104 results on '"Mueller DL"'
Search Results
2. A2.33 Citrullinated self antigen-specific blood B cells carry cross-reactive immunoglobulins with effector potential
- Author
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Titcombe, PJ, primary, Amara, K, additional, Barsness, LO, additional, Zhang, N, additional, Krishnamurthy, A, additional, Shmagel, A, additional, Hansson, M, additional, Israelsson, L, additional, Sahlström, P, additional, Giacobbe, L, additional, Catrina, AI, additional, Gillespie, EC, additional, Klareskog, L, additional, Peterson, EJ, additional, Malmström, V, additional, and Mueller, DL, additional more...
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- 2016
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3. Decay channels of AlL2,3excitons and the absence of OKexcitons in α-Al2O3
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D. L. Ederer, O'Brien Wl, Mueller Dl, Woronick Sc, Shinn Nd, Dong Qy, Jianjun Jia, and T. A. Callcott
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Physics ,chemistry.chemical_classification ,Absorption spectroscopy ,Absorption edge ,chemistry ,Computer Science::Information Retrieval ,Exciton ,Atomic physics ,Single crystal ,Inorganic compound ,Spectral line ,Non-radiative recombination ,Auger - Abstract
The Al {ital L}{sub 2,3} and O {ital K} thresholds for single-crystal {alpha}-Al{sub 2}O{sub 3} have been studied by photoemission. Energy-distribution curves, constant-initial-state (CIS), and constant-final-state (CFS) spectra are reported and compared to the absorption spectrum reported previously. An exciton appears as a doublet at threshold in the Al {ital L}{sub 2,3} CFS, CIS, and absorption spectra. The details of the Al {ital L}{sub 2,3} CFS spectrum and absorption spectrum are similar, while the exciton is the only feature present in the CIS spectrum. Comparisons of the various Al {ital L}{sub 2,3} spectra allow the probabilities of different exciton decay channels to be determined. The probability for nonradiative direct recombination of the exciton is found to be (8{plus minus}1)% and the probability for Auger decay of the exciton is found to be (72{plus minus}20)%. Comparisons of the O {ital K} CIS and CFS spectra suggest that no O {ital K} exciton is formed. more...
- Published
- 1991
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4. Intermediate coupling inL2-L3core excitons of MgO,Al2O3, andSiO2
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O'Brien Wl, Jan-Erik Rubensson, Dong Qy, Mueller Dl, Jianjun Jia, Thomas A. Callcott, and D. L. Ederer
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Physics ,Crystallography ,Reflection (mathematics) ,Absorption spectroscopy ,Band gap ,Exchange interaction ,Coupling (probability) ,Single crystal ,Energy (signal processing) ,Spectral line - Abstract
The ${\mathit{L}}_{23}$ reflection spectra for single-crystal MgO, \ensuremath{\alpha}-${\mathrm{Al}}_{2}$${\mathrm{O}}_{3}$, and \ensuremath{\alpha}-${\mathrm{SiO}}_{2}$ are measured. These reflection spectra are used to generate absorption spectra that agree well with electron-total-yield and electron-energy-loss measurements. Exciton features are shown to exist in the band gap by comparing the valence-band maximum plus optical band gap to the observed transition energies. The energy splitting of the ${\mathit{L}}_{2\mathrm{\ensuremath{-}}}$${\mathit{L}}_{3}$ excitons, as seen in reflection, is clearly resolved for ${\mathrm{Al}}_{2}$${\mathrm{O}}_{3}$ and ${\mathrm{SiO}}_{2}$, while in electron-total-yield measurements the doublets are not resolved for ${\mathrm{Al}}_{2}$${\mathrm{O}}_{3}$. This resolution allows the calculation of the exchange energy using intermediate-coupling theory. more...
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- 1991
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5. Resonant absorption and emission from localized core-hole states in Al2O3 and SiO2
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Dong Qy, D. L. Ederer, Jan-Erik Rubensson, Thomas A. Callcott, O'Brien Wl, Mueller Dl, and Jianjun Jia
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Physics ,Nuclear and High Energy Physics ,Band gap ,Astrophysics::High Energy Astrophysical Phenomena ,Exciton ,Electron ,Spectral line ,Core (optical fiber) ,Condensed Matter::Materials Science ,Reflection (mathematics) ,Excited state ,Emission spectrum ,Atomic physics ,Instrumentation - Abstract
We have compared the Al L23 and Si L23 emission and reflection spectra of Al2O3 and SiO2 to obtain information on the nature of the excited states in the presence of the L23 holes. A 5 m Rowland spectrometer, using a 600 l/mm grating mounted in grazing incidence was used to detect both electron excited soft X-ray emission and near normal soft X-ray reflection. We report fine structure in the emission spectra above the L23 edges which coincides with structure in the reflection spectra. These features appear both in the bandgap and in the conduction band. Such features within the bandgap are typically identified as excitons, while those in the conduction band must be localized excited states. Therefore, measurements of ϵ2, for SiO2 and Al2O3 above the L23 edge should be interpreted in terms of localized excitations in the presence of a core hole, rather than interband transitions. more...
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- 1991
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6. Neuroblastoma: a specific sonographic tissue pattern
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Amundson, GM, primary, Trevenen, CL, additional, Mueller, DL, additional, Rubin, SZ, additional, and Wesenberg, RL, additional
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- 1987
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7. Acute scrotal abnormalities in children: diagnosis by combined sonography and scintigraphy
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Mueller, DL, primary, Amundson, GM, additional, Rubin, SZ, additional, and Wesenberg, RL, additional
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- 1988
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8. BATF represses BIM to sustain tolerant T cells in the periphery.
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Titcombe PJ, Silva Morales M, Zhang N, and Mueller DL
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- Bcl-2-Like Protein 11 genetics, T-Lymphocytes, Regulatory, Autoantigens, Transcription Factor AP-1, Clonal Anergy
- Abstract
T cells that encounter self-antigens after exiting the thymus avert autoimmunity through peripheral tolerance. Pathways for this include an unresponsive state known as anergy, clonal deletion, and T regulatory (Treg) cell induction. The transcription factor cues and kinetics that guide distinct peripheral tolerance outcomes remain unclear. Here, we found that anergic T cells are epigenetically primed for regulation by the non-classical AP-1 family member BATF. Tolerized BATF-deficient CD4+ T cells were resistant to anergy induction and instead underwent clonal deletion due to proapoptotic BIM (Bcl2l11) upregulation. During prolonged antigen exposure, BIM derepression resulted in fewer PD-1+ conventional T cells as well as loss of peripherally induced FOXP3+ Treg cells. Simultaneous Batf and Bcl2l11 knockdown meanwhile restored anergic T cell survival and Treg cell maintenance. The data identify the AP-1 nuclear factor BATF as a dominant driver of sustained T cell anergy and illustrate a mechanism for divergent peripheral tolerance fates., (© 2023 Titcombe et al.) more...
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- 2023
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9. Immune tolerance of food is mediated by layers of CD4 + T cell dysfunction.
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Hong SW, Krueger PD, Osum KC, Dileepan T, Herman A, Mueller DL, and Jenkins MK
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- Allergens immunology, Antibody Formation, Dietary Proteins immunology, Gastrointestinal Tract cytology, Gastrointestinal Tract immunology, Gliadin immunology, Inflammation, Interleukin-2 immunology, Liver cytology, Liver immunology, Lymphoid Tissue cytology, Lymphoid Tissue immunology, Peptide Fragments immunology, T Follicular Helper Cells cytology, T Follicular Helper Cells immunology, T-Lymphocytes, Regulatory cytology, T-Lymphocytes, Regulatory immunology, Th1 Cells cytology, Th1 Cells immunology, CD4-Positive T-Lymphocytes cytology, CD4-Positive T-Lymphocytes immunology, Food, Immune Tolerance immunology
- Abstract
Gastrointestinal health depends on the adaptive immune system tolerating the foreign proteins in food
1,2 . This tolerance is paradoxical because the immune system normally attacks foreign substances by generating inflammation. Here we addressed this conundrum by using a sensitive cell enrichment method to show that polyclonal CD4+ T cells responded to food peptides, including a natural one from gliadin, by proliferating weakly in secondary lymphoid organs of the gut-liver axis owing to the action of regulatory T cells. A few food-specific T cells then differentiated into T follicular helper cells that promoted a weak antibody response. Most cells in the expanded population, however, lacked canonical T helper lineage markers and fell into five subsets dominated by naive-like or T follicular helper-like anergic cells with limited capacity to form inflammatory T helper 1 cells. Eventually, many of the T helper lineage-negative cells became regulatory T cells themselves through an interleukin-2-dependent mechanism. Our results indicate that exposure to food antigens causes cognate CD4+ naive T cells to form a complex set of noncanonical hyporesponsive T helper cell subsets that lack the inflammatory functions needed to cause gut pathology and yet have the potential to produce regulatory T cells that may suppress it., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.) more...- Published
- 2022
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10. Characteristics and in-hospital outcomes of patients undergoing complex bifurcation versus nonbifurcation percutaneous coronary intervention.
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Nikolakopoulos I, Vemmou E, Karacsonyi J, Garberich R, Stanberry L, Mueller DL, Kostantinis ST, Simsek B, Rangan BV, Burke MN, and Brilakis ES
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- Coronary Angiography, Hospitals, Humans, Risk Factors, Treatment Outcome, Coronary Artery Disease diagnostic imaging, Coronary Artery Disease surgery, Drug-Eluting Stents, Percutaneous Coronary Intervention adverse effects
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- 2022
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11. Different Hierarchies of Anti-Modified Protein Autoantibody Reactivities in Rheumatoid Arthritis.
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Sahlström P, Hansson M, Steen J, Amara K, Titcombe PJ, Forsström B, Stålesen R, Israelsson L, Piccoli L, Lundberg K, Klareskog L, Mueller DL, Catrina AI, Skriner K, Malmström V, and Grönwall C
- Subjects
- Anti-Citrullinated Protein Antibodies immunology, Autoantigens immunology, Epitopes immunology, Female, Humans, Male, Arthritis, Rheumatoid immunology, Autoantibodies immunology
- Abstract
Objective: Anti-citrullinated protein antibodies (ACPAs) are a hallmark of seropositive rheumatoid arthritis (RA). Yet, the precise disease-relevant autoantigens that are targeted by ACPAs remains a matter of debate. This study utilized patient-derived monoclonal ACPAs, rather than serum autoantibody analysis, to characterize the multireactivity to different protein modifications and to reveal autoantibody subsets in patients with RA., Methods: Twelve human monoclonal ACPAs (positive by the second-generation cyclic citrullinated peptide test) were generated from 6 RA patients, and a head-to-head comparison of their reactivities was performed. For profiling, we used a complementary DNA-based protein array (Engine GmbH) and 3 peptide-screening platforms with RA autoantigens (Thermo Fisher Scientific), citrullinated and carbamylated peptides (NimbleGen/Roche), or histone-derived peptides with different posttranslational modifications (JPT Histone Code), covering >207,000 peptides (>7,800 gene products)., Results: The fine-specificity profiles of the investigated ACPAs varied, but all of the monoclonal ACPAs displayed multireactivity to a large number of citrullinated peptides/proteins, each characterized by specific binding properties. ACPA subsets could be defined by clone-distinct consensus binding motifs (e.g., Cit-Gly, Gly-Cit, or Arg-Cit-Asp), with the most common ACPA recognition being that of a Gly in the +1 flanking position, but with additional amino acid preferences. For ACPA protein recognition, we observed a preference for citrullinated RNA-binding proteins with high Arg/Gly content. Six of the 12 ACPA clones also bound acetylated lysine (KAc) or homocitrulline peptide motifs, displaying a similar affinity or higher apparent affinity than that for citrullinated peptides., Conclusion: ACPAs and anti-modified protein autoantibodies represent overlapping facets of RA autoimmunity and bind to a wide variety of modified proteins, extending well beyond the historically recognized set of RA autoantigens. So far, KAc reactivity has been detected only in the context of anti-carbamylated and anti-citrullinated peptide autoantibody responses, postulating the existence of hierarchies of autoreactivity in RA. Future investigations of ACPA fine specificities and functionality should take into consideration the presence of consensus Cit/Carb/KAc motifs and the multireactivity of these autoantibodies in patients with RA., (© 2020 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.) more...
- Published
- 2020
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12. Bronchoperitoneal and Enterocutaneous Fistula Development Following a Colorectal Anastomosis Leak.
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Ebeling PA, Malmquist J, Beale K, Mueller DL, and Kempenich J
- Abstract
Bronchoperitoneal fistulas are rare but serious pathologies that pose numerous treatment challenges to physicians. There is usually a delay in diagnosis, and treatment recommendations are mainly derived from case reports. Here, we present an interesting case of a patient who developed a left bronchoperitoneal fistula and two subsequent enterocutaneous fistulas resulting from a massive intra-abdominal phlegmon eroding through the left diaphragm. The patient experienced numerous medical complications during his hospital stay and required multiple operations. However, 18 months after his initial post-operative complication, the bronchoperitoneal fistula has healed, and the patient has undergone successful intestinal reconstruction. This case highlights multiple uncommon disease processes and the treatment strategies used., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2019, Ebeling et al.) more...
- Published
- 2019
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13. Adenosine 2a Receptor Signal Blockade of Murine Autoimmune Arthritis via Inhibition of Pathogenic Germinal Center-Follicular Helper T Cells.
- Author
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Schmiel SE, Kalekar LA, Zhang N, Blankespoor TW, Robinson LJ, and Mueller DL
- Subjects
- Adenosine analogs & derivatives, Adenosine pharmacology, Adenosine A2 Receptor Agonists, Adoptive Transfer, Animals, Autoantigens, Autoimmune Diseases, CD4-Positive T-Lymphocytes, Cytokines immunology, Disease Models, Animal, Germinal Center, Glucose-6-Phosphate Isomerase immunology, Mice, Mice, Knockout, Mice, Transgenic, Phenethylamines pharmacology, Receptor, Adenosine A2A genetics, Receptors, Antigen, T-Cell, alpha-beta genetics, Signal Transduction, T-Lymphocytes, Helper-Inducer drug effects, Arthritis, Experimental immunology, Receptor, Adenosine A2A immunology, T-Lymphocytes, Helper-Inducer immunology
- Abstract
Objective: CD4 germinal center (GC)-follicular helper T (Tfh) cells are important in the pathogenesis of autoimmune arthritis. Previous studies have shown that adenosine 2a receptor (A2aR; Adora2a) signaling can divert CD4 T cells away from the GC-Tfh cell lineage during the primary response to foreign antigens. This study was undertaken to examine the effects of A2aR signaling on CD4 T cells during the recognition of self antigen in a murine model of autoimmune arthritis., Methods: Wild-type and Adora2a-deficient mouse KRN T cell receptor-transgenic CD4 T cells specific for glucose-6-phosphate isomerase (GPI)/I-A
g7 were transferred into immunodeficient Tcra-/- I-Ag7 -expressing mice to induce arthritis. Recipients were then treated with either the selective A2aR agonist CGS-21680 (CGS) or phosphate buffered saline alone. Severity of disease, autoantibody titers, KRN T cell numbers and phenotype, and GPI-specific isotype class-switched plasmablasts were tracked., Results: CGS treatment inhibited the development of arthritis and differentiation of KRN GC-Tfh cells, blocked the appearance of high-affinity GPI-specific and IgG1 isotype class-switched polyclonal plasmablasts, and led to a reduction in serum titers of anti-GPI IgG1. In addition, therapeutic administration of CGS after the onset of arthritis blocked further disease progression in association with reductions in the number of KRN GC-Tfh cells and anti-GPI IgG1 serum titers., Conclusion: Strong A2aR signaling diverts autoreactive CD4 T cell differentiation away from the GC-Tfh cell lineage, thus reducing help for the differentiation of dangerous autoreactive B cells that promote arthritis. These data in a mouse model of autoimmune arthritis suggest that A2aR and its downstream signaling pathways in CD4 T cells may be promising therapeutic targets for interfering with potentially dangerous autoreactive GC-Tfh cell differentiation., (© 2018, American College of Rheumatology.) more...- Published
- 2019
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14. Recognition of Amino Acid Motifs, Rather Than Specific Proteins, by Human Plasma Cell-Derived Monoclonal Antibodies to Posttranslationally Modified Proteins in Rheumatoid Arthritis.
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Steen J, Forsström B, Sahlström P, Odowd V, Israelsson L, Krishnamurthy A, Badreh S, Mathsson Alm L, Compson J, Ramsköld D, Ndlovu W, Rapecki S, Hansson M, Titcombe PJ, Bang H, Mueller DL, Catrina AI, Grönwall C, Skriner K, Nilsson P, Lightwood D, Klareskog L, and Malmström V more...
- Subjects
- Antibodies, Monoclonal immunology, Autoantibodies immunology, Female, Humans, Male, Middle Aged, Protein Carbamylation, Protein Processing, Post-Translational, Synovial Fluid cytology, Amino Acid Motifs immunology, Anti-Citrullinated Protein Antibodies immunology, Arthritis, Rheumatoid immunology, Autoantigens immunology, Immunoglobulin G immunology, Plasma Cells immunology
- Abstract
Objective: Antibodies against posttranslationally modified proteins are a hallmark of rheumatoid arthritis (RA), but the emergence and pathogenicity of these autoantibodies are still incompletely understood. The aim of this study was to analyze the antigen specificities and mutation patterns of monoclonal antibodies (mAb) derived from RA synovial plasma cells and address the question of antigen cross-reactivity., Methods: IgG-secreting cells were isolated from RA synovial fluid, and the variable regions of the immunoglobulins were sequenced (n = 182) and expressed in full-length mAb (n = 93) and also as germline-reverted versions. The patterns of reactivity with 53,019 citrullinated peptides and 49,211 carbamylated peptides and the potential of the mAb to promote osteoclastogenesis were investigated., Results: Four unrelated anti-citrullinated protein autoantibodies (ACPAs), of which one was clonally expanded, were identified and found to be highly somatically mutated in the synovial fluid of a patient with RA. The ACPAs recognized >3,000 unique peptides modified by either citrullination or carbamylation. This highly multireactive autoantibody feature was replicated for Ig sequences derived from B cells from the peripheral blood of other RA patients. The plasma cell-derived mAb were found to target distinct amino acid motifs and partially overlapping protein targets. They also conveyed different effector functions as revealed in an osteoclast activation assay., Conclusion: These findings suggest that the high level of cross-reactivity among RA autoreactive B cells is the result of different antigen encounters, possibly at different sites and at different time points. This is consistent with the notion that RA is initiated in one context, such as in the mucosal organs, and thereafter targets other sites, such as the joints., (© 2018 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.) more...
- Published
- 2019
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15. Differential ACPA Binding to Nuclear Antigens Reveals a PAD-Independent Pathway and a Distinct Subset of Acetylation Cross-Reactive Autoantibodies in Rheumatoid Arthritis.
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Lloyd KA, Wigerblad G, Sahlström P, Garimella MG, Chemin K, Steen J, Titcombe PJ, Marklein B, Zhou D, Stålesen R, Ossipova E, Lundqvist C, Ekwall O, Rönnelid J, Mueller DL, Karlsson MCI, Kaplan MJ, Skriner K, Klareskog L, Wermeling F, Malmström V, and Grönwall C more...
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- Acetylation, Adult, Aged, Animals, Anti-Citrullinated Protein Antibodies metabolism, Antigens, Nuclear metabolism, Apoptosis immunology, Arthritis, Rheumatoid blood, Autoantigens metabolism, CRISPR-Cas Systems, Cells, Cultured, Cross Reactions, Extracellular Traps immunology, Extracellular Traps metabolism, Female, Gene Knockout Techniques, Histones immunology, Histones metabolism, Humans, Male, Mice, Mice, Knockout, Middle Aged, Neutrophils immunology, Neutrophils metabolism, Primary Cell Culture, Protein Processing, Post-Translational immunology, Protein-Arginine Deiminase Type 4, Protein-Arginine Deiminases genetics, Protein-Arginine Deiminases immunology, Anti-Citrullinated Protein Antibodies immunology, Antigens, Nuclear immunology, Arthritis, Rheumatoid immunology, Autoantigens immunology, Protein-Arginine Deiminases metabolism
- Abstract
Rheumatoid arthritis (RA) associated anti-citrullinated protein autoantibodies (ACPA) target a wide range of modified proteins. Citrullination occurs during physiological processes such as apoptosis, yet little is known about the interaction of ACPA with nuclear antigens or apoptotic cells. Since uncleared apoptotic cells and neutrophil extracellular trap (NET) products have been postulated to be central sources of autoantigen and immunostimulation in autoimmune disease, we sought to characterize the anti-nuclear and anti-neutrophil reactivities of ACPA. Serology showed that a subset of anti-CCP2 seropositive RA patients had high reactivity to full-length citrullinated histones. In contrast, seronegative RA patients displayed elevated IgG reactivity to native histone compared to controls, but no citrulline-specific reactivity. Screening of 10 single B-cell derived monoclonal ACPA from RA patients revealed that four ACPA exhibited strong binding to apoptotic cells and three of these had anti-nuclear (ANA) autoantibody reactivity. Modified histones were confirmed to be the primary targets of this anti-nuclear ACPA subset following immunoprecipitation from apoptotic cell lysates. Monoclonal ACPA were also screened for reactivities against stimulated murine and human neutrophils, and all the nuclear-reactive monoclonal ACPA bound to NETs. Intriguingly, one ACPA mAb displayed a contrasting cytoplasmic perinuclear neutrophil binding and may represent a different NET-reactive ACPA subset. Notably, studies of CRISPR-Cas9 PAD4 KO cells and cells from PAD KO mice showed that the cytoplasmic NET-binding was fully dependent on PAD4, whilst nuclear- and histone-mediated NET reactivity was largely PAD-independent. Our further analysis revealed that the nuclear binding could be explained by consensus-motif driven ACPA cross-reactivity to acetylated histones. Specific acetylated histone peptides targeted by the monoclonal antibodies were identified and the anti-modified protein autoantibody (AMPA) profile of the ACPA was found to correlate with the functional activity of the antibodies. In conclusion, when investigating monoclonal ACPA, we could group ACPA into distinct subsets based on their nuclear binding-patterns and acetylation-mediated binding to apoptotic cells, neutrophils, and NETs. Differential anti-modified protein reactivities of RA-autoantibody subsets could have an important functional impact and provide insights in RA pathogenesis. more...
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- 2019
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16. Alum adjuvant is more effective than MF59 at prompting early germinal center formation in response to peptide-protein conjugates and enhancing efficacy of a vaccine against opioid use disorders.
- Author
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Robinson C, Baehr C, Schmiel SE, Accetturo C, Mueller DL, and Pravetoni M
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- Adjuvants, Immunologic chemistry, Alum Compounds chemistry, Animals, B-Lymphocytes immunology, Drug Overdose, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Oxycodone chemistry, Oxycodone immunology, Peptides chemistry, Peptides immunology, Polysorbates chemistry, Proteins chemistry, Proteins immunology, Squalene chemistry, Vaccines, Conjugate administration & dosage, Vaccines, Conjugate immunology, Adjuvants, Immunologic administration & dosage, Alum Compounds administration & dosage, Germinal Center drug effects, Opioid-Related Disorders immunology, Opioid-Related Disorders therapy, Polysorbates administration & dosage, Squalene administration & dosage
- Abstract
Opioid use disorders (OUD) and fatal overdoses are a national emergency in the United States. Therapeutic vaccines offer a promising strategy to treat OUD and reduce the incidence of overdose. Immunization with opioid-based haptens conjugated to immunogenic carriers elicits opioid-specific antibodies that block opioid distribution to the brain and reduce opioid-induced behavior and toxicity in pre-clinical models. This study tested whether the efficacy of a lead oxycodone conjugate vaccine was improved by formulation in either aluminum hydroxide or the squalene-based oil-in-water emulsion MF59 adjuvant, which was recently FDA-approved for influenza vaccines in subjects 65
+ years old. In adult BALB/c mice, alum formulation was more effective than MF59 at promoting the early expansion of hapten-specific B cells and the production of oxycodone-specific serum IgG antibodies, as well as blocking oxycodone distribution to the brain and oxycodone-induced motor activity. Alum was also more effective than MF59 at promoting early differentiation of peptide-specific MHCII-restricted CD4+ Tfh and GC-Tfh cells in adult C57Bl/6 mice immunized with a model peptide-protein conjugate. In contrast, alum and MF59 were equally effective in promoting hapten-specific B cells and peptide-specific MHCII-restricted CD4+ T cell differentiation in older C57Bl/6 mice. These data suggest that alum is a more effective adjuvant than MF59 for conjugate vaccines targeting synthetic small molecule haptens or peptide antigens in adult, but not aged, mice. more...- Published
- 2019
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17. Pathogenic Citrulline-Multispecific B Cell Receptor Clades in Rheumatoid Arthritis.
- Author
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Titcombe PJ, Wigerblad G, Sippl N, Zhang N, Shmagel AK, Sahlström P, Zhang Y, Barsness LO, Ghodke-Puranik Y, Baharpoor A, Hansson M, Israelsson L, Skriner K, Niewold TB, Klareskog L, Svensson CI, Amara K, Malmström V, and Mueller DL more...
- Subjects
- Adult, Anti-Citrullinated Protein Antibodies immunology, Antibodies, Monoclonal blood, Antibodies, Monoclonal immunology, Arthritis, Rheumatoid immunology, Autoantibodies immunology, Autoantigens immunology, Biomarkers blood, Case-Control Studies, Citrulline immunology, Cross Reactions, Female, Filaggrin Proteins, Humans, Male, Peptides, Cyclic immunology, Receptors, Antigen, B-Cell immunology, Anti-Citrullinated Protein Antibodies blood, Arthritis, Rheumatoid blood, Autoantibodies blood, Autoantigens blood, Receptors, Antigen, B-Cell blood
- Abstract
Objective: Anti-citrullinated protein antibodies (ACPAs) have proven highly useful as biomarkers for rheumatoid arthritis (RA). However, composition and functionality of the associated autoreactive B cell repertoire have not been directly assessed. We aimed to selectively investigate citrullinated autoantigen-specific B cell receptors (BCRs) involved in RA and initiate studies on their pathogenicity., Methods: Blood samples were obtained from patients in a University of Minnesota cohort with ACPA-positive RA (n = 89). Tetramer sets bearing citrullinated filaggrin peptide cfc1 or citrullinated α-enolase peptide were constructed to specifically capture autoreactive B cells from the unaltered, polyclonal repertoire in RA patients. Citrullinated peptide tetramer-bound B cells were subjected to flow cytometric cell sorting and single-cell IGH, IGK, and IGL gene sequencing for B cell lineage determinations. BCR gene sequences were also expressed as recombinant monoclonal antibodies (mAb) for direct evaluation of citrullinated autoantigen binding and effector functionality., Results: Using citrullinated peptide tetramer enrichment to investigate single autoreactive blood B cells, we identified biased V-region gene usage and conserved junction arrangements in BCRs from RA patients. Parsimonious clustering of related immunoglobulin gene nucleotide sequences revealed clonal expansions of rare individual B cell clades, in parallel with divergent sequence mutations. Correspondingly, recombinant mAb generated from such BCR lineages demonstrated citrulline-dependent cross-reactivity extending beyond the citrullinated peptides used for B cell capture. A pair of citrullinated autoantigen-specific mAb with cross-reactive binding profiles also promoted arthritis in mice., Conclusion: Our findings suggest that broad ACPA specificities in RA arise from a restricted repertoire of evolving citrulline-multispecific B cell clades with pathogenic potential., (© 2018, American College of Rheumatology.) more...
- Published
- 2018
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18. Variable domain N-linked glycosylation and negative surface charge are key features of monoclonal ACPA: Implications for B-cell selection.
- Author
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Lloyd KA, Steen J, Amara K, Titcombe PJ, Israelsson L, Lundström SL, Zhou D, Zubarev RA, Reed E, Piccoli L, Gabay C, Lanzavecchia A, Baeten D, Lundberg K, Mueller DL, Klareskog L, Malmström V, and Grönwall C more...
- Subjects
- Amino Acid Motifs genetics, Anti-Citrullinated Protein Antibodies genetics, Antibodies, Monoclonal genetics, Cell Differentiation, Cells, Cultured, Clone Cells, Computational Biology, Glycosylation, Humans, Immunoglobulin Variable Region genetics, Lymphocyte Activation, Synovial Fluid immunology, Anti-Citrullinated Protein Antibodies metabolism, Antibodies, Monoclonal metabolism, Arthritis, Rheumatoid immunology, B-Lymphocytes immunology, Immunoglobulin Variable Region metabolism
- Abstract
Autoreactive B cells have a central role in the pathogenesis of rheumatoid arthritis (RA), and recent findings have proposed that anti-citrullinated protein autoantibodies (ACPA) may be directly pathogenic. Herein, we demonstrate the frequency of variable-region glycosylation in single-cell cloned mAbs. A total of 14 ACPA mAbs were evaluated for predicted N-linked glycosylation motifs in silico, and compared to 452 highly-mutated mAbs from RA patients and controls. Variable region N-linked motifs (N-X-S/T) were strikingly prevalent within ACPA (100%) compared to somatically hypermutated (SHM) RA bone marrow plasma cells (21%), and synovial plasma cells from seropositive (39%) and seronegative RA (7%). When normalized for SHM, ACPA still had significantly higher frequency of N-linked motifs compared to all studied mAbs including highly mutated HIV broadly-neutralizing and malaria-associated mAbs. The Fab glycans of ACPA-mAbs were highly sialylated, contributed to altered charge, but did not influence antigen binding. The analysis revealed evidence of unusual B-cell selection pressure and SHM-mediated decrease in surface charge and isoelectric point in ACPA. It is still unknown how these distinct features of anti-citrulline immunity may have an impact on pathogenesis. However, it is evident that they offer selective advantages for ACPA
+ B cells, possibly through non-antigen driven mechanisms., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.) more...- Published
- 2018
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19. Role of bone marrow-derived CD11c + dendritic cells in systolic overload-induced left ventricular inflammation, fibrosis and hypertrophy.
- Author
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Wang H, Kwak D, Fassett J, Liu X, Yao W, Weng X, Xu X, Xu Y, Bache RJ, Mueller DL, and Chen Y
- Subjects
- Animals, Antigen Presentation immunology, Bone Marrow Cells immunology, CD11c Antigen immunology, CD8-Positive T-Lymphocytes immunology, Cardiomegaly immunology, Disease Models, Animal, Flow Cytometry, Mice, Mice, Inbred C57BL, Myocarditis immunology, Dendritic Cells immunology, Hypertrophy, Left Ventricular immunology, Lymphocyte Activation immunology, Ventricular Remodeling immunology
- Abstract
Inflammatory responses play an important role in the development of left ventricular (LV) hypertrophy and dysfunction. Recent studies demonstrated that increased T-cell infiltration and T-cell activation contribute to LV hypertrophy and dysfunction. Dendritic cells (DCs) are professional antigen-presenting cells that orchestrate immune responses, especially by modulating T-cell function. In this study, we investigated the role of bone marrow-derived CD11c
+ DCs in transverse aortic constriction (TAC)-induced LV fibrosis and hypertrophy in mice. We observed that TAC increased the number of CD11c+ cells and the percentage of CD11c+ MHCII+ (major histocompatibility complex class II molecule positive) DCs in the LV, spleen and peripheral blood in mice. Using bone marrow chimeras and an inducible CD11c+ DC ablation model, we found that depletion of bone marrow-derived CD11c+ DCs significantly attenuated LV fibrosis and hypertrophy in mice exposed to 24 weeks of moderate TAC. CD11c+ DC ablation significantly reduced TAC-induced myocardial inflammation as indicated by reduced myocardial CD45+ cells, CD11b+ cells, CD8+ T cells and activated effector CD8+ CD44+ T cells in LV tissues. Moreover, pulsing of autologous DCs with LV homogenates from TAC mice promoted T-cell proliferation. These data indicate that bone marrow-derived CD11c+ DCs play a maladaptive role in hemodynamic overload-induced cardiac inflammation, hypertrophy and fibrosis through the presentation of cardiac self-antigens to T cells. more...- Published
- 2017
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20. Relationship between CD4 Regulatory T Cells and Anergy In Vivo.
- Author
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Kalekar LA and Mueller DL
- Subjects
- Animals, Humans, Clonal Anergy immunology, T-Lymphocytes, Regulatory immunology
- Abstract
Selective suppression of effector CD4
+ T cell functions is necessary to prevent immune cell-mediated damage to healthy tissues. This appears especially true during pregnancy or in individuals predisposed to autoimmunity. Foxp3+ regulatory T (Treg ) cells and induction of anergy, an acquired state of T cell functional unresponsiveness in Foxp3- cells, have both been implicated as mechanisms to suppress dangerous immune responses to tissue-restricted self-Ags. Anergic CD4+ T cells and Treg cells share a number of phenotypic and mechanistic traits-including the expression of CD73 and folate receptor 4, and the epigenetic modification of Treg cell signature genes-and an interesting relationship between these two subsets has recently emerged. In this review, we will compare and contrast these two subsets, as well as explore the role of anergy in the generation of peripheral Treg cells., (Copyright © 2017 by The American Association of Immunologists, Inc.) more...- Published
- 2017
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21. Cutting Edge: Adenosine A2a Receptor Signals Inhibit Germinal Center T Follicular Helper Cell Differentiation during the Primary Response to Vaccination.
- Author
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Schmiel SE, Yang JA, Jenkins MK, and Mueller DL
- Subjects
- Animals, Cell Differentiation immunology, Flow Cytometry, Germinal Center immunology, Mice, Mice, Inbred C57BL, Vaccination, Lymphocyte Activation immunology, Receptor, Adenosine A2A immunology, T-Lymphocytes, Helper-Inducer immunology, Vaccines immunology
- Abstract
Adenosine A2a receptor (A2aR) signaling acts as a barrier to autoimmunity by promoting anergy, inducing regulatory T cells, and inhibiting effector T cells. However, in vivo effects of A2aR signaling on polyclonal CD4 T cells during a primary response to foreign Ag has yet to be determined. To address this problem, we immunized mice with peptide Ag 2W1S coupled to PE in CFA and treated with the selective A2aR agonist CGS-21680 (CGS). 2W1S:I-A
b -specific tetramer-binding CD4 T cells did not become anergic or differentiate into Foxp3+ regulatory T cells. Additionally, CGS treatment did not inhibit Th1 or Th17 differentiation. However, CGS did abrogate germinal center T follicular helper cells, and blunted PE-specific germinal center B cell responses. The use of A2aR-deficient CD4 T cells established that this CGS effect was T cell intrinsic. Therefore, this study has identified a unique role for A2aRs in regulating CD4 T cell differentiation during vaccination., (Copyright © 2017 by The American Association of Immunologists, Inc.) more...- Published
- 2017
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22. CD4(+) T cell anergy prevents autoimmunity and generates regulatory T cell precursors.
- Author
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Kalekar LA, Schmiel SE, Nandiwada SL, Lam WY, Barsness LO, Zhang N, Stritesky GL, Malhotra D, Pauken KE, Linehan JL, O'Sullivan MG, Fife BT, Hogquist KA, Jenkins MK, and Mueller DL
- Subjects
- Adoptive Transfer, Animals, Arthritis, Experimental immunology, CD4-Positive T-Lymphocytes immunology, Cell Proliferation, Cytokines immunology, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry, Forkhead Transcription Factors immunology, Genes, T-Cell Receptor alpha, Immunoblotting, Male, Mice, Mice, Knockout, Neuropilin-1 metabolism, Pregnancy, Receptors, Antigen, T-Cell immunology, Reverse Transcriptase Polymerase Chain Reaction, Self Tolerance, Thymocytes immunology, Autoimmunity immunology, Cell Differentiation immunology, Clonal Anergy immunology, Histocompatibility, Maternal-Fetal immunology, Peripheral Tolerance immunology, Precursor Cells, T-Lymphoid immunology, T-Lymphocytes, Regulatory immunology
- Abstract
The role of anergy, an acquired state of T cell functional unresponsiveness, in natural peripheral tolerance remains unclear. In this study, we found that anergy was selectively induced in fetal antigen-specific maternal CD4(+) T cells during pregnancy. A naturally occurring subpopulation of anergic polyclonal CD4(+) T cells, enriched for self antigen-specific T cell antigen receptors, was also present in healthy hosts. Neuropilin-1 expression in anergic conventional CD4(+) T cells was associated with hypomethylation of genes related to thymic regulatory T cells (Treg cells), and this correlated with their ability to differentiate into Foxp3(+) Treg cells that suppressed immunopathology. Thus, our data suggest that not only is anergy induction important in preventing autoimmunity but also it generates the precursors for peripheral Treg cell differentiation. more...
- Published
- 2016
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23. The frequency of naive and early-activated hapten-specific B cell subsets dictates the efficacy of a therapeutic vaccine against prescription opioid abuse.
- Author
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Laudenbach M, Baruffaldi F, Vervacke JS, Distefano MD, Titcombe PJ, Mueller DL, Tubo NJ, Griffith TS, and Pravetoni M
- Subjects
- Animals, Antibodies immunology, Antibody Specificity immunology, Disease Models, Animal, Germinal Center immunology, Humans, Immunization, Lymphocyte Activation immunology, Lymphocyte Count, Male, Mice, Oxycodone chemistry, Oxycodone immunology, Spleen immunology, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, Vaccines administration & dosage, B-Lymphocyte Subsets immunology, Haptens immunology, Opioid-Related Disorders prevention & control, Vaccines immunology
- Abstract
Translation of therapeutic vaccines for addiction, cancer, or other chronic noncommunicable diseases has been slow because only a small subset of immunized subjects achieved effective Ab levels. We hypothesize that individual variability in the number of naive and early-activated hapten-specific B cells determines postvaccination serum Ab levels and vaccine efficacy. Using a model vaccine against the highly abused prescription opioid oxycodone, the polyclonal B cell population specific for an oxycodone-based hapten (6OXY) was analyzed by flow cytometry paired with Ag-based magnetic enrichment. A higher frequency of 6OXY-specific B cells in either spleen biopsies or blood, before and after immunization, correlated to subsequent greater oxycodone-specific serum Ab titers and their efficacy in blocking oxycodone distribution to the brain and oxycodone-induced behavior in mice. The magnitude of 6OXY-specific B cell activation and vaccine efficacy was tightly correlated to the size of the CD4(+) T cell population. The frequency of enriched 6OXY-specific B cells was consistent across various mouse tissues. These data provide novel evidence that variations in the frequency of naive or early-activated vaccine-specific B and T cells can account for individual responses to vaccines and may predict the clinical efficacy of a therapeutic vaccine., (Copyright © 2015 by The American Association of Immunologists, Inc.) more...
- Published
- 2015
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24. Absence of clinical findings reliably excludes unstable cervical spine injuries in children 5 years or younger.
- Author
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Hale DF, Fitzpatrick CM, Doski JJ, Stewart RM, and Mueller DL
- Subjects
- Cervical Vertebrae diagnostic imaging, Child, Preschool, Diagnosis, Differential, Female, Humans, Incidence, Injury Severity Score, Male, Neurologic Examination, Retrospective Studies, Spinal Injuries epidemiology, Trauma Centers, United States epidemiology, Wounds, Nonpenetrating epidemiology, Cervical Vertebrae injuries, Registries, Spinal Injuries diagnosis, Tomography, X-Ray Computed methods, Wounds, Nonpenetrating diagnosis
- Abstract
Background: Increased accessibility and rapidity of computed tomography (CT) have led to increased use and radiation exposure to pediatric trauma patients. The thyroid is radiosensitive and therefore at risk for developing malignancy from radiation exposure during cervical spine CT. This analysis aimed to determine which preelementary trauma patients warrant cervical spine CT by defining incidence and clinical characteristics of preelementary cervical spine injury., Methods: This was a retrospective review of pre-elementary trauma patients from 1998 to 2010 with cervical spine injury admitted to a Level I trauma center. Patients were identified from the trauma registry using DRG International Classification of Diseases-9th Rev. codes and reviewed for demographics, mechanism of injury, clinical presentation, injury location, injury type, treatment, and outcome., Results: A total of 2,972 preelementary trauma patients were identified. Twenty-two (0.74%) had confirmed cervical spine injuries. Eleven (50%) were boys, and the mean (SD) age was 3 (1.7) years. The most common mechanism of injury was motor vehicle collision (n = 16, 73%). The majority (59%) were in extremis, and 12 (55%) arrived intubated. The median Glasgow Coma Scale (GCS) score was 3 (interquartile range, 3-10); the median Injury Severity Score (ISS) was 33 (interquartile range, 17-56). Nineteen injuries (76%) were at the level of C4 level and higher. The mortality rate was 50%. All patients had clinical findings suggestive of or diagnostic for cervical spine injury; 18 (82%) had abnormal neurologic examination result, 2 (9%) had torticollis, and 2 (9%) had neck pain., Conclusion: The incidence of cervical spine injury in preelementary patients was consistent with previous reports. Missing a cervical spine injury in asymptomatic preelementary patients is extremely low. Reserving cervical spine CT to symptomatic preelementary patients would decrease unnecessary radiation exposure to the thyroid., Level of Evidence: Therapeutic study, level IV. more...
- Published
- 2015
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25. Natural history and clinical implications of nondepressed skull fracture in young children.
- Author
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Hassan SF, Cohn SM, Admire J, Nunez-Cantu O, Arar Y, Myers JG, Dent DL, Eastridge BJ, Cestero RF, Gunst M, Markowski H, Keric N, Liao L, and Mueller DL
- Subjects
- Child, Child, Preschool, Female, Glasgow Coma Scale, Humans, Infant, Infant, Newborn, Length of Stay, Male, Neurologic Examination, Skull Fractures therapy, Skull Fractures complications, Skull Fractures diagnosis
- Abstract
Background: Head injury is the most common cause of neurologic disability and mortality in children. Previous studies have demonstrated that depressed skull fractures (SFs) represent approximately one quarter of all SFs in children and approximately 10% percent of hospital admissions after head injury. We hypothesized that nondepressed SFs (NDSFs) in children are not associated with adverse neurologic outcomes., Methods: Medical records were reviewed for all children 5 years or younger with SFs who presented to our Level I trauma center during a 4-year period. Data collected included patient demographics, Glasgow Coma Scale (GCS) score at admission, level of consciousness at the time of injury, type of SF (depressed SF vs. NDSF), magnitude of the SF depression, evidence of neurologic deficit, and the requirement for neurosurgical intervention., Results: We evaluated 1,546 injured young children during the study period. From this cohort, 563 had isolated head injury, and 223 of them had SF. Of the SF group, 163 (73%) had NDSFs, of whom 128 (78%) presented with a GCS score of 15. None of the NDSF patients with a GCS score of 15 required neurosurgical intervention or developed any neurologic deficit. Of the remaining 35 patients with NDSF and GCS score less than 15, 7 (20%) had a temporary neurologic deficit that resolved before discharge, 4 (11%) developed a persistent neurologic deficit, and 2 died (6%)., Conclusion: Children 5 years or younger with NDSFs and a normal neurologic examination result at admission do not develop neurologic deterioration., Level of Evidence: Epidemiological study, level III. more...
- Published
- 2014
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26. Cutting edge: type 1 diabetes occurs despite robust anergy among endogenous insulin-specific CD4 T cells in NOD mice.
- Author
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Pauken KE, Linehan JL, Spanier JA, Sahli NL, Kalekar LA, Binstadt BA, Moon JJ, Mueller DL, Jenkins MK, and Fife BT
- Subjects
- Animals, Insulin immunology, Interferon-gamma metabolism, Mice, Mice, Inbred NOD, Pancreas cytology, Pancreas immunology, CD4-Positive T-Lymphocytes immunology, Clonal Anergy immunology, Diabetes Mellitus, Experimental immunology, Diabetes Mellitus, Type 1 immunology
- Abstract
Insulin-specific CD4(+) T cells are required for type 1 diabetes. How these cells are regulated and how tolerance breaks down are poorly understood because of a lack of reagents. Therefore, we used an enrichment method and tetramer reagents to track insulin-specific CD4(+) T cells in diabetes-susceptible NOD and resistant B6 mice expressing I-A(g7). Insulin-specific cells were detected in both strains, but they only became activated, produced IFN-γ, and infiltrated the pancreas in NOD mice. Unexpectedly, the majority of Ag-experienced cells in NOD mice displayed an anergic phenotype, but this population decreased with age as tolerance was lost. B6 mice expressing I-A(g7) were protected because insulin-specific cells did not become effector or anergic T cells but remained naive. These data suggest that NOD mice promote tolerance through anergy induction, but a small proportion of autoreactive T cells escape anergy to provoke type 1 diabetes. more...
- Published
- 2013
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27. Macrophage scavenger receptor 1 (Msr1, SR-A) influences B cell autoimmunity by regulating soluble autoantigen concentration.
- Author
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Haasken S, Auger JL, Taylor JJ, Hobday PM, Goudy BD, Titcombe PJ, Mueller DL, and Binstadt BA
- Subjects
- Animals, Arthritis, Experimental immunology, Autoantibodies biosynthesis, Autoantigens metabolism, CD4-Positive T-Lymphocytes immunology, Glucose-6-Phosphate Isomerase blood, Glucose-6-Phosphate Isomerase metabolism, Lymphocyte Activation, Macrophages immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, Scavenger Receptors, Class A genetics, Scavenger Receptors, Class A immunology, Autoantibodies immunology, Autoantigens immunology, Autoimmunity, B-Lymphocytes immunology, Glucose-6-Phosphate Isomerase immunology, Scavenger Receptors, Class A metabolism
- Abstract
The class A macrophage scavenger receptor Msr1 (SR-A, CD204) has been reported to participate in the maintenance of immunological tolerance. We investigated the role of Msr1 in a mouse model of autoantibody-dependent arthritis. Genetic deficiency of Msr1 in K/BxN TCR transgenic mice decreased the incidence and severity of arthritis because of decreased autoantibody production. Despite normal initial activation of autoreactive CD4(+) T cells, potentially autoreactive B cells in Msr1(-/-) K/BxN mice retained a naive phenotype and did not expand. This was not due to an intrinsic B cell defect. Rather, we found that macrophages lacking Msr1 were inefficient at taking up the key autoantigen glucose-6-phosphate isomerase and that Msr1-deficient mice had elevated serum concentrations of glucose-6-phosphate isomerase. Arthritis developed normally when bone marrow from Msr1(-/-) K/BxN mice was transplanted into hosts whose macrophages did express Msr1. Thus, Msr1 can regulate the concentration of a soluble autoantigen. In this model, the absence of Msr1 led to higher levels of soluble autoantigen and protected mice from developing pathogenic autoantibodies, likely because of altered cognate interactions of autoreactive T and B cells with impaired differentiation of follicular Th cells. more...
- Published
- 2013
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28. Murine thymic selection quantified using a unique method to capture deleted T cells.
- Author
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Stritesky GL, Xing Y, Erickson JR, Kalekar LA, Wang X, Mueller DL, Jameson SC, and Hogquist KA
- Subjects
- Animals, Apoptosis Regulatory Proteins genetics, Apoptosis Regulatory Proteins immunology, Bcl-2-Like Protein 11, Membrane Proteins genetics, Membrane Proteins immunology, Mice, Mice, Knockout, Nuclear Receptor Subfamily 4, Group A, Member 1 genetics, Nuclear Receptor Subfamily 4, Group A, Member 1 immunology, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins immunology, Clonal Deletion physiology, Histocompatibility Antigens immunology, Models, Immunological, T-Lymphocytes, Regulatory immunology, Thymus Gland immunology
- Abstract
Thymic positive and negative selection events generate a T-cell repertoire that is MHC restricted and self-tolerant. The number of T cells undergoing positive and negative selection in normal mice has never been firmly established. We generated mice that lack the proapoptotic molecule Bim (bcl2l11) together with a Nur77(GFP) transgene, which allowed the identification and enumeration of T cells that would normally undergo clonal deletion. Using this method, we report the striking observation that six times more cells undergo negative selection than complete positive selection. Seventy-five percent of the negatively selected cells are deleted at the double positive stage in the thymic cortex, compared with 25% at the single positive stage in the medulla. The fact that more thymocytes are highly reactive to MHC than are weakly reactive is inconsistent with a random model of recognition and suggests that T-cell recognition is MHC biased. Furthermore, Bim(-/-) mice had an increased number of GFP(hi) cells in the peripheral lymphoid tissue and a corresponding increase in antigen experienced or anergic cell phenotype. Our data also show that the CD4+ T cells that are clonally deleted experienced only slightly stronger T-cell receptor signaling than those that developed into regulatory T cells. more...
- Published
- 2013
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29. Deletion and anergy of polyclonal B cells specific for ubiquitous membrane-bound self-antigen.
- Author
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Taylor JJ, Martinez RJ, Titcombe PJ, Barsness LO, Thomas SR, Zhang N, Katzman SD, Jenkins MK, and Mueller DL
- Subjects
- Adoptive Transfer, Animals, Arthritis immunology, Arthritis metabolism, Autoantigens metabolism, B-Lymphocytes metabolism, Cell Membrane immunology, Cell Membrane metabolism, Clone Cells immunology, Clone Cells metabolism, Female, Flow Cytometry, Glycosylphosphatidylinositols chemistry, Glycosylphosphatidylinositols immunology, Glycosylphosphatidylinositols metabolism, Lymphocyte Count, Male, Mice, Mice, 129 Strain, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Knockout, Ovalbumin chemistry, Ovalbumin immunology, Ovalbumin metabolism, Protein Multimerization, Receptors, Antigen, B-Cell immunology, Receptors, Antigen, B-Cell metabolism, Autoantigens immunology, B-Lymphocytes immunology, Clonal Anergy immunology, Clonal Deletion immunology
- Abstract
B cell tolerance to self-antigen is critical to preventing antibody-mediated autoimmunity. Previous work using B cell antigen receptor transgenic animals suggested that self-antigen-specific B cells are either deleted from the repertoire, enter a state of diminished function termed anergy, or are ignorant to the presence of self-antigen. These mechanisms have not been assessed in a normal polyclonal repertoire because of an inability to detect rare antigen-specific B cells. Using a novel detection and enrichment strategy to assess polyclonal self-antigen-specific B cells, we find no evidence of deletion or anergy of cells specific for antigen not bound to membrane, and tolerance to these types of antigens appears to be largely maintained by the absence of T cell help. In contrast, a combination of deleting cells expressing receptors with high affinity for antigen with anergy of the undeleted lower affinity cells maintains tolerance to ubiquitous membrane-bound self-antigens. more...
- Published
- 2012
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30. Estimating thyroid dose in pediatric CT exams from surface dose measurement.
- Author
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Al-Senan R, Mueller DL, and Hatab MR
- Subjects
- Child, Preschool, Humans, Infant, Infant, Newborn, Radiometry, Software, Wounds, Nonpenetrating diagnostic imaging, Organs at Risk radiation effects, Radiation Dosage, Thyroid Gland radiation effects, Tomography, X-Ray Computed adverse effects
- Abstract
The purpose of this study was to investigate the possibility of estimating pediatric thyroid doses from CT using surface neck doses. Optically stimulated luminescence dosimeters were used to measure the neck surface dose of 25 children ranging in ages between one and three years old. The neck circumference for each child was measured. The relationship between obtained surface doses and thyroid dose was studied using acrylic phantoms of various sizes and with holes of different depths. The ratios of hole-to-surface doses were used to convert patients' surface dose to thyroid dose. ImPACT software was utilized to calculate thyroid dose after applying the appropriate age correction factors. A paired t-test was performed to compare thyroid doses from our approach and ImPACT. The ratio of thyroid to surface dose was found to be 1.1. Thyroid doses ranged from 20 to 80 mGy. Comparison showed no statistical significance (p = 0.18). In addition, the average of surface dose variation along the z-axis in helical scans was studied and found to range between 5% (in 10 cm diameter phantom/24 mm collimation/pitch 1.0) and 8% (in 16 cm diameter phantom/12 mm collimation/pitch 0.7). We conclude that surface dose is an acceptable predictor for pediatric thyroid dose from CT. The uncertainty due to surface dose variability may be reduced if narrower collimation is used with a pitch factor close to 1.0. Also, the results did not show any effect of thyroid depth on the measured dose. more...
- Published
- 2012
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31. Arthritogenic self-reactive CD4+ T cells acquire an FR4hiCD73hi anergic state in the presence of Foxp3+ regulatory T cells.
- Author
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Martinez RJ, Zhang N, Thomas SR, Nandiwada SL, Jenkins MK, Binstadt BA, and Mueller DL
- Subjects
- Animals, Antigens, CD genetics, Antigens, Neoplasm genetics, Arthritis, Rheumatoid genetics, Clonal Anergy genetics, Glucose-6-Phosphate Isomerase genetics, Glucose-6-Phosphate Isomerase immunology, Lymphopenia genetics, Lymphopenia immunology, Mice, Mice, Transgenic, Receptors, Cell Surface genetics, T-Lymphocytes, Regulatory pathology, Tetraspanins genetics, Antigens, CD immunology, Antigens, Neoplasm immunology, Arthritis, Rheumatoid immunology, Clonal Anergy immunology, Receptors, Cell Surface immunology, T-Lymphocytes, Regulatory immunology, Tetraspanins immunology
- Abstract
Rheumatoid arthritis develops in association with a defect in peripheral CD4(+) T cell homeostasis. T cell lymphopenia has also been shown to be a barrier to CD4(+) T cell clonal anergy induction. We therefore explored the relationship between clonal anergy induction and the avoidance of autoimmune arthritis by tracking the fate of glucose-6-phosphate isomerase (GPI)-reactive CD4(+) T cells in the setting of selective T cell lymphopenia. CD4(+) T cell recognition of self-GPI peptide/MHC class II complexes in normal murine hosts did not lead to arthritis and instead caused those T cells to develop a Folate receptor 4(hi)CD73(hi) anergic phenotype. In contrast, hosts selectively depleted of polyclonal Foxp3(+)CD4(+) regulatory T cells could not make GPI-specific CD4(+) T cells anergic and failed to control arthritis. This suggests that autoimmune arthritis develops in the setting of lymphopenia when Foxp3(+)CD4(+) regulatory T cells are insufficient to functionally inactivate all autoreactive CD4(+) T cells that encounter self-Ag. more...
- Published
- 2012
- Full Text
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32. Pregnancy and rheumatoid arthritis: insights into the immunology of fetal tolerance and control of autoimmunity.
- Author
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Amin S, Peterson EJ, Reed AM, and Mueller DL
- Subjects
- Adult, Female, Humans, Maternal-Fetal Exchange immunology, Arthritis, Rheumatoid immunology, Autoimmunity immunology, Fetus immunology, Immune Tolerance immunology, Pregnancy immunology, Pregnancy Complications immunology
- Abstract
It has long been recognized that symptoms and signs of rheumatoid arthritis (RA) frequently improve spontaneously during pregnancy, only to flare postpartum. Although the mechanisms behind this phenomenon remain poorly understood, there is growing interest in the immunologic changes that occur during healthy pregnancy as a possible explanation. Because the maternal immune system must adapt during pregnancy to accept the semi-allogeneic fetus, it has been hypothesized that these natural changes induced by pregnancy on maternal immune regulatory cells may have the additional benefit of controlling the immunopathology driving disease activity in RA. Here, we review our current understanding on the effects of pregnancy on RA and highlight some of the recent literature related to advancing our understanding on the immunology of pregnancy as well as the immunologic changes in RA during pregnancy. more...
- Published
- 2011
- Full Text
- View/download PDF
33. Pediatric radiation exposure during the initial evaluation for blunt trauma.
- Author
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Mueller DL, Hatab M, Al-Senan R, Cohn SM, Corneille MG, Dent DL, Michalek JE, Myers JG, Wolf SE, and Stewart RM
- Subjects
- Child, Preschool, Female, Humans, Infant, Infant, Newborn, Male, Prospective Studies, Risk Factors, Neoplasms, Radiation-Induced etiology, Radiation Dosage, Thyroid Neoplasms etiology, Tomography, X-Ray Computed adverse effects, Wounds, Nonpenetrating diagnostic imaging
- Abstract
Background: Increased utilization of computed tomography (CT) scans for evaluation of blunt trauma patients has resulted in increased doses of radiation to patients. Radiation dose is relatively amplified in children secondary to body size, and children are more susceptible to long-term carcinogenic effects of radiation. Our aim was to measure radiation dose received in pediatric blunt trauma patients during initial CT evaluation and to determine whether doses exceed doses historically correlated with an increased risk of thyroid cancer., Methods: A prospective cohort study of patients aged 0 years to 17 years was conducted over 6 months. Dosimeters were placed on the neck, chest, and groin before CT scanning to measure surface radiation. Patient measurements and scanning parameters were collected prospectively along with diagnostic findings on CT imaging. Cumulative effective whole body dose and organ doses were calculated., Results: The mean number of scans per patient was 3.1 ± 1.3. Mean whole body effective dose was 17.43 mSv. Mean organ doses were thyroid 32.18 mGy, breast 10.89 mGy, and gonads 13.15 mGy. Patients with selective CT scanning defined as ≤2 scans had a statistically significant decrease in radiation dose compared with patients with >2 scans., Conclusions: Thyroid doses in 71% of study patients fell within the dose range historically correlated with an increased risk of thyroid cancer and whole body effective doses fell within the range of historical doses correlated with an increased risk of all solid cancers and leukemia. Selective scanning of body areas as compared with whole body scanning results in a statistically significant decrease in all doses., (Copyright © 2011 by Lippincott Williams & Wilkins) more...
- Published
- 2011
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- View/download PDF
34. Mechanisms maintaining peripheral tolerance.
- Author
-
Mueller DL
- Subjects
- Animals, Antigen Presentation immunology, Apoptosis immunology, Humans, Models, Immunological, Receptors, Antigen, T-Cell immunology, Dendritic Cells immunology, Immune Tolerance immunology, Major Histocompatibility Complex immunology, T-Lymphocytes immunology
- Abstract
The presentation of self-peptide-MHC complexes in the periphery to potentially autoreactive T cells that have escaped negative selection in the thymus poses an important problem to the immune system. In this review, I discuss data that reveal barriers preventing peripheral T cell recognition of self-peptide-MHC complexes, as well as the physiological mechanisms that ensure the elimination or functional inactivation (anergy) of T cells that do come to recognize self-peptide-MHC and threaten the health of the individual. more...
- Published
- 2010
- Full Text
- View/download PDF
35. Gene regulation and chromatin remodeling by IL-12 and type I IFN in programming for CD8 T cell effector function and memory.
- Author
-
Agarwal P, Raghavan A, Nandiwada SL, Curtsinger JM, Bohjanen PR, Mueller DL, and Mescher MF
- Subjects
- Acetylation, Animals, Antigen Presentation, Cell Differentiation, Histones metabolism, Mice, T-Box Domain Proteins genetics, CD8-Positive T-Lymphocytes immunology, Chromatin Assembly and Disassembly immunology, Gene Expression Regulation immunology, Immunologic Memory genetics, Interferon Type I physiology, Interleukin-12 physiology
- Abstract
A third signal that can be provided by IL-12 or type I IFN is required for differentiation of naive CD8 T cells responding to Ag and costimulation. The cytokines program development of function and memory within 3 days of initial stimulation, and we show here that programming involves regulation of a common set of approximately 355 genes including T-bet and eomesodermin. Much of the gene regulation program is initiated in response to Ag and costimulation within 24 h but is then extinguished unless a cytokine signal is available. Histone deacetylase inhibitors mimic the effects of IL-12 or type I IFN signaling, indicating that the cytokines relieve repression and allow continued gene expression by promoting increased histone acetylation. In support of this, increased association of acetylated histones with the promoter loci of granzyme B and eomesodermin is shown to occur in response to IL-12, IFN-alpha, or histone deacetylase inhibitors. Thus, IL-12 and IFN-alpha/beta enforce in common a complex gene regulation program that involves, at least in part, chromatin remodeling to allow sustained expression of a large number of genes critical for CD8 T cell function and memory. more...
- Published
- 2009
- Full Text
- View/download PDF
36. Casitas B-lineage lymphoma b inhibits antigen recognition and slows cell cycle progression at late times during CD4+ T cell clonal expansion.
- Author
-
Zhang R, Zhang N, and Mueller DL
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Animals, Antigens genetics, Antigens, CD genetics, Antigens, CD immunology, Cell Cycle genetics, Extracellular Signal-Regulated MAP Kinases genetics, Extracellular Signal-Regulated MAP Kinases immunology, Mice, Mice, Knockout, Phospholipase C gamma genetics, Phospholipase C gamma immunology, Phosphorylation, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt immunology, Proto-Oncogene Proteins c-cbl genetics, Receptors, Antigen, T-Cell genetics, Time Factors, Adaptor Proteins, Signal Transducing immunology, Antigens immunology, CD4-Positive T-Lymphocytes immunology, Cell Cycle immunology, Proto-Oncogene Proteins c-cbl immunology, Receptors, Antigen, T-Cell immunology
- Abstract
Optimal clonal expansion of CD4(+) T cells during the primary response to Ag requires prolonged TCR recognition of peptide Ag/MHC complexes. In this study, we investigated the capacity of Casitas B-lineage lymphoma b (Cbl-b) to counter-regulate late TCR signals necessary for continued cell division in vivo. During the first 24 h of a primary response to Ag, Cblb(-/-) 5C.C7 CD4(+) T cells demonstrated no alteration in CD69, CD25, and CD71 up-regulation or cell growth as compared with wild-type cells. Nevertheless, beyond 24 h, both the expression of CD71 and the rate of cell division were increased in the genetic absence of Cbl-b, leading to an augmented clonal expansion. This deregulation of late T cell proliferation in the absence of Cbl-b resulted in part from an inability of Cblb(-/-) T cells to desensitize Akt, PLCgamma-1, and ERK phosphorylation events downstream of the TCR/CD3 complex, in addition to their failure to undergo a growth arrest in the absence of Ag. These observations now suggest a novel role for Cbl-b in triggering the exit from cell cycle at the end of a CD4(+) T cell clonal expansion. more...
- Published
- 2008
- Full Text
- View/download PDF
37. Langerhans cells are not required for efficient skin graft rejection.
- Author
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Obhrai JS, Oberbarnscheidt M, Zhang N, Mueller DL, Shlomchik WD, Lakkis FG, Shlomchik MJ, and Kaplan DH
- Subjects
- Animals, Antigens, Surface genetics, Antigens, Surface metabolism, Female, Graft Rejection pathology, H-Y Antigen immunology, Hypersensitivity, Delayed immunology, Hypersensitivity, Delayed pathology, Langerhans Cells pathology, Lectins, C-Type genetics, Lectins, C-Type metabolism, Male, Mannose-Binding Lectins genetics, Mannose-Binding Lectins metabolism, Mice, Mice, Inbred C57BL, Mice, Transgenic, Models, Animal, Sex Characteristics, Skin Transplantation pathology, Tumor Necrosis Factor Receptor Superfamily, Member 7 immunology, Graft Rejection immunology, Langerhans Cells immunology, Skin Transplantation immunology
- Abstract
The mechanism of skin allograft rejection has been thought to require presentation of graft antigen by resident epidermal Langerhans cells (LCs). We have previously engineered mice that have a selective and constitutive absence of epidermal LCs. By using donor skin from these LC-deficient mice, we show that LCs are not required for rejection of major (FVB --> B6) or minor (H-Y, male --> female on B6 background) antigen-mismatched skin grafts. On the FVB background, where H-Y mismatched grafts are normally maintained indefinitely, grafts lacking LCs are efficiently rejected. Thus, LCs in the donor graft are required for long-term skin engraftment, which supports a regulatory role for LCs in skin graft acceptance. more...
- Published
- 2008
- Full Text
- View/download PDF
38. Proliferating CD4+ T cells undergo immediate growth arrest upon cessation of TCR signaling in vivo.
- Author
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Yarke CA, Dalheimer SL, Zhang N, Catron DM, Jenkins MK, and Mueller DL
- Subjects
- Adoptive Transfer, Animals, Antibodies, Monoclonal pharmacology, CD28 Antigens analysis, CD4-Positive T-Lymphocytes cytology, Cell Cycle, Cell Proliferation, Ligands, Major Histocompatibility Complex immunology, Mice, Receptors, Antigen, T-Cell antagonists & inhibitors, Signal Transduction, CD4-Positive T-Lymphocytes immunology, Cell Division, Lymphocyte Activation, Receptors, Antigen, T-Cell physiology
- Abstract
To investigate the role of TCR signaling in the exit of CD4+ T cells from cell cycle, we took advantage of a low frequency TEa T cell adoptive transfer technique as well as the Y-Ae mAb to interrupt Ag/MHC recognition before the completion of clonal expansion. Termination of TCR signaling after 36 h of Ag exposure caused an immediate reduction in cell size and deceleration of G1->SG2M phase cell cycle progression. As a consequence, clonal expansion in the absence of durable TCR signaling decreased by two-thirds. Thus, CD4+ T cells scan for the presence Ag throughout their clonal expansion response, and continuously adjust their rate of cell growth and G1->S phase transition to match their intensity of TCR signaling. more...
- Published
- 2008
- Full Text
- View/download PDF
39. Allopeptide-specific CD4(+) T cells facilitate the differentiation of directly alloreactive graft-infiltrating CD8(+) T Cells.
- Author
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Richards DM, Zhang N, Dalheimer SL, and Mueller DL
- Subjects
- Animals, Antigens, CD immunology, Antigens, Differentiation, T-Lymphocyte immunology, CD4 Antigens genetics, CD8-Positive T-Lymphocytes cytology, Cell Differentiation immunology, Graft Rejection immunology, Lectins, C-Type, Lymphocyte Activation, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, T-Lymphocytes, Helper-Inducer immunology, Transplantation, Homologous pathology, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Transplantation, Homologous immunology
- Abstract
To investigate the mechanism of CD4(+) T-cell help during the activation and differentiation of directly alloreactive CD8(+) T cells, we examined the development of obliterative airways disease (OAD) following transplantation of airways into fully mismatched recipient mice deficient in CD4(+) T cells. BALB/c trachea allografts became fibrosed significantly less frequently in B6 CD4(-/-) recipients as compared to wildtype controls. Furthermore, class I-directed cytotoxicity failed to develop in the absence of CD4(+) T cells. The infiltration of graft tissue by primed L(d)-specific directly alloreactive 2C CD8(+) T cells was not found to depend on the presence of CD4(+) T cells. Nevertheless, graft-infiltrating 2C CD8(+) T cells failed to express CD69 and granzyme B when CD4(+) T-cell help was unavailable. Importantly, reconstitution of B6 CD4(-/-) recipient mice with graft peptide-specific TCR-Tg CD4(+) T cells (OT-II or TEa) capable of recognizing antigen only on recipient APC allowed for full expression of CD69 and granzyme B by the directly alloreactive CD8(+) T cells and restored the capacity of recipients to reject their allografts. These results demonstrate that indirectly alloreactive CD4(+) T cells ensure the optimal activation and differentiation of graft-infiltrating directly alloreactive CD8(+) T cells independent of donor APC recognition. more...
- Published
- 2007
- Full Text
- View/download PDF
40. mTOR at the crossroads of T cell proliferation and tolerance.
- Author
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Mondino A and Mueller DL
- Subjects
- Animals, Clonal Anergy immunology, Humans, Lymphocyte Activation physiology, T-Lymphocytes immunology, TOR Serine-Threonine Kinases, Cell Proliferation, Immune Tolerance immunology, Protein Kinases physiology, Signal Transduction immunology, T-Lymphocytes cytology
- Abstract
Several events control the activation, proliferation, and the continued Ag responsiveness of naïve and memory T lymphocytes. Here we review the individual contributions of TCR, CD28, and IL-2-driven signaling to T cell proliferation and anergy avoidance. The role of mTOR as a rheostat capable of integrating extracellular, plasma membrane-associated, and intracellular signals with relevance to T cell priming and tolerance is discussed. more...
- Published
- 2007
- Full Text
- View/download PDF
41. Linking diacylglycerol kinase to T cell anergy.
- Author
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Mueller DL
- Subjects
- Animals, Diglycerides metabolism, Humans, Lymphocyte Activation immunology, Signal Transduction immunology, Clonal Anergy immunology, Diacylglycerol Kinase physiology, T-Lymphocytes enzymology, T-Lymphocytes immunology
- Published
- 2006
- Full Text
- View/download PDF
42. p300/Cyclic AMP-responsive element binding-binding protein mediates transcriptional coactivation by the CD28 T cell costimulatory receptor.
- Author
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Nandiwada SL, Li W, Zhang R, and Mueller DL
- Subjects
- Acetylation, Animals, CD28 Antigens physiology, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism, CREB-Binding Protein metabolism, Cells, Cultured, Histones metabolism, Humans, Jurkat Cells, Lymphocyte Activation genetics, Mice, Mice, Inbred BALB C, Mice, Transgenic, Phosphorylation, Promoter Regions, Genetic, Protein Transport genetics, Protein Transport immunology, Proto-Oncogene Proteins c-fos biosynthesis, Proto-Oncogene Proteins c-fos genetics, RNA Polymerase II metabolism, Serine metabolism, Signal Transduction immunology, ets-Domain Protein Elk-1 metabolism, p300-CBP Transcription Factors metabolism, CD28 Antigens metabolism, CREB-Binding Protein physiology, Transcriptional Activation immunology, p300-CBP Transcription Factors physiology
- Abstract
During Ag stimulation of T cells, the recognition of B7 molecules by the CD28 costimulatory receptor increases the level of c-Fos, a component of the AP-1 transactivator known to bind the 5' Il2 gene enhancer. In this study, we show that the costimulation of Fos transcription by CD28 is associated with increased binding of p300/CREB-binding protein (CBP) molecules at the Fos promoter, and is blocked by an adenoviral E1A molecular antagonist of p300/CBP. Furthermore, transcriptional activation by a C-terminal domain of CBP is strengthened when CD28 molecules are actively signaling. This increased amount and activity of p300/CBP molecules at the Fos gene correlated with higher histone H4 acetylation and RNA polymerase II association with the promoter. These data suggest a global mechanism whereby CD28 signaling influences the rate and intensity of new gene expression during Ag recognition via direct control over the coactivator function of p300/CBP. more...
- Published
- 2006
- Full Text
- View/download PDF
43. Sustained B7/CD28 interactions and resultant phosphatidylinositol 3-kinase activity maintain G1-->S phase transitions at an optimal rate.
- Author
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Bonnevier JL, Yarke CA, and Mueller DL
- Subjects
- Animals, B7-1 Antigen immunology, Blotting, Western, CD28 Antigens immunology, CD4-Positive T-Lymphocytes immunology, Cell Growth Processes physiology, Cyclosporine pharmacology, Enzyme Inhibitors pharmacology, Flow Cytometry, G1 Phase immunology, Interleukin-2 immunology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Ovalbumin immunology, Protein Kinases immunology, Receptors, Antigen, T-Cell immunology, S Phase immunology, Signal Transduction, TOR Serine-Threonine Kinases, B7-1 Antigen metabolism, CD28 Antigens metabolism, CD4-Positive T-Lymphocytes cytology, G1 Phase physiology, Phosphatidylinositol 3-Kinases metabolism, S Phase physiology
- Abstract
Twenty-four hours of TCR engagement and CD28 costimulation was found sufficient to elicit an optimal rate of cell division over a 72-h period only when a high concentration of IL-2 was produced in the culture and remained readily available to the CD4(+) T cells. The cell division response could be aborted following 24 h of stimulation by the simultaneous abrogation of IL-2R signaling and the blockade of CD28 or TCR ligands. Biochemical and pharmacologic studies indicated that a phosphatidylinositol 3-kinase-Akt signaling cascade costimulated by the TCR and CD28 maintained the blasting cell division rate at a maximal level beyond 24 h even when IL-2 was withdrawn, neutralized, or exhausted. These data show that CD4(+) T cells remain sensitive to antigens (Ag) and costimulatory signals throughout the clonal expansion response. Furthermore, only those T cells that perceive the presence of a continued threat in the form of Ag/MHC complexes and B7 costimulatory ligands or a high concentration of a growth factor are directed to remain in cell cycle. more...
- Published
- 2006
- Full Text
- View/download PDF
44. CD25+Foxp3+ regulatory T cells facilitate CD4+ T cell clonal anergy induction during the recovery from lymphopenia.
- Author
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Vanasek TL, Nandiwada SL, Jenkins MK, and Mueller DL
- Subjects
- Adoptive Transfer, Animals, CD4-Positive T-Lymphocytes metabolism, CD4-Positive T-Lymphocytes pathology, CD4-Positive T-Lymphocytes transplantation, Cell Proliferation, Cells, Cultured, Clonal Anergy genetics, Lymphopenia genetics, Mice, Mice, Transgenic, T-Lymphocytes, Regulatory immunology, CD4-Positive T-Lymphocytes immunology, Clonal Anergy immunology, Forkhead Transcription Factors biosynthesis, Lymphopenia immunology, Receptors, Interleukin-2 biosynthesis, T-Lymphocytes, Regulatory physiology
- Abstract
T cell clonal anergy induction in lymphopenic nu/nu mice was found to be ineffective. Exposure to a tolerizing peptide Ag regimen instead induced aggressive CD4(+) cell cycle progression and increased Ag responsiveness (priming). Reconstitution of T cell-deficient mice by an adoptive transfer of mature peripheral lymphocytes was accompanied by the development of a CD25(+)Foxp3(+)CTLA-4(+)CD4(+) regulatory T cell population that acted to dampen Ag-driven cell cycle progression and facilitate the induction of clonal anergy in nearby responder CD25(-)CD4(+) T cells. Thus, an early recovery of CD25(+) regulatory T cells following a lymphopenic event can prevent exuberant Ag-stimulated CD4(+) cell cycle progression and promote the development of clonal anergy. more...
- Published
- 2006
- Full Text
- View/download PDF
45. Prolonged TCR/CD28 engagement drives IL-2-independent T cell clonal expansion through signaling mediated by the mammalian target of rapamycin.
- Author
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Colombetti S, Basso V, Mueller DL, and Mondino A
- Subjects
- Animals, CD28 Antigens immunology, Cell Line, Clonal Anergy immunology, Clone Cells, Cyclin D, Cyclin E biosynthesis, Cyclin E genetics, Cyclins biosynthesis, Cyclins genetics, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Transgenic, Phosphatidylinositol 3-Kinases physiology, Rats, Rats, Sprague-Dawley, Receptors, Antigen, T-Cell genetics, Receptors, Antigen, T-Cell immunology, T-Lymphocytes enzymology, TOR Serine-Threonine Kinases, CD28 Antigens metabolism, Cell Proliferation, Interleukin-2 physiology, Protein Kinases physiology, Receptors, Antigen, T-Cell metabolism, Signal Transduction immunology, T-Lymphocytes immunology
- Abstract
Proliferation of Ag-specific T cells is central to the development of protective immunity. The concomitant stimulation of the TCR and CD28 programs resting T cells to IL-2-driven clonal expansion. We report that a prolonged occupancy of the TCR and CD28 bypasses the need for autocrine IL-2 secretion and sustains IL-2-independent lymphocyte proliferation. In contrast, a short engagement of the TCR and CD28 only drives the expansion of cells capable of IL-2 production. TCR/CD28- and IL-2-driven proliferation revealed a different requirement for PI3K and for the mammalian target of rapamycin (mTOR). Thus, both PI3K and mTOR activities were needed for T cells to proliferate to TCR/CD28-initiated stimuli and for optimal cyclin E expression. In contrast, either PI3K or mTOR were sufficient for IL-2-driven cell proliferation as they independently mediated cyclin E induction. Interestingly, rapamycin delayed cell cycle entry of IL-2-sufficient T cells, but did not prevent their expansion. Together, our findings indicate that the TCR, CD28, and IL-2 independently control T cell proliferation via distinct signaling pathways involving PI3K and mTOR. These data suggest that Ag persistence and the availability of costimulatory signals and of autocrine and paracrine growth factors individually shape T lymphocyte expansion in vivo. more...
- Published
- 2006
- Full Text
- View/download PDF
46. Gene expression profiling in murine obliterative airway disease.
- Author
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Lande JD, Dalheimer SL, Mueller DL, Hertz MI, and King RA
- Subjects
- Animals, Bronchiolitis Obliterans pathology, Cluster Analysis, Disease Models, Animal, Epithelial Cells metabolism, Epithelium metabolism, Graft Rejection, Graft Survival, Histocompatibility Antigens Class I chemistry, Immune System, Immunoglobulin G chemistry, Interferon-gamma metabolism, Lung Transplantation pathology, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Models, Biological, Models, Statistical, Phylogeny, Protein Binding, RNA metabolism, RNA, Messenger metabolism, Reverse Transcriptase Polymerase Chain Reaction, Time Factors, Trachea pathology, Transplantation, Homologous, Bronchiolitis Obliterans metabolism, Gene Expression Regulation, Oligonucleotide Array Sequence Analysis methods, Trachea metabolism
- Abstract
Lung and heart-lung transplantation are effective treatments for many diseases unresponsive to other therapy. However, long-term survival of recipients is limited by the development of obliterative bronchiolitis (OB). In this study, microarray analysis of a heterotopic mouse model of obliterative airway disease (OAD) was used to test the hypothesis that the expression and patterns of genes will correlate with specific changes in tracheal tissue developing a response to allotransplantation and the infiltrating cells manifesting these changes. Expression profiles observed were in accordance with the current paradigm of a predictable sequence of events, beginning with airway injury; an innate immune response followed by an adaptive immune response, including both cell-mediated and humoral components; and eventual loss of airway epithelial cells. These observations confirm and expand the list of genes and molecular processes that can be studied as potential surrogate markers or targets for intervention of OB. more...
- Published
- 2005
- Full Text
- View/download PDF
47. Sharing of class I MHC molecules between donor and host promotes the infiltration of allografts by mHAg-reactive CD8 T cells.
- Author
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Dalheimer SL, Richards DM, and Mueller DL
- Subjects
- Animals, Antigen-Presenting Cells immunology, Histocompatibility Antigens Class I genetics, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Skin Transplantation, Time Factors, Transplantation, Homologous, CD8-Positive T-Lymphocytes immunology, Cell Movement immunology, Histocompatibility immunology, Histocompatibility Antigens Class I immunology, Transplantation
- Abstract
Indirect recognition of minor histocompatibility antigens (mHAg) and/or MHC-encoded allopeptides is an important barrier to long-term allograft acceptance following solid organ transplantation. Efficient priming of CD8+ T cells can occur after allotransplantation as a consequence of cross-presentation of donor-derived proteins by the graft recipient's APC. Consistent with this, draining lymph node clonal expansion of OVA-reactive OT-I CD8+ T cells following placement of OVA-transgenic skin grafts did not depend on graft expression of K(b). However, OT-I T cells did accumulate in OVA-transgenic skin grafts most efficiently only when both the donor and host expressed K(b). OT-I infiltration of (B6-OVA x BALB/c)F1 grafts in B6 recipients was not suppressed by graft expression of H-2d. Furthermore, B6 animals transplanted with both B6-OVA and BALB/c-OVA skin had more OT-I T cells infiltrating their B6-OVA MHC-matched graft. Therefore, class I MHC matching between donor and host may not always favor an avoidance of alloreactivity within the graft tissue. more...
- Published
- 2005
- Full Text
- View/download PDF
48. E3 ubiquitin ligases and their control of T cell autoreactivity.
- Author
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Bonnevier JL, Zhang R, and Mueller DL
- Subjects
- Autoimmune Diseases enzymology, Autoimmune Diseases immunology, Clonal Anergy immunology, T-Lymphocytes immunology, Ubiquitin-Protein Ligases immunology
- Abstract
A loss of T cell tolerance underlies the development of most autoimmune diseases. The design of therapeutic strategies to reinstitute immune tolerance, however, is hampered by uncertainty regarding the molecular mechanisms involved in the inactivation of potentially autoreactive T cells. Recently, E3 ubiquitin ligases have been shown to mediate the development of a durable state of unresponsiveness in T cells called clonal anergy. In this review, we will discuss the mechanisms used by E3 ligases to control the activation of T cells and prevent the development of autoimmunity. more...
- Published
- 2005
- Full Text
- View/download PDF
49. Visualizing the first 50 hr of the primary immune response to a soluble antigen.
- Author
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Catron DM, Itano AA, Pape KA, Mueller DL, and Jenkins MK
- Subjects
- Animals, Cell Movement immunology, Humans, Lymph Nodes immunology, Microscopy, Video, Antigen Presentation immunology, Antigen-Presenting Cells immunology, Cell Communication immunology, Models, Immunological, T-Lymphocytes immunology
- Abstract
Recently, static and dynamic imaging methods have produced the first glimpses of the interactions between antigen-specific T cells and peptide-MHC-bearing antigen-presenting cells in the lymph nodes. Using data from these experiments, we produced a numerically, spatially, and temporally scaled simulation of the first 50 hr of the primary T cell-dependent immune response. The simulation highlights how lymph node structure facilitates antigen presentation to rare, naive, antigen-specific CD4+ T cells. more...
- Published
- 2004
- Full Text
- View/download PDF
50. E3 ubiquitin ligases as T cell anergy factors.
- Author
-
Mueller DL
- Subjects
- Animals, Humans, Models, Immunological, Clonal Anergy immunology, Self Tolerance immunology, Signal Transduction immunology, T-Lymphocytes immunology, Ubiquitin-Protein Ligases immunology
- Abstract
E3 ubiquitin ligases have emerged as key molecular regulators of immune cell function. Three families of proteins with ubiquitin ligase activity have been described (the HECT, RING and U-box proteins), and each may be involved in the regulation of immune responses during infection by targeting specific inhibitory molecules for proteolytic destruction. Several HECT and RING E3 proteins have now also been linked to the induction and maintenance of immune self-tolerance: c-Cbl, Cbl-b, GRAIL, Itch and Nedd4 each negatively regulate T cell growth factor production and proliferation. This review will discuss the relationship between the ubiquitination of select components of the antigen-sensing signaling apparatus in T cells and the development and maintenance of the clonal anergy state. more...
- Published
- 2004
- Full Text
- View/download PDF
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