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Article ; Online: PTPN22 R620W gene editing in T cells enhances low-avidity TCR responses

Warren Anderson / Fariba Barahmand-pour-Whitman / Peter S Linsley / Karen Cerosaletti / Jane H Buckner / David J Rawlings

eLife, Vol

2023 Volume 12

Abstract: A genetic variant in the gene PTPN22 (R620W, rs2476601) is strongly associated with increased risk for multiple autoimmune diseases and linked to altered TCR regulation and T cell activation. Here, we utilize Crispr/Cas9 gene editing with donor DNA ... ...

Abstract	A genetic variant in the gene PTPN22 (R620W, rs2476601) is strongly associated with increased risk for multiple autoimmune diseases and linked to altered TCR regulation and T cell activation. Here, we utilize Crispr/Cas9 gene editing with donor DNA repair templates in human cord blood-derived, naive T cells to generate PTPN22 risk edited (620W), non-risk edited (620R), or knockout T cells from the same donor. PTPN22 risk edited cells exhibited increased activation marker expression following non-specific TCR engagement, findings that mimicked PTPN22 KO cells. Next, using lentiviral delivery of T1D patient-derived TCRs against the pancreatic autoantigen, islet-specific glucose-6 phosphatase catalytic subunit-related protein (IGRP), we demonstrate that loss of PTPN22 function led to enhanced signaling in T cells expressing a lower avidity self-reactive TCR, but not a high-avidity TCR. In this setting, loss of PTPN22 mediated enhanced proliferation and Th1 skewing. Importantly, expression of the risk variant in association with a lower avidity TCR also increased proliferation relative to PTPN22 non-risk T cells. Together, these findings suggest that, in primary human T cells, PTPN22 rs2476601 contributes to autoimmunity risk by permitting increased TCR signaling and activation in mildly self-reactive T cells, thereby potentially expanding the self-reactive T cell pool and skewing this population toward an inflammatory phenotype.
Keywords	T cells ; Crisper/ Cas9 ; transgenic TCR ; cord blood ; PTPN22 ; SNP ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	610 ; 570
Language	English
Publishing date	2023-03-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Diminished responses to mRNA-based SARS-CoV-2 vaccines in individuals with rheumatoid arthritis on immune-modifying therapies

Samuel D. Klebanoff / Lauren B. Rodda / Chihiro Morishima / Mark H. Wener / Yevgeniy Yuzefpolskiy / Estelle Bettelli / Jane H. Buckner / Cate Speake / Marion Pepper / Daniel J. Campbell

JCI Insight, Vol 8, Iss

2023 Volume 15

Abstract: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder that causes debilitating swelling and destruction of the joints. People with RA are treated with drugs that actively suppress one or more parts of their immune system, and these may ... ...

Abstract	Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder that causes debilitating swelling and destruction of the joints. People with RA are treated with drugs that actively suppress one or more parts of their immune system, and these may alter the response to vaccination against SARS-CoV-2. In this study, we analyzed blood samples from a cohort of patients with RA after receiving a 2-dose mRNA COVID-19 vaccine regimen. Our data show that individuals on the cytotoxic T lymphocyte antigen 4–Ig therapy abatacept had reduced levels of SARS-CoV-2–neutralizing antibodies after vaccination. At the cellular level, these patients showed reduced activation and class switching of SARS-CoV-2–specific B cells, as well as reduced numbers and impaired helper cytokine production by SARS-CoV-2–specific CD4+ T cells. Individuals on methotrexate showed similar but less severe defects in vaccine response, whereas individuals on the B cell–depleting therapy rituximab had a near-total loss of antibody production after vaccination. These data define a specific cellular phenotype associated with impaired response to SARS-CoV-2 vaccination in patients with RA on different immune-modifying therapies and help inform efforts to improve vaccination strategies in this vulnerable population.
Keywords	Autoimmunity ; Vaccines ; Medicine ; R
Subject code	610
Language	English
Publishing date	2023-08-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Early Prognostic Indicators of Subsequent Hospitalization in Patients with Mild COVID-19

Alyssa Ylescupidez / Aaron Rips / Henry T. Bahnson / Cate Speake / Punam Verma / Anne M. Hocking / Jane H. Buckner / Uma Malhotra

Journal of Clinical Medicine, Vol 10, Iss 1562, p

2021 Volume 1562

Abstract: Comprehensive data on early prognostic indicators in patients with mild COVID-19 remains sparse. In this single center case series, we characterized the initial clinical presentation in 180 patients with mild COVID-19 and defined the earliest predictors ... ...

Abstract	Comprehensive data on early prognostic indicators in patients with mild COVID-19 remains sparse. In this single center case series, we characterized the initial clinical presentation in 180 patients with mild COVID-19 and defined the earliest predictors of subsequent deterioration and need for hospitalization. Three broad patient phenotypes and four symptom clusters were characterized, differentiated by varying risk for adverse outcomes. Among 14 symptoms assessed, subjective shortness of breath (SOB) most strongly associated with adverse outcomes (odds ratio (OR) 21.3, 95% confidence interval (CI): 2.7–166.4; p < 0.0001). In combination, SOB and number of comorbidities were highly predictive of subsequent hospitalization (area under the curve (AUC) 92%). Additionally, initial lymphopenia (OR 21.0, 95% CI: 2.1–210.1; p = 0.002) and male sex (OR 3.5, 95% CI: 0.9–13.0; p = 0.05) were associated with increased risk of poor outcomes. Patients with known comorbidities, especially multiple, and those presenting with subjective SOB or lymphopenia should receive close monitoring and consideration for preemptive treatment, even when presenting with mild symptoms.
Keywords	COVID-19 ; SARS CoV-2 ; pathophysiology ; prognostic indicators ; pandemic ; comorbidities ; Medicine ; R
Subject code	610
Language	English
Publishing date	2021-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Crosstalk between CD4 T cells and synovial fibroblasts from human arthritic joints promotes hyaluronan-dependent leukocyte adhesion and inflammatory cytokine expression in vitro

Inkyung Kang / Christian Hundhausen / Stephen P. Evanko / Prasanthi Malapati / Gail Workman / Christina K. Chan / Cliff Rims / Gary S. Firestein / David L. Boyle / Kevin M. MacDonald / Jane H. Buckner / Thomas N. Wight

Matrix Biology Plus, Vol 14, Iss , Pp 100110- (2022)

2022

Abstract: The content and organization of hyaluronan (HA) in the extracellular matrix (ECM) have been identified as strong indicators of inflammation in joint disease, although the source and role of HA as an effector of inflammation is not clear. In this study, ... ...

Abstract	The content and organization of hyaluronan (HA) in the extracellular matrix (ECM) have been identified as strong indicators of inflammation in joint disease, although the source and role of HA as an effector of inflammation is not clear. In this study, we established co-cultures of activated human CD4 T cells with fibroblast-like synoviocytes (FLS) from osteoarthritis (OA) and rheumatoid arthritis (RA) subjects and examined the role of HA in promoting inflammatory events. Co-cultures of RA FLS with activated CD4 T cells generated an HA-enriched ECM that promoted enhanced monocyte adhesion compared to co-cultures of OA FLS with activated CD4 T cells. In addition, both OA FLS and RA FLS co-cultures with activated CD4 T cells elicited significant increases in the expression of IL1β, TNF, and IL6, with the increase in IL6 expression most prominent in RA co-cultures. Blocking HA synthesis and accumulation with 4-methylumbelliferone reduced expression of IL6, IL1β, and TNF in both OA FLS and RA FLS co-cultures. The increase in HA synthesis in the co-cultures was mimicked by IL6 trans-signaling of FLS in the absence of CD4 T cells. Inhibition of HA synthesis blocked the increase in IL6 by RA FLS mediated by IL6 trans-signaling, suggesting that the HA synthetic pathway may be a key mediator in IL6 expression by FLS. Overall, our study indicates that HA-enriched ECM generated by co-cultures of activated CD4 T cells with FLS from human joints creates a pathogenic microenvironment by promoting adhesion of leukocytes and expression of inflammatory cytokines including IL6.
Keywords	Arthritis ; Extracellular matrix ; Hyaluronan ; IL6 ; Synovial fibroblasts ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: IL-6–targeted therapies to block the cytokine or its receptor drive distinct alterations in T cell function

Cate Speake / Tania Habib / Katharina Lambert / Christian Hundhausen / Sandra Lord / Matthew J. Dufort / Samuel O. Skinner / Alex Hu / MacKenzie Kinsman / Britta E. Jones / Megan D. Maerz / Megan Tatum / Anne M. Hocking / Gerald T. Nepom / Carla J. Greenbaum / Jane H. Buckner

JCI Insight, Vol 7, Iss

2022 Volume 22

Abstract: Therapeutics that inhibit IL-6 at different points in its signaling pathway are in clinical use, yet whether the immunological effects of these interventions differ based on their molecular target is unknown. We performed short-term interventions in ... ...

Abstract	Therapeutics that inhibit IL-6 at different points in its signaling pathway are in clinical use, yet whether the immunological effects of these interventions differ based on their molecular target is unknown. We performed short-term interventions in individuals with type 1 diabetes using anti–IL-6 (siltuximab) or anti–IL-6 receptor (IL-6R; tocilizumab) therapies and investigated the impact of this in vivo blockade on T cell fate and function. Immune outcomes were influenced by the target of the therapeutic intervention (IL-6 versus IL-6R) and by peak drug concentration. Tocilizumab reduced ICOS expression on T follicular helper cell populations and T cell receptor–driven (TCR-driven) STAT3 phosphorylation. Siltuximab reversed resistance to Treg-mediated suppression and increased TCR-driven phosphorylated STAT3 and production of IL-10, IL-21, and IL-27 by T effectors. Together, these findings indicate that the context of IL-6 blockade in vivo drives distinct T cell–intrinsic changes that may influence therapeutic outcomes.
Keywords	Autoimmunity ; Immunology ; Medicine ; R
Subject code	616
Language	English
Publishing date	2022-11-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Shared recognition of citrullinated tenascin-C peptides by T and B cells in rheumatoid arthritis

Jing Song / Anja Schwenzer / Alicia Wong / Sara Turcinov / Cliff Rims / Lorena Rodriguez Martinez / David Arribas-Layton / Christina Gerstner / Virginia S. Muir / Kim S. Midwood / Vivianne Malmström / Eddie A. James / Jane H. Buckner

JCI Insight, Vol 6, Iss

2021 Volume 5

Abstract: Tenascin-C (TNC), an extracellular matrix protein that has proinflammatory properties, is a recently described antibody target in rheumatoid arthritis (RA). In this study, we utilized a systematic discovery process and identified 5 potentially novel ... ...

Abstract	Tenascin-C (TNC), an extracellular matrix protein that has proinflammatory properties, is a recently described antibody target in rheumatoid arthritis (RA). In this study, we utilized a systematic discovery process and identified 5 potentially novel citrullinated TNC (cit-TNC) T cell epitopes. CD4+ T cells specific for these epitopes were elevated in the peripheral blood of subjects with RA and showed signs of activation. Cit-TNC–specific T cells were also present among synovial fluid T cells and secreted IFN-γ. Two of these cit-TNC T cell epitopes were also recognized by antibodies within the serum and synovial fluid of individuals with RA. Detectable serum levels of cit-TNC–reactive antibodies were prevalent among subjects with RA and positively associated with cyclic citrullinated peptide (CCP) reactivity and the HLA shared epitope. Furthermore, cit-TNC–reactive antibodies were correlated with rheumatoid factor and elevated in subjects with a history of smoking. This work confirms cit-TNC as an autoantigen that is targeted by autoreactive CD4+ T cells and autoantibodies in patients with RA. Furthermore, our findings raise the possibility that coinciding epitopes recognized by both CD4+ T cells and B cells have the potential to amplify autoimmunity and promote the development and progression of RA.
Keywords	Autoimmunity ; Immunology ; Medicine ; R
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	American Society for Clinical investigation
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: A novel and rapid method to quantify Treg mediated suppression of CD4 T cells

Long, Anna E / Megan Tatum / Carmen Mikacenic / Jane H. Buckner

Journal of Immunological Methods. 2017,

2017

Abstract: Measuring regulatory T cell suppression provides important insight into T cell dysfunction in autoimmune disease. However, to date, suppression assays are limited by the requirement for freshly isolated cells, and significant cell numbers. Here, we ... ...

Abstract	Measuring regulatory T cell suppression provides important insight into T cell dysfunction in autoimmune disease. However, to date, suppression assays are limited by the requirement for freshly isolated cells, and significant cell numbers. Here, we present a novel and rapid in vitro assay using effector T cell surface expression of both CD25 and CD134 as a surrogate marker of regulatory T cell-mediated suppression. This surface marker-based suppression assay works for frozen samples and for samples with limited cell numbers. It is also shorter taking two days to complete compared to the four days required for proliferation-based assays. Furthermore, this assay works with both in vitro expanded and natural Tregs, as well as anti-CD3/anti-CD28 bead-based and APC stimulation conditions. In conclusion, we have developed and validated a new suppression assay for cryopreserved samples with limited cell numbers that may be helpful to investigate T cell regulation in the context of infection or autoimmune diseases.
Keywords	CD4-positive T-lymphocytes ; autoimmune diseases ; cryopreservation ; in vitro studies ; rapid methods
Language	English
Size	p. .
Publishing place	Elsevier B.V.
Document type	Article
Note	Pre-press version
ZDB-ID	120142-6
ISSN	1872-7905 ; 0022-1759
ISSN (online)	1872-7905
ISSN	0022-1759
DOI	10.1016/j.jim.2017.06.009
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Evaluating associations of joint swelling, joint stiffness and joint pain with physical activity in first-degree relatives of patients with rheumatoid arthritis

Michael H Weisman / Joachim H Ix / Jill M Norris / James R ODell / Ted R Mikuls / Kevin D Deane / V Michael Holers / M Kristen Demoruelle / Jane H Buckner / Richard M Keating / Jan M Hughes-Austin / Samuel R Ward

BMJ Open, Vol 11, Iss

Studies of the Aetiology of Rheumatoid Arthritis (SERA), a prospective cohort study

2021 Volume 9

Keywords	Medicine ; R
Language	English
Publishing date	2021-09-01T00:00:00Z
Publisher	BMJ Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: S1P1 deletion differentially affects TH17 and Regulatory T cells

Ahmet Eken / Rebekka Duhen / Akhilesh K. Singh / Mallory Fry / Jane H. Buckner / Mariko Kita / Estelle Bettelli / Mohamed Oukka

Scientific Reports, Vol 7, Iss 1, Pp 1-

2017 Volume 13

Abstract: Abstract Sphingosine-1 phosphate receptor 1 (S1P1) is critical for the egress of T and B cells out of lymphoid organs. Although S1P1 agonist fingolimod is currently used for the treatment of multiple sclerosis (MS) little is known how S1P1 signaling ... ...

Abstract	Abstract Sphingosine-1 phosphate receptor 1 (S1P1) is critical for the egress of T and B cells out of lymphoid organs. Although S1P1 agonist fingolimod is currently used for the treatment of multiple sclerosis (MS) little is known how S1P1 signaling regulates Th17 and Treg cell homeostasis. To study the impact of S1P1 signaling on Th17 and Treg cell biology, we specifically deleted S1P1 in Th17 and Treg cells using IL-17A Cre and Foxp3 Cre mice, respectively. Deletion of S1P1 in Th17 cells conferred resistance to experimental autoimmune encephalomyelitis (EAE). On the other hand, permanent deletion of S1P1 in Treg cells resulted in autoimmunity and acute deletion rendered mice more susceptible to EAE. Importantly, our study revealed that S1P1 not only regulated the egress of Treg cells out of lymphoid organs and subsequent non-lymphoid tissue distribution but also their phenotypic diversity. Most of the Treg cells found in S1P1-deficient mice as well as MS patients on fingolimod therapy had an activated phenotype and were more prone to apoptosis, thus converted to effector Treg. Our results provide novel insight into the functions of S1P1 and potential impact of long term fingolimod use on Th17 and Treg cell biology and general health in MS patients.
Keywords	Medicine ; R ; Science ; Q
Subject code	570
Language	English
Publishing date	2017-10-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Efficient ex vivo analysis of CD4+ T-cell responses using combinatorial HLA class II tetramer staining

Hannes Uchtenhagen / Cliff Rims / Gabriele Blahnik / I-Ting Chow / William W. Kwok / Jane H. Buckner / Eddie A. James

Nature Communications, Vol 7, Iss 1, Pp 1-

2016 Volume 12

Abstract: Detection of antigen specificity in a blood sample is limited by low frequencies of individual clones. Here the authors develop an MHC class II combinatorial technique and apply it to immunophenotype human CD4+ T cells of multiple specificities in ... ...

Abstract	Detection of antigen specificity in a blood sample is limited by low frequencies of individual clones. Here the authors develop an MHC class II combinatorial technique and apply it to immunophenotype human CD4+ T cells of multiple specificities in response to influenza vaccine in single blood samples.
Keywords	Science ; Q
Language	English
Publishing date	2016-08-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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