162 results match your criteria: "Gwen Knapp Center for Lupus and Immunology Research[Affiliation]"

While single-cell sequencing technologies have revealed tissue heterogeneity, resolving mixed cellular libraries into cellular clones is essential for many pooled screens and clonal lineage tracing. Fluorescent proteins are limited in number, while DNA barcodes can only be read after cell lysis. To overcome these limitations, we used influenza virus hemagglutinins to engineer a genetically encoded cell-surface protein barcoding system.

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B-1a cells are long-lived, self-renewing innate-like B cells that predominantly inhabit the peritoneal and pleural cavities. In contrast to conventional B-2 cells, B-1a cells have a receptor repertoire that is biased towards bacterial and self-antigens, promoting a rapid response to infection and clearing of apoptotic cells. Although B-1a cells are known to primarily originate from fetal tissues, the mechanisms by which they arise has been a topic of debate for many years.

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In B lymphopoiesis, activation of the pre-B cell antigen receptor (pre-BCR) is associated with both cell cycle exit and Igk recombination. Yet how the pre-BCR mediates these functions remains unclear. Here, we demonstrate that the pre-BCR initiates a feed-forward amplification loop mediated by the transcription factor interferon regulatory factor 4 and the chemokine receptor C-X-C motif chemokine receptor 4 (CXCR4).

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Quantifying in situ adaptive immune cell cognate interactions in humans.

Nat Immunol

April 2019

Department of Medicine, Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL, USA.

Two-photon excitation microscopy (TPEM) has revolutionized the understanding of adaptive immunity. However, TPEM usually requires animal models and is not amenable to the study of human disease. The recognition of antigen by T cells requires cell contact and is associated with changes in T cell shape.

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BRWD1 orchestrates epigenetic landscape of late B lymphopoiesis.

Nat Commun

September 2018

Department of Medicine, Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, Illinois, USA.

Transcription factor (TF) networks determine cell fate in hematopoiesis. However, how TFs cooperate with other regulatory mechanisms to instruct transcription remains poorly understood. Here we show that in small pre-B cells, the lineage restricted epigenetic reader BRWD1 closes early development enhancers and opens the enhancers of late B lymphopoiesis to TF binding.

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Humoral Immunity to Vimentin in HLA-DRB1*03 Patients With Pulmonary Sarcoidosis.

Front Immunol

July 2018

Respiratory Medicine Unit, Department of Medicine, Solna and Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.

Vimentin has been implicated in pulmonary sarcoidosis as a T-cell autoantigen, particularly in the context of , the Vα2.3/Vβ22 T-cell receptor (TCR), and Löfgren's syndrome. As vimentin is a known antigenic target in B-cell-mediated autoimmunity, we investigated humoral anti-vimentin responses in pulmonary sarcoidosis and their relationship with .

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The limited ability of current influenza virus vaccines to protect from antigenically drifted or shifted viruses creates a public health problem that has led to the need to develop effective, broadly protective vaccines. While current influenza virus vaccines mostly induce an immune response against the immunodominant and variable head domain of the hemagglutinin, the major surface glycoprotein of the virus, the hemagglutinin stalk domain has been identified to harbor neutralizing B-cell epitopes that are conserved among and even between influenza A virus subtypes. A complete understanding of the differences in evolution between the main target of current vaccines and this more conserved stalk region are missing.

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Origins and specificity of auto-antibodies in Sm+ SLE patients.

J Autoimmun

June 2018

Gwen Knapp Center for Lupus and Immunology Research, Department of Pathology, University of Chicago, Chicago, IL, 60637, USA.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease accompanied by production of autoantibodies directed to a variety of self-proteins and nucleic acids. The genetic basis of SLE is also complex with at least 40 susceptibility loci identified. This complexity suggests that there are a variety of SLE manifestations; nevertheless, SLE is treated as a single disease clinically.

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In the original PDF version of this Article, which was published on 16 October 2017, the publication date was incorrectly given as 11 October 2017. This has now been corrected in the PDF; the HTML version of the paper was correct from the time of publication.

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Igβ ubiquitination activates PI3K signals required for endosomal sorting.

J Exp Med

December 2017

Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, Departments of Medicine and Pathology, University of Chicago, Chicago, IL

A wealth of in vitro data has demonstrated a central role for receptor ubiquitination in endocytic sorting. However, how receptor ubiquitination functions in vivo is poorly understood. Herein, we report that ablation of B cell antigen receptor ubiquitination in vivo uncouples the receptor from CD19 phosphorylation and phosphatidylinositol 3-kinase (PI3K) signals.

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Zbtb16-encoded PLZF is a signature transcription factor (TF) that directs the acquisition of T-helper effector programs during the development of multiple innate lymphocyte lineages, including natural killer T cell, innate lymphoid cell, mucosal-associated invariant T cell and γδ lineages. PLZF is also essential in osteoblast and spermatogonial development. How Zbtb16 itself is regulated in different lineages is incompletely understood.

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In this study, we report that antigen-specific CD19CD27CD21 (CD21) B cells are transiently induced 14 to 28 days after immunization, at the time germinal centers (GCs) peak. Although clonally related to memory B cells and plasmablasts, CD21 cells form distinct clades within phylogenetic trees based on accumulated variable gene mutations, supporting exit from active GCs. CD21 cells express a transcriptional program, suggesting that they are primed for plasma cell differentiation and are refractory to GC differentiation, although they do not spontaneously secrete antibody.

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Molecular understanding of serological immunity to influenza has been confounded by the complexity of the polyclonal antibody response in humans. Here we used high-resolution proteomics analysis of immunoglobulin (referred to as Ig-seq) coupled with high-throughput sequencing of transcripts encoding B cell receptors (BCR-seq) to quantitatively determine the antibody repertoire at the individual clonotype level in the sera of young adults before and after vaccination with trivalent seasonal influenza vaccine. The serum repertoire comprised between 40 and 147 clonotypes that were specific to each of the three monovalent components of the trivalent influenza vaccine, with boosted pre-existing clonotypes accounting for ∼60% of the response.

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Refined protocol for generating monoclonal antibodies from single human and murine B cells.

J Immunol Methods

November 2016

Department of Medicine, Section of Rheumatology, Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, 924 E 57th Street R422, Chicago, IL 60637, USA; Committee on Immunology, University of Chicago, USA. Electronic address:

Generating monoclonal antibodies from single B cells is a valuable tool for characterizing the specificity and functional properties of humoral responses. We and others developed protocols that have facilitated major advances in our understanding of B cell development, tolerance, and effector responses to HIV and influenza. Here, we demonstrate various refinements and dramatically reduce the time required to produce recombinant antibodies.

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Use of Eculizumab in Atypical Hemolytic Uremic Syndrome, Complicating Systemic Lupus Erythematosus.

J Clin Rheumatol

September 2016

From the *Pritzker School of Medicine, †Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, and ‡Section of Hematology and Oncology, University of Chicago, Chicago, IL.

Atypical hemolytic uremic syndrome is characterized by the presence of thrombocytopenia, microangiopathic hemolytic anemia, and end-organ injury. In this report, we describe two patients with systemic lupus erythematosus who presented with findings compatible with atypical hemolytic uremic syndrome, complicated by acute kidney injury that was refractory to conventional therapies. Both patients exhibited a response to eculizumab, a monoclonal antibody to complement protein C5, with stabilization of their platelet count.

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Overview of pathophysiology and treatment of human lupus nephritis.

Curr Opin Rheumatol

September 2016

Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, Illinois, USA.

Purpose Of Review: Despite recent developments and treatment successes, the outcome, and prognosis of patients with lupus nephritis (LuN) have not greatly changed since the 1980s. This review covers the application of new concepts to the understanding of renal inflammation and the study of new pharmacologic agents to improve patient outcomes.

Recent Findings: Studies have shown that the presence of anti-vimentin antibodies and T follicular helper cells in patient biopsies is associated with more severe interstitial inflammation, which has been tied to faster disease progression and onset of end-stage renal disease.

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Article Synopsis
  • Immunoglobulin E (IgE) typically plays a role in allergic reactions, activating mast cells and basophils to release histamine; however, recent findings indicate its involvement in systemic lupus erythematosus (SLE).
  • In SLE, specific IgE antibodies for double-stranded DNA (dsDNA) activate plasmacytoid dendritic cells (pDCs), leading to increased production of interferon-α (IFN-α), which is important for immune responses against viruses.
  • The presence of dsDNA-specific IgE in patient serum correlates with the severity of SLE, indicating that IgE not only contributes to allergies but also enhances autoimmune responses, complicating the disease pathology.
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Immune history profoundly affects broadly protective B cell responses to influenza.

Sci Transl Med

December 2015

Department of Medicine, Section of Rheumatology, Gwen Knapp Center for Lupus and Immunology Research, The University of Chicago, Chicago, IL 60637, USA. Committee on Immunology, The University of Chicago, Chicago, IL 60637, USA.

Generating a broadly protective influenza vaccine is critical to global health. Understanding how immune memory influences influenza immunity is central to this goal. We undertook an in-depth study of the B cell response to the pandemic 2009 H1N1 vaccine over consecutive years.

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Nephritis is a common complication of systemic lupus erythematosus for which current therapies often prove inadequate. Current lupus nephritis classification systems emphasize glomerular acuity and scarring. However, tubulointerstitial inflammation (TII) and scarring are much better predictors of progression to renal failure.

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Objective: Studies suggest that circulating type I interferon (IFN) may predict response to biological agents in rheumatoid arthritis (RA). Prediction of response prior to initiating therapy would represent a major advancement.

Methods: We studied sera from a test set of 32 patients with RA from the Auto-immune Biomarkers Collaborative Network Consortium and a validation set of 92 patients with RA from the Treatment Efficacy and Toxicity in Rheumatoid Arthritis Database and Repository registry.

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Histone reader BRWD1 targets and restricts recombination to the Igk locus.

Nat Immunol

October 2015

Department of Medicine, Section of Rheumatology and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, Illinois, USA.

B lymphopoiesis requires that immunoglobulin genes be accessible to RAG1-RAG2 recombinase. However, the RAG proteins bind widely to open chromatin, which suggests that additional mechanisms must restrict RAG-mediated DNA cleavage. Here we show that developmental downregulation of interleukin 7 (IL-7)-receptor signaling in small pre-B cells induced expression of the bromodomain-family member BRWD1, which was recruited to a specific epigenetic landscape at Igk dictated by pre-B cell receptor (pre-BCR)-dependent Erk activation.

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RAG Represents a Widespread Threat to the Lymphocyte Genome.

Cell

August 2015

Department of Immunobiology, Yale University School of Medicine, 300 Cedar Street, Box 208011, New Haven, CT 06520-8011, USA; Howard Hughes Medical Institute, 295 Congress Avenue, New Haven, CT 06511, USA. Electronic address:

The RAG1 endonuclease, together with its cofactor RAG2, is essential for V(D)J recombination but is a potent threat to genome stability. The sources of RAG1 mis-targeting and the mechanisms that have evolved to suppress it are poorly understood. Here, we report that RAG1 associates with chromatin at thousands of active promoters and enhancers in the genome of developing lymphocytes.

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Oral tolerance is dependent on the complex architecture of the mucosal system of the gastrointestinal tract, its associated lymphoid tissue, and specialized immune cells. Changes in this architecture or the failure of any of its components may hinder the generation of oral tolerance. The larynx and esophagus are the gateway to the gastrointestinal tract, serving as the site of oral antigen introduction to the immune system and may have an important role in establishing tolerance.

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Balancing Proliferation with Igκ Recombination during B-lymphopoiesis.

Front Immunol

June 2014

Department of Medicine, Section of Rheumatology, Gwen Knapp Center for Lupus and Immunology Research, The University of Chicago, Chicago, IL , USA.

The essential events of B-cell development are the stochastic and sequential rearrangement of immunoglobulin heavy (Igμ) and then light chain (Igκ followed by Igλ) loci. The counterpoint to recombination is proliferation, which both maintains populations of pro-B cells undergoing Igμ recombination and expands the pool of pre-B cells expressing the Igμ protein available for subsequent Igκ recombination. Proliferation and recombination must be segregated into distinct and mutually exclusive developmental stages.

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Cell distance mapping identifies functional T follicular helper cells in inflamed human renal tissue.

Sci Transl Med

April 2014

Section of Rheumatology, Department of Medicine and Gwen Knapp Center for Lupus and Immunology Research, University of Chicago, Chicago, IL 60637, USA.

T follicular helper (TFH) cells are critical for B cell activation in germinal centers and are often observed in human inflamed tissue. However, it is difficult to know if they contribute in situ to inflammation. Expressed markers define TFH subsets associated with distinct functions in vitro.

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