed mice induced an increased frequency of Tregs via an IDO-dependent mechanism in in vitro cultures. Importantly, joint homogenates from EGCG-fed mice exhibited significantly increased levels of Nuclear Factor, Erythroid 2-Like 2 (Nrf-2) and Heme oxygenase-1 (HO-1) compared with PBS-fed mice.

Conclusions: This is the first report of upregulation of the Nrf-2 antioxidant pathway in EGCG-mediated immunoregulation. EGCG ameliorated experimental arthritis in mice by eliciting IDO-producing DCs, increasing frequencies of T regs and inducing the activation of the Nrf-2 antioxidant pathway. It remains to be established whether EGCG is useful for the prevention and treatment of rheumatoid arthritis and other inflammatory disorders.
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http://dx.doi.org/10.1186/s12950-015-0097-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4570740PMC
September 2015

Lipoapoptosis induced by saturated free fatty acids stimulates monocyte migration: a novel role for Pannexin1 in liver cells.

Purinergic Signal 2015 Sep 9;11(3):347-59. Epub 2015 Jun 9.

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, 75390-8884, USA.

Recruitment of monocytes in the liver is a key pathogenic feature of hepatic inflammation in nonalcoholic steatohepatitis (NASH), but the mechanisms involved are poorly understood. Here, we studied migration of human monocytes in response to supernatants obtained from liver cells after inducing lipoapoptosis with saturated free fatty acids (FFA). Lipoapoptotic supernatants stimulated monocyte migration with the magnitude similar to a monocyte chemoattractant protein, CCL2 (MCP-1). Inhibition of c-Jun NH2-terminal kinase (JNK) in liver cells with SP600125 blocked migration of monocytes in a dose-dependent manner, indicating that JNK stimulates release of chemoattractants in lipoapoptosis. Notably, treatment of supernatants with Apyrase to remove ATP potently inhibited migration of THP-1 monocytes and partially blocked migration of primary human monocytes. Inhibition of the CCL2 receptor (CCR2) on THP-1 monocytes with RS102895, a specific CCR2 inhibitor, did not block migration induced by lipoapoptotic supernatants. Consistent with these findings, lipoapoptosis stimulated pathophysiological extracellular ATP (eATP) release that increased supernatant eATP concentration from 5 to ~60 nM. Importantly, inhibition of Panx1 expression in liver cells with short hairpin RNA (shRNA) decreased supernatant eATP concentration and inhibited monocyte migration, indicating that monocyte migration is mediated in part by Panx1-dependent eATP release. Moreover, JNK inhibition decreased supernatant eATP concentration and inhibited Pannexin1 activation, as determined by YoPro-1 uptake in liver cells in a dose-dependent manner. These results suggest that JNK regulates activation of Panx1 channels, and provide evidence that Pannexin1-dependent pathophysiological eATP release in lipoapoptosis is capable of stimulating migration of human monocytes, and may participate in the recruitment of monocytes in chronic liver injury induced by saturated FFA.
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http://dx.doi.org/10.1007/s11302-015-9456-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529853PMC
September 2015

Seeking balance: Potentiation and inhibition of multiple sclerosis autoimmune responses by IL-6 and IL-10.

Cytokine 2015 Jun 17;73(2):236-44. Epub 2015 Mar 17.

Rheumatic Diseases Division, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8884, United States. Electronic address:

The cytokines IL-6 and IL-10 are produced by cells of the adaptive and innate arms of the immune system and they appear to play key roles in genetically diverse autoimmune diseases such as relapsing remitting multiple sclerosis (MS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Whereas previous intense investigations focused on the generation of autoantibodies and their contribution to immune-mediated pathogenesis in these diseases; more recent attention has focused on the roles of cytokines such as IL-6 and IL-10. In response to pathogens, antigen presenting cells (APC), including B cells, produce IL-6 and IL-10 in order to up-or down-regulate immune cell activation and effector responses. Evidence of elevated levels of the proinflammatory cytokine IL-6 has been routinely observed during inflammatory responses and in a number of autoimmune diseases. Our recent studies suggest that MS peripheral blood B cells secrete higher quantities of IL-6 and less IL-10 than B cells from healthy controls. Persistent production of IL-6, in turn, contributes to T cell expansion and the functional hyperactivity of APC such as MS B cells. Altered B cell activity can have a profound impact on resultant T cell effector functions. Enhanced signaling through the IL-6 receptor can effectively inhibit cytolytic activity, induce T cell resistance to IL-10-mediated immunosuppression and increase skewing of autoreactive T cells to a pathogenic Th17 phenotype. Our recent findings and studies by others support a role for the indirect attenuation of B cell responses by Glatiramer acetate (GA) therapy. Our studies suggest that GA therapy temporarily permits homeostatic regulatory mechanisms to be reinstated. Future studies of mechanisms underlying dysregulated B cell cytokine production could lead to the identification of novel targets for improved immunoregulatory therapies for autoimmune diseases.
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http://dx.doi.org/10.1016/j.cyto.2015.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4437890PMC
June 2015

BiP, From Putting Out Fires to Fanning the Flames in Rheumatoid Arthritis.

Authors:
Laurie S Davis

Arthritis Rheumatol 2015 May;67(5):1147-50

University of Texas Southwestern Medical Center, Dallas.

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http://dx.doi.org/10.1002/art.39052DOI Listing
May 2015

The effect of glatiramer acetate therapy on functional properties of B cells from patients with relapsing-remitting multiple sclerosis.

JAMA Neurol 2014 Nov;71(11):1421-8

Department of Neurology and Neurotherapeutics, The University of Texas Southwestern Medical Center, Dallas3Department of Immunology, The University of Texas Southwestern Medical Center, Dallas.

Importance: This study describes what is, to our knowledge, the previously unknown effect of glatiramer acetate therapy on B cells in patients with relapsing-remitting multiple sclerosis (MS).

Objective: To determine whether glatiramer acetate therapy normalizes dysregulated B-cell proliferation and cytokine production in patients with MS.

Design, Setting, And Participants: Twenty-two patients with MS who were receiving glatiramer acetate therapy and 22 treatment-naive patients with MS were recruited at The University of Texas Southwestern Medical Center MS clinic. Cell samples from healthy donors were obtained from HemaCare (Van Nuys, California) or Carter Blood Bank (Dallas, Texas). Treatment-naive patients with MS had not received any disease-modifying therapies for at least 3 months before the study.

Exposures: Glatiramer acetate therapy for at least 3 months at the time of the study.

Main Outcomes And Measures: B-cell phenotype and proliferation and immunoglobulin and cytokine secretion.

Results: A restoration of interleukin 10 production by peripheral B cells was observed in patients undergoing glatiramer acetate therapy as well as a significant reduction of interleukin 6 production in a subset of patients who received therapy for less than 32 months. Furthermore, proliferation in response to high-dose CD40L was altered and immunoglobulin production was elevated in in vitro-activated B cells obtained from patients who received glatiramer acetate.

Conclusions And Relevance: Glatiramer acetate therapy remodels the composition of the B-cell compartment and influences cytokine secretion and immunoglobulin production. These data suggest that glatiramer acetate therapy affects several aspects of dysregulated B-cell function in MS that may contribute to the therapeutic mechanisms of glatiramer acetate.
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http://dx.doi.org/10.1001/jamaneurol.2014.1472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4335670PMC
November 2014

Editorial: macrophages and dendritic cells in motion: tracking inflammation and fibrosis.

Authors:
Laurie S Davis

Arthritis Rheumatol 2014 Jun;66(6):1414-7

University of Texas Southwestern Medical Center, Dallas.

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http://dx.doi.org/10.1002/art.38407DOI Listing
June 2014

SLE peripheral blood B cell, T cell and myeloid cell transcriptomes display unique profiles and each subset contributes to the interferon signature.

PLoS One 2013 24;8(6):e67003. Epub 2013 Jun 24.

Department of Immunology, The University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by defective immune tolerance combined with immune cell hyperactivity resulting in the production of pathogenic autoantibodies. Previous gene expression studies employing whole blood or peripheral blood mononuclear cells (PBMC) have demonstrated that a majority of patients with active disease have increased expression of type I interferon (IFN) inducible transcripts known as the IFN signature. The goal of the current study was to assess the gene expression profiles of isolated leukocyte subsets obtained from SLE patients. Subsets including CD19(+) B lymphocytes, CD3(+)CD4(+) T lymphocytes and CD33(+) myeloid cells were simultaneously sorted from PBMC. The SLE transcriptomes were assessed for differentially expressed genes as compared to healthy controls. SLE CD33(+) myeloid cells exhibited the greatest number of differentially expressed genes at 208 transcripts, SLE B cells expressed 174 transcripts and SLE CD3(+)CD4(+) T cells expressed 92 transcripts. Only 4.4% (21) of the 474 total transcripts, many associated with the IFN signature, were shared by all three subsets. Transcriptional profiles translated into increased protein expression for CD38, CD63, CD107a and CD169. Moreover, these studies demonstrated that both SLE lymphoid and myeloid subsets expressed elevated transcripts for cytosolic RNA and DNA sensors and downstream effectors mediating IFN and cytokine production. Prolonged upregulation of nucleic acid sensing pathways could modulate immune effector functions and initiate or contribute to the systemic inflammation observed in SLE.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0067003PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3691135PMC
February 2014

Antibody-independent B cell effector functions in relapsing remitting multiple sclerosis: clues to increased inflammatory and reduced regulatory B cell capacity.

Autoimmunity 2012 Aug 18;45(5):400-14. Epub 2012 Apr 18.

University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.

The pathogenic role for B cells in the context of relapsing remitting multiple sclerosis (MS) is incompletely defined. Although classically considered a T cell-mediated disease, B cell-depleting therapies showed efficacy in treating the clinical symptoms of RRMS without decreasing plasma cells or total immunoglobulin (Ig) levels. Here, we discuss the potential implications of antibody-independent B cell effector functions that could contribute to autoimmunity with particular focus on antigen presentation, cytokine secretion, and stimulation of T cell subsets. We highlight differences between memory and naïve B cells from MS patients such as our recent findings of hyper-proliferation from MS memory B cells in response to CD40 engagement. We discuss the implications of IL6 overproduction in contrast to limited IL10 production by B cells from MS patients and comment on the impact of these functions on yet unexplored aspects of B cells in autoimmune disease. Finally, we contextualize B cell effector functions with respect to current immunomodulatory therapies for MS and show that glatiramer acetate (GA) does not directly modulate B cell proliferation or cytokine secretion.
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http://dx.doi.org/10.3109/08916934.2012.665529DOI Listing
August 2012

Early gene expression changes with rush immunotherapy.

Clin Mol Allergy 2011 Sep 30;9:12. Epub 2011 Sep 30.

Department of Internal Medicine, Division of Rheumatic Diseases, University of Texas Southwestern Medical Center, Dallas, TX, 75390-8884, USA.

Background: To examine whether whole genome expression profiling could reveal changes in mRNA expression of peripheral blood mononuclear cells (PBMC) from allergic patients undergoing rush immunotherapy (RIT) that might be manifest within the first few months of treatment.

Methods: For this study, PBMC from three allergic patients undergoing RIT were assessed at four timepoints: prior to RIT, at 1 week and 7 week post-RIT, during build-up and at 4 months, after establishment of a maintenance dose. PBMC mRNA gene expression changes over time were determined by oligonucleotide microarrays using the Illumina Human-6 BeadChip Platform, which simultaneously interrogates expression profiles of > 47,000 transcripts. Differentially expressed genes were identified using well-established statistical analysis for microarrays. In addition, we analyzed peripheral blood basophil high-affinity IgE receptor (Fc epsilon RI) expression and T-regulatory cell frequency as detected by expression of CD3+CD4+CD25bright cells at each timepoint using flow cytometry.

Results: In comparing the initial 2 timepoints with the final 2 timepoints and analyzing for genes with ≥1.5-fold expression change (p less than or equal to 0.05, BH-FDR), we identified 507 transcripts. At a 2-fold change (p less than or equal to 0.05, BH-FDR), we found 44 transcripts. Of these, 28 were up-regulated and 16 were down-regulated genes. From these datasets, we have identified changes in immunologically relevant genes from both the innate and adaptive response with upregulation of expressed genes for molecules including IL-1β, IL-8, CD40L, BTK and BCL6. At the 4 month timepoint, we noted a downward trend in Fc epsilon RI expression in each of the three patients and increased allergen-specific IgG4 levels. No change was seen in the frequency of peripheral T-regulatory cells expressed over the four timepoints.

Conclusions: We observed significant changes in gene expression early in peripheral blood samples from allergic patients undergoing RIT. Moreover, serum levels for allergen specific IgG4 also increased over the course of treatment. These studies suggest that RIT induces rapid and dynamic alterations in both innate and adaptive immunity which can be observed in the periphery of allergic patients. These alterations could be directly related to the therapeutic shift in the allergen-specific class of immunoglobulin.
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http://dx.doi.org/10.1186/1476-7961-9-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3195724PMC
September 2011

IL-12 selectively programs effector pathways that are stably expressed in human CD8+ effector memory T cells in vivo.

Blood 2011 Oct 10;118(14):3890-900. Epub 2011 Aug 10.

Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

CD8(+) cytotoxic T lymphocytes play a major role in defense against intracellular pathogens, and their functions are specified by antigen recognition and innate cytokines. IL-12 and IFN-α/β are potent "signal 3" cytokines that are involved in both effector and memory cell development. Although the majority of effector cells are eliminated as inflammation resolves, some survive within the pool of memory cells and retain immediate effector function. In this study, we demonstrate that IL-12 instructs a unique program of effector cell differentiation that is distinct from IFN-α/β. Moreover, effector memory (T(EM)) cells within peripheral blood display many common attributes of cells differentiated in vitro in response to IL-12, including proinflammatory cytokine secretion and lytic activity. A pattern of IL-12-induced genes was identified that demarcate T(EM) from central memory cells, and the ontologies of these genes correlated precisely with their effector functions. Further, we uncovered a unique program of gene expression that was acutely regulated by IL-12 and reflected in stable gene expression patterns within T(EM), but not T central memory cells in vivo. Thus, this study directly links a selective set of IL-12-induced genes to the programming of effector functions within the stable population of human CD8(+) T(EM) cells in vivo.
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http://dx.doi.org/10.1182/blood-2011-05-357111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3193266PMC
October 2011

The role of cytokines in the pathogenesis and treatment of systemic lupus erythematosus.

J Interferon Cytokine Res 2011 Oct 25;31(10):781-9. Epub 2011 Jul 25.

Division of Rheumatology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas 75390-8884, USA.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterized by a defect in immune tolerance and exacerbated by both the innate and adaptive arms of the immune response. SLE-associated immune hyperactivity can be detected systemically as elevations in levels of cytokines along with their upregulated receptors expressed by hematopoietic cells. Importantly, increased levels of cytokines and their receptors can be observed in target organs, and it is clear that they have important roles in disease pathogenesis. Recent therapeutic strategies have focused on proximal cytokines, such as interferon-α, interleukin (IL)-1, IL-6, and tumor necrosis factor as a result of the efficacious use of biologic agents for intervention in rheumatoid arthritis and other autoimmune diseases. Despite the recent advances in understanding the cytokine networks involved in autoimmune diseases and more specifically in SLE, the diagnosis and prognosis of lupus remain a challenge. Lupus is heterogeneous and unpredictable; moreover, the frequency and severity of flares can be difficult to determine and treat. A better understanding of the regulation of expression of key cytokines and their receptors can likely provide important clues to the pathogenic mechanisms underlying specific forms of SLE, and pave the way toward more effective therapeutics.
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http://dx.doi.org/10.1089/jir.2011.0047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3189549PMC
October 2011

Memory B cells from a subset of treatment-naïve relapsing-remitting multiple sclerosis patients elicit CD4(+) T-cell proliferation and IFN-γ production in response to myelin basic protein and myelin oligodendrocyte glycoprotein.

Eur J Immunol 2010 Oct;40(10):2942-56

Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Recent evidence suggests that B- and T-cell interactions may be paramount in relapsing-remitting MS (RRMS) disease pathogenesis. We hypothesized that memory B-cell pools from RRMS patients may specifically harbor a subset of potent neuro-APC that support neuro-Ag reactive T-cell proliferation and cytokine secretion. To test this hypothesis, we compared CD80 and HLA-DR expression, IL-10 and lymphotoxin-α secretion, neuro-Ag binding capacity, and neuro-Ag presentation by memory B cells from RRMS patients to naïve B cells from RRMS patients and to memory and naïve B cells from healthy donors (HD). We identified memory B cells from some RRMS patients that elicited CD4(+) T-cell proliferation and IFN-γ secretion in response to myelin basic protein and myelin oligodendrocyte glycoprotein. Notwithstanding the fact that the phenotypic parameters that promote efficient Ag presentation were observed to be similar between RRMS and HD memory B cells, a corresponding capability to elicit CD4(+) T-cell proliferation in response to myelin basic protein and myelin oligodendrocyte glycoprotein was not observed in HD memory B cells. Our results demonstrate for the first time that the memory B-cell pool in RRMS harbors neuro-Ag specific B cells that can activate T cells.
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http://dx.doi.org/10.1002/eji.201040516DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3072802PMC
October 2010

Dysregulated expression of CXCR4/CXCL12 in subsets of patients with systemic lupus erythematosus.

Arthritis Rheum 2010 Nov;62(11):3436-46

University of Texas Southwestern Medical Center, Dallas, TX 75390-8884, USA.

Objective: CXCR4 is a chemokine with multiple effects on the immune system. In murine lupus models, we demonstrated that monocytes, neutrophils, and B cells overexpressed CXCR4 and that its ligand, CXCL12, was up-regulated in diseased kidneys. We undertook this study to determine whether CXCR4 expression was increased in peripheral blood leukocytes from patients with systemic lupus erythematosus (SLE) and whether CXCL12 expression was increased in kidneys from patients with SLE.

Methods: Peripheral blood leukocytes from 31 SLE patients, 8 normal controls, and 9 patients with rheumatoid arthritis were prospectively analyzed by flow cytometry for CXCR4 expression. Biopsy samples (n = 14) from patients with lupus nephritis (LN) were immunostained with anti-CXCL12 antibody.

Results: CD19+ B cells and CD4+ T cells from SLE patients displayed a >2-fold increase (P = 0.0001) and >3-fold increase (P < 0.0001), respectively, in median CXCR4 expression compared with that in controls (n = 7-8). Moreover, CXCR4 expression on B cells was 1.61-fold higher in patients with SLE Disease Activity Index (SLEDAI) scores >10 (n = 8) than in patients with SLEDAI scores ≤10 (n = 16) (P = 0.0008), 1.71-fold higher in patients with class IV LN (n = 5) than in patients with other classes of LN (n = 7) (P = 0.02), and 1.40-fold higher in patients with active neuropsychiatric SLE (NPSLE) (n = 6) than in patients with inactive NPSLE (n = 18) (P = 0.01). CXCL12 was significantly up-regulated in the tubules and glomeruli of kidneys in patients with LN (n = 14), with the percentage of positive cells correlating positively with the severity of LN.

Conclusion: CXCR4 appears to be up-regulated in multiple leukocyte subsets in SLE patients. The heightened expression of CXCR4 on B cells in active NPSLE and of CXCL12 in nephritic kidneys suggests that the CXCR4/CXCL12 axis might be a potential therapeutic target for SLE patients with kidney and/or central nervous system involvement.
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http://dx.doi.org/10.1002/art.27685DOI Listing
November 2010

T cells in chronic rhinosinusitis with nasal polyposis.

Curr Opin Otolaryngol Head Neck Surg 2010 Jun;18(3):200-5

Department of Otolaryngology, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9035, USA.

Purpose Of Review: The cause of nasal polyp disease remains controversial. Examination of the T lymphocytes involved in nasal polyp inflammation may lead to an improved understanding of the cause, prognosis, and treatment of chronic rhinosinusitis with nasal polyposis.

Recent Findings: T lymphocytes are important directors of the inflammatory process in allergic rhinitis and asthma, but the role of T lymphocytes in chronic rhinosinusitis with nasal polyposis has not been thoroughly investigated. The T lymphocyte infiltrate in nasal polyps may vary based upon genetic factors, polyp histology, or the presence of asthma/atopy. Staphylococcal enterotoxins, which are known to activate T cells, stimulate proinflammatory cytokine secretion by nasal polyp cells, whereas regulatory cytokines are not similarly up regulated by enterotoxin exposure. The inflammation in nasal polyps may be related to deficient function of regulatory T cells. New data on staphylococcal enterotoxins and regulatory T cells point to possible roles for T cells in chronic rhinosinusitis with nasal polyposis.

Summary: Further study of the T cell compartment in nasal polyps may lead to a better understanding of the intrinsic and extrinsic factors responsible for nasal polyp inflammation.
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http://dx.doi.org/10.1097/MOO.0b013e3283382082DOI Listing
June 2010

Peripheral blood mononuclear cells from allergic fungal rhinosinusitis adults express a Th2 cytokine response to fungal antigens.

Am J Rhinol Allergy 2009 May-Jun;23(3):281-7

Department of Otorhinolaryngology-Head and Neck Surgery, University of Texas Medical School at Houston, Houston, Texas 77030, USA.

Background: The etiology of allergic fungal rhinosinusitis (AFRS) remains controversial. Initially thought to represent an immunoglobulin E (IgE)-mediated hypersensitivity to fungal antigens, additional data have implicated other non-IgE and cellular-mediated pathways. The aim of this study was to characterize T-helper type 1 (Th1) and Th2 immune responses of blood lymphocytes from AFRS patients by fungal antigen stimulation to help differentiate these possible pathways.

Methods: Peripheral blood mononuclear cells (PBMCs) isolated from AFRS patients (n = 10) and healthy controls (HCs; n = 11) were exposed to four different fungal extracts (Alternaria, Aspergillus, Cladosporium, and Penicillium) in duplicate. After a 72-hour incubation, the supernatants were analyzed for cytokine levels of three Th1 (interferon [IFN] gamma, interleukin [IL]-2, and tumor necrosis factor alpha) and three Th2 (IL-10, IL-5, and IL-4) cytokines by cytometric bead array flow cytometry. Serum fungal-specific IgE levels were measured by ImmunoCAP (Pharmacia Diagnostics, Kalamazoo, MI).

Results: Fungal extracts of Alternaria and Cladosporium stimulated higher levels of IL-5 from PBMCs in AFRS when compared with HCs (p < 0.05). IL-4 was also elevated for Alternaria in AFRS versus HCs (p < 0.05). A skewed Th2 response to fungal antigen exposure was confirmed by an elevated IL-5/IFN-gamma ratio in AFRS subjects (p < 0.05). Initial studies suggest a correlation between percent T-cell activation and IL-5 expression to IgE levels. Fungal antigens stimulated a notable but not statistically significant increase in IL-10 response in HCs.

Conclusion: In AFRS patients, fungal antigens stimulated T-cell activation, inducing a predominantly Th2 immune response. Healthy controls expressed an inhibitory cytokine IL-10 when exposed to these fungal antigens, possibly serving as a protective response.
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http://dx.doi.org/10.2500/ajra.2009.23.3311DOI Listing
July 2009

Cutting edge: a T-bet-independent role for IFN-alpha/beta in regulating IL-2 secretion in human CD4+ central memory T cells.

J Immunol 2008 Dec;181(12):8204-8

Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

IL-2 is a hallmark cytokine secreted by central memory CD4(+) T cells (T(CM)). Although naive cells rapidly secrete IL-2 in response to Ag stimulation, IL-12 inhibits IL-2 secretion in daughter cells as they differentiate into Th1 cells. In this study, we uncover a unique role for IFN-alpha in regulating IL-2 secretion by human T(CM) cells. IFN-alpha synergized with IL-12 to enhance a subset of cells that secreted high and sustained levels of IL-2. These IL-2-secreting cells displayed phenotypic and functional characteristics of T(CM) and were capable of generating IFN-gamma-secreting effectors upon secondary activation. T-bet has been implicated in negatively regulating IL-2 secretion in murine T cells; however, T-bet expression did not inhibit IFN-alpha-dependent IL-2 secretion in human T(CM) cells. Thus, our results highlight a unique role for IFN-alpha in regulating the development of IL-2-secreting human T(CM) cells.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2596627PMC
http://dx.doi.org/10.4049/jimmunol.181.12.8204DOI Listing
December 2008

Combined deficiency of proapoptotic regulators Bim and Fas results in the early onset of systemic autoimmunity.

Immunity 2008 Feb;28(2):206-17

Department of Molecular Microbiology & Immunology, School of Medicine, Saint Louis University, Saint Louis, MO 63104, USA.

Alterations in the stoichiometric balance between members of Bcl-2 and Fas apoptotic pathway could lead to the pathogenesis of systemic lupus erythematosus (SLE). We showed that patients with SLE displayed increased expression in antiapoptotic members of the Bcl-2 and Fas apoptotic pathways in isolated mononuclear cells. Further, mice (Bcl2l11(-/-)Fas(lpr/lpr)) lacking the Bcl-2 pro-apoptotic member, Bim (Bcl2l11(-/-)) and and with an lpr mutation in the gene encoding Fas (Fas(lpr/lpr)) developed severe SLE-like disease by 16 weeks of age unlike Bcl2l11(-/-) or Fas(lpr/lpr) mice. Bcl2l11(-/-)Fas(lpr/lpr) antigen-presenting cells (APCs) were markedly activated, and their numbers were increased in lymphoid tissues and in kidneys, yet numerous TUNEL-positive cells were observed in glomeruli of Bcl2l11(-/-)Fas(lpr/lpr) mice. These data demonstrate that dysregulation of the Bcl-2 or Fas pathways can alter the function of APCs, thereby leading to SLE pathogenesis.
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http://dx.doi.org/10.1016/j.immuni.2007.12.015DOI Listing
February 2008

Shared signaling networks active in B cells isolated from genetically distinct mouse models of lupus.

J Clin Invest 2007 Aug;117(8):2186-96

Division of Rheumatology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8884, USA.

Though B cells play key roles in lupus pathogenesis, the molecular circuitry and its dysregulation in these cells as disease evolves remain poorly understood. To address this, a comprehensive scan of multiple signaling axes using multiplexed Western blotting was undertaken in several different murine lupus strains. PI3K/AKT/mTOR (mTOR, mammalian target of rapamycin), MEK1/Erk1/2, p38, NF-kappaB, multiple Bcl-2 family members, and cell-cycle molecules were observed to be hyperexpressed in lupus B cells in an age-dependent and lupus susceptibility gene-dose-dependent manner. Therapeutic targeting of the AKT/mTOR axis using a rapamycin (sirolimus) derivative ameliorated the serological, cellular, and pathological phenotypes associated with lupus. Surprisingly, the targeting of this axis was associated with the crippling of several other signaling axes. These studies reveal that lupus pathogenesis is contingent upon the activation of an elaborate network of signaling cascades that is shared among genetically distinct mouse models and raise hope that targeting pivotal nodes in these networks may offer therapeutic benefit.
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http://dx.doi.org/10.1172/JCI30398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1913486PMC
August 2007