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Results: 1 to 10 of 89

Publication Record


Prostaglandin regulation of T cell biology.
Maseda D, Ricciotti E, Crofford LJ
(2019) Pharmacol Res 149: 104456
MeSH Terms: Animals, Autoimmune Diseases, Cell Differentiation, Drug Discovery, Humans, Immunity, Inflammation, Prostaglandins, T-Lymphocytes
Show Abstract · Added March 25, 2020
Prostaglandins (PG) are pleiotropic bioactive lipids involved in the control of many physiological processes, including key roles in regulating inflammation. This links PG to the modulation of the quality and magnitude of immune responses. T cells, as a core part of the immune system, respond readily to inflammatory cues from their environment, and express a diverse array of PG receptors that contribute to their function and phenotype. Here we put in context our knowledge about how PG affect T cell biology, and review advances that bring light into how specific T cell functions that have been newly discovered are modulated through PG. We will also comment on drugs that target PG metabolism and sensing, their effect on T cell function during disease, and we will finally discuss how we can design new approaches that modulate PG in order to maximize desired therapeutic T cell effects.
Published by Elsevier Ltd.
0 Communities
1 Members
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9 MeSH Terms
Adverse events 2.0-Let us get SERIOs: New reporting for adverse event outcomes needed in the era of immunooncology.
Heinzerling L, Ascierto PA, Dummer R, Gogas H, Grob JJ, Lebbe C, Long GV, McArthur G, Moslehi JJ, Neilan TG, Ribas A, Robert C, Schadendorf D, Wolchok JD, Hauschild A
(2019) Eur J Cancer 112: 29-31
MeSH Terms: Adverse Drug Reaction Reporting Systems, Antineoplastic Agents, Autoimmune Diseases, Drug-Related Side Effects and Adverse Reactions, Humans, Immunotherapy, Neoplasms
Added November 12, 2019
0 Communities
1 Members
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7 MeSH Terms
Interstitial Pneumonia With Autoimmune Features: An Emerging Challenge at the Intersection of Rheumatology and Pulmonology.
Wilfong EM, Lentz RJ, Guttentag A, Tolle JJ, Johnson JE, Kropski JA, Kendall PL, Blackwell TS, Crofford LJ
(2018) Arthritis Rheumatol 70: 1901-1913
MeSH Terms: Autoimmune Diseases, Connective Tissue Diseases, Female, Humans, Lung Diseases, Interstitial, Male, Pulmonary Medicine, Rheumatology
Show Abstract · Added March 25, 2020
Interstitial lung disease (ILD) remains a cause of significant morbidity and mortality in patients with connective tissue disease (CTD)-associated ILD. While some patients meet clear classification criteria for a systemic rheumatic disease, a subset of patients do not meet classification criteria but still benefit from immunosuppressive therapy. In 2015, the American Thoracic Society and European Respiratory Society described classification criteria for interstitial pneumonia with autoimmune features (IPAF) to identify patients with lung-predominant CTD who lack sufficient features of a systemic rheumatic disease to meet classification criteria. Although these criteria are imperfect, they are an important attempt to classify the patient with undifferentiated disease for future study. Rheumatologists play a key role in the evaluation of potential IPAF in patients, especially as many patients with a myositis-spectrum disease (e.g., non-Jo-1 antisynthetase syndrome, anti-melanoma differentiation-associated protein 5 antibody inflammatory myositis, or anti-PM/Scl antibody-associated inflammatory myositis) would be classified under IPAF using the currently available criteria for inflammatory myositis, and would therefore benefit from rheumatologic comanagement. The aim of this review was to describe the historical context that led to the development of these criteria and to discuss the limitations of the current criteria, diagnostic challenges, treatment options, and strategies for disease monitoring.
© 2018, American College of Rheumatology.
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MeSH Terms
Bruton's Tyrosine Kinase Is Not Essential for B Cell Survival beyond Early Developmental Stages.
Nyhoff LE, Clark ES, Barron BL, Bonami RH, Khan WN, Kendall PL
(2018) J Immunol 200: 2352-2361
MeSH Terms: Agammaglobulinaemia Tyrosine Kinase, Animals, Autoimmune Diseases, B-Lymphocyte Subsets, Cell Survival, Cells, Cultured, Immunoglobulin M, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptors, Antigen, B-Cell, Signal Transduction
Show Abstract · Added March 3, 2020
Bruton's tyrosine kinase (Btk) is a crucial regulator of B cell signaling and is a therapeutic target for lymphoma and autoimmune disease. BTK-deficient patients suffer from humoral immunodeficiency, as their B cells fail to progress beyond the bone marrow. However, the role of Btk in fully developed, mature peripheral B cells is not well understood. Analysis using BTK inhibitors is complicated by suboptimal inhibition, off-target effects, or failure to eliminate BTK's adaptor function. Therefore a mouse model was developed and used to excise after B cell populations were established. Mice lacking from birth are known to have reduced follicular (FO) compartments, with expanded transitional populations, suggesting a block in development. In adult mice, excision did not reduce FO B cells, which persisted for weeks. Autoimmune-prone B1 cells also survived conditional excision, contrasting their near absence in global -deficient mice. Therefore, Btk supports BCR signaling during selection into the FO and B1 compartments, but is not needed to maintain these cell populations. B1-related natural IgM levels remained normal, contrasting global deficiency, but B cell proliferation and T-independent type II immunization responses were blunted. Thus, B cells have nuanced signaling responses that are differentially regulated by Btk for development, survival, and function. These findings raise the possibility that Btk may also be expendable for survival of mature human B cells, therefore requiring prolonged dosing to be effective, and that success of BTK inhibitors may depend in part on off-target effects.
Copyright © 2018 by The American Association of Immunologists, Inc.
0 Communities
1 Members
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MeSH Terms
MR-PheWAS: exploring the causal effect of SUA level on multiple disease outcomes by using genetic instruments in UK Biobank.
Li X, Meng X, Spiliopoulou A, Timofeeva M, Wei WQ, Gifford A, Shen X, He Y, Varley T, McKeigue P, Tzoulaki I, Wright AF, Joshi P, Denny JC, Campbell H, Theodoratou E
(2018) Ann Rheum Dis 77: 1039-1047
MeSH Terms: Adult, Arthritis, Autoimmune Diseases, Biological Specimen Banks, Celiac Disease, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Gout, Humans, Hypertension, Male, Mendelian Randomization Analysis, Middle Aged, Multimorbidity, Myocardial Infarction, Prognosis, Risk Assessment, United Kingdom, Uric Acid
Show Abstract · Added March 14, 2018
OBJECTIVES - We aimed to investigate the role of serum uric acid (SUA) level in a broad spectrum of disease outcomes using data for 120 091 individuals from UK Biobank.
METHODS - We performed a phenome-wide association study (PheWAS) to identify disease outcomes associated with SUA genetic risk loci. We then implemented conventional Mendelianrandomisation (MR) analysis to investigate the causal relevance between SUA level and disease outcomes identified from PheWAS. We next applied MR Egger analysis to detect and account for potential pleiotropy, which conventional MR analysis might mistake for causality, and used the HEIDI (heterogeneity in dependent instruments) test to remove cross-phenotype associations that were likely due to genetic linkage.
RESULTS - Our PheWAS identified 25 disease groups/outcomes associated with SUA genetic risk loci after multiple testing correction (P<8.57e-05). Our conventional MR analysis implicated a causal role of SUA level in three disease groups: inflammatory polyarthropathies (OR=1.22, 95% CI 1.11 to 1.34), hypertensive disease (OR=1.08, 95% CI 1.03 to 1.14) and disorders of metabolism (OR=1.07, 95% CI 1.01 to 1.14); and four disease outcomes: gout (OR=4.88, 95% CI 3.91 to 6.09), essential hypertension (OR=1.08, 95% CI 1.03 to 1.14), myocardial infarction (OR=1.16, 95% CI 1.03 to 1.30) and coeliac disease (OR=1.41, 95% CI 1.05 to 1.89). After balancing pleiotropic effects in MR Egger analysis, only gout and its encompassing disease group of inflammatory polyarthropathies were considered to be causally associated with SUA level. Our analysis highlighted a locus () that may influence SUA level and multiple cardiovascular and autoimmune diseases via pleiotropy.
CONCLUSIONS - Elevated SUA level is convincing to cause gout and inflammatory polyarthropathies, and might act as a marker for the wider range of diseases with which it associates. Our findings support further investigation on the clinical relevance of SUA level with cardiovascular, metabolic, autoimmune and respiratory diseases.
© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
0 Communities
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20 MeSH Terms
Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels.
Jiang X, O'Reilly PF, Aschard H, Hsu YH, Richards JB, Dupuis J, Ingelsson E, Karasik D, Pilz S, Berry D, Kestenbaum B, Zheng J, Luan J, Sofianopoulou E, Streeten EA, Albanes D, Lutsey PL, Yao L, Tang W, Econs MJ, Wallaschofski H, Völzke H, Zhou A, Power C, McCarthy MI, Michos ED, Boerwinkle E, Weinstein SJ, Freedman ND, Huang WY, Van Schoor NM, van der Velde N, Groot LCPGM, Enneman A, Cupples LA, Booth SL, Vasan RS, Liu CT, Zhou Y, Ripatti S, Ohlsson C, Vandenput L, Lorentzon M, Eriksson JG, Shea MK, Houston DK, Kritchevsky SB, Liu Y, Lohman KK, Ferrucci L, Peacock M, Gieger C, Beekman M, Slagboom E, Deelen J, Heemst DV, Kleber ME, März W, de Boer IH, Wood AC, Rotter JI, Rich SS, Robinson-Cohen C, den Heijer M, Jarvelin MR, Cavadino A, Joshi PK, Wilson JF, Hayward C, Lind L, Michaëlsson K, Trompet S, Zillikens MC, Uitterlinden AG, Rivadeneira F, Broer L, Zgaga L, Campbell H, Theodoratou E, Farrington SM, Timofeeva M, Dunlop MG, Valdes AM, Tikkanen E, Lehtimäki T, Lyytikäinen LP, Kähönen M, Raitakari OT, Mikkilä V, Ikram MA, Sattar N, Jukema JW, Wareham NJ, Langenberg C, Forouhi NG, Gundersen TE, Khaw KT, Butterworth AS, Danesh J, Spector T, Wang TJ, Hyppönen E, Kraft P, Kiel DP
(2018) Nat Commun 9: 260
MeSH Terms: Amidohydrolases, Autoimmune Diseases, Cohort Studies, European Continental Ancestry Group, Female, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Vesicular Transport Proteins, Vitamin D
Show Abstract · Added January 3, 2019
Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10 at rs8018720 in SEC23A, and P = 1.9×10 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.
0 Communities
1 Members
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MeSH Terms
Bruton's Tyrosine Kinase Deficiency Inhibits Autoimmune Arthritis in Mice but Fails to Block Immune Complex-Mediated Inflammatory Arthritis.
Nyhoff LE, Barron BL, Johnson EM, Bonami RH, Maseda D, Fensterheim BA, Han W, Blackwell TS, Crofford LJ, Kendall PL
(2016) Arthritis Rheumatol 68: 1856-68
MeSH Terms: Agammaglobulinaemia Tyrosine Kinase, Animals, Antigen-Antibody Complex, Arthritis, Autoimmune Diseases, Male, Mice, Protein-Tyrosine Kinases
Show Abstract · Added October 12, 2016
OBJECTIVE - Bruton's tyrosine kinase (BTK) is a B cell signaling protein that also contributes to innate immunity. BTK inhibitors prevent autoimmune arthritis but have off-target effects, and the mechanisms of protection remain unknown. We undertook these studies using genetic deletion to investigate the role of BTK in adaptive and innate immune responses that drive inflammatory arthritis.
METHODS - BTK-deficient K/BxN mice were generated to study the role of BTK in a spontaneous model that requires both adaptive and innate immunity. The K/BxN serum-transfer model was used to bypass the adaptive system and elucidate the role of BTK in innate immune contributions to arthritis.
RESULTS - BTK deficiency conferred disease protection to K/BxN mice, confirming outcomes of BTK inhibitors. B lymphocytes were profoundly reduced, more than in other models of BTK deficiency. Subset analysis revealed loss of B cells at all developmental stages. Germinal center B cells were also decreased, with downstream effects on numbers of follicular helper T cells and greatly reduced autoantibodies. In contrast, total IgG was only mildly decreased. Strikingly, and in contrast to small molecule inhibitors, BTK deficiency had no effect in the serum-transfer model of arthritis.
CONCLUSION - BTK contributes to autoimmune arthritis primarily through its role in B cell signaling and not through innate immune components.
© 2016, American College of Rheumatology.
1 Communities
4 Members
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8 MeSH Terms
The role of Bruton's tyrosine kinase in autoimmunity and implications for therapy.
Crofford LJ, Nyhoff LE, Sheehan JH, Kendall PL
(2016) Expert Rev Clin Immunol 12: 763-73
MeSH Terms: Agammaglobulinaemia Tyrosine Kinase, Animals, Anti-Inflammatory Agents, Autoantibodies, Autoimmune Diseases, Autoimmunity, B-Lymphocytes, Humans, Immune Tolerance, Lymphocyte Activation, Protein-Tyrosine Kinases, Receptors, Antigen, B-Cell, Signal Transduction
Show Abstract · Added July 18, 2017
Bruton's tyrosine kinase (BTK) mediates B cell signaling and is also present in innate immune cells but not T cells. BTK propagates B cell receptor (BCR) responses to antigen-engagement as well as to stimulation via CD40, toll-like receptors (TLRs), Fc receptors (FCRs) and chemokine receptors. Importantly, BTK can modulate signaling, acting as a "rheostat" rather than an "on-off" switch; thus, overexpression leads to autoimmunity while decreased levels improve autoimmune disease outcomes. Autoreactive B cells depend upon BTK for survival to a greater degree than normal B cells, reflected as loss of autoantibodies with maintenance of total antibody levels when BTK is absent. This review describes contributions of BTK to immune tolerance, including studies testing BTK-inhibitors for treatment of autoimmune diseases.
1 Communities
2 Members
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13 MeSH Terms
At the Bedside: Neutrophil extracellular traps (NETs) as targets for biomarkers and therapies in autoimmune diseases.
Barnado A, Crofford LJ, Oates JC
(2016) J Leukoc Biol 99: 265-78
MeSH Terms: Acetylcysteine, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Antibodies, Monoclonal, Antimalarials, Apoptosis, Atherosclerosis, Autoantigens, Autoimmune Diseases, Biomarkers, Deoxyribonuclease I, Extracellular Traps, Female, Humans, Hydrolases, Immunosuppressive Agents, Interferon-alpha, Lupus Erythematosus, Systemic, Molecular Targeted Therapy, Neutrophils, Pregnancy, Pregnancy Complications, Protein Processing, Post-Translational, Protein-Arginine Deiminase Type 4, Protein-Arginine Deiminases, Thrombophilia, Thrombosis, Translational Medical Research, Vitamin D
Show Abstract · Added March 25, 2020
Neutrophil extracellular traps are associated with a unique form of cell death distinct from apoptosis or necrosis, whereby invading microbes are trapped and killed. Neutrophil extracellular traps can contribute to autoimmunity by exposing autoantigens, inducing IFN-α production, and activating the complement system. The association of neutrophil extracellular traps with autoimmune diseases, particularly systemic lupus erythematosus, will be reviewed. Increased neutrophil extracellular trap formation is seen in psoriasis, antineutrophil cytoplasmic antibody-associated vasculitis, antiphospholipid antibody syndrome rheumatoid arthritis, and systemic lupus erythematosus. Neutrophil extracellular traps may promote thrombus formation in antineutrophil cytoplasmic antibody-associated vasculitis and antiphospholipid antibody syndrome. In systemic lupus erythematosus, increased neutrophil extracellular trap formation is associated with increased disease activity and renal disease, suggesting that neutrophil extracellular traps could be a disease activity marker. Neutrophil extracellular traps can damage and kill endothelial cells and promote inflammation in atherosclerotic plaques, which may contribute to accelerated atherosclerosis in systemic lupus erythematosus. As neutrophil extracellular traps induce IFN-α production, measuring neutrophil extracellular traps may estimate IFN-α levels and identify which systemic lupus erythematosus patients have elevated levels and may be more likely to respond to emerging anti-IFN-α therapies. In addition to anti-IFN-α therapies, other novel agents, such as N-acetyl-cysteine, DNase I, and peptidylarginine deiminase inhibitor 4, target neutrophil extracellular traps. Neutrophil extracellular traps offer insight into the pathogenesis of autoimmune diseases and provide promise in developing disease markers and novel therapeutic agents in systemic lupus erythematosus. Priority areas for basic research based on clinical research insights will be identified, specifically the potential role of neutrophil extracellular traps as a biomarker and therapeutic target in systemic lupus erythematosus.
© Society for Leukocyte Biology.
0 Communities
1 Members
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MeSH Terms
A case of subepidermal blistering disease with autoantibodies to multiple laminin subunits who developed later autoantibodies to alpha-5 chain of type IV collagen associated with membranous glomerulonephropathy.
Sueki H, Sato Y, Ohtoshi S, Nakada T, Yoshimura A, Tateishi C, Borza DB, Fader W, Ghohestani RF, Hirako Y, Koga H, Ishii N, Tsuchisaka A, Qian H, Li X, Hashimoto T
(2015) Acta Derm Venereol 95: 826-9
MeSH Terms: Aged, Autoantibodies, Autoimmune Diseases, Biopsy, Blister, Collagen Type IV, Female, Fluorescent Antibody Technique, Glomerulonephritis, Membranous, Glucocorticoids, Humans, Kidney, Laminin, Plasma Exchange, Predictive Value of Tests, Protein Subunits, Skin, Time Factors
Show Abstract · Added December 2, 2016
We report a 68-year-old Japanese female patient with subepidermal blistering disease with autoantibodies to multiple laminins, who subsequently developed membranous glomerulonephropathy. At skin disease stage, immunofluorescence demonstrated IgG anti-basement membrane zone antibodies reactive with dermal side of NaCl-split skin. Immunoblotting of human dermal extract, purified laminin-332, hemidesmosome-rich fraction and laminin-521 trimer recombinant protein (RP) detected laminin γ-1 and α-3 and γ-2 subunits of laminin-332. Three years after skin lesions disappeared, nephrotic symptoms developed. Antibodies to α-3 chain of type IV collagen (COL4A3) were negative, thus excluding the diagnosis of Goodpasture syndrome. All anti-laminin antibodies disappeared. Additional IB and ELISA studies of RPs of various COL4 chains revealed reactivity with COL4A5, but not with COL4A6 or COL4A3. Although diagnosis of anti-laminin γ-1 (p200) pemphigoid or anti-laminin-332-type mucous membrane pemphigoid could not be made, this case was similar to previous cases with autoantibodies to COL4A5 and/or COL4A6.
1 Communities
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18 MeSH Terms