المؤلفون: Arger, Nicholas K, Machiraju, Siddharth, Allen, Isabel E, Woodruff, Prescott G, Koth, Laura L

مصطلحات موضوعية: Lung, Bronchoalveolar Lavage Fluid, Humans, Sarcoidosis, Pulmonary, T-Box Domain Proteins, Prognosis, Case-Control Studies, Adult, Aged, Middle Aged, Female, Male, Interferon-gamma, Nuclear Receptor Subfamily 1, Group F, Member 3, Th17 Cells, Biomarkers, RORγt, T-bet, Th1, Th17, Th17.1, chemokine, interferon-gamma, sarcoidosis, Autoimmune Disease, Clinical Research, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, 1, ROR gamma t, Immunology, Medical Microbiology

الوصف: Background: Interferon-gamma (IFN-γ) is a key mediator of sarcoidosis-related granulomatous inflammation. Previous findings of IFN-γ-producing Th17 cells in bronchoalveolar lavage fluid from sarcoidosis patients invokes the transition of Th17.0 cells to Th17.1 cells in the disease's pathogenesis. Since the T-bet transcription factor is crucial for this transition, the goal of this study was to determine if T-bet expression in Th17.0 cells reflects the extent of granulomatous inflammation in sarcoidosis patients as assessed by clinical outcomes. Methods: Using a case-control study design, we identified two groups of sarcoidosis subjects (total N = 43) with pulmonary function tests (PFTs) that either (1) changed (increased or decreased) longitudinally or (2) were stable. We used flow cytometry to measure the transcription factors T-bet and RORγt in Th1, Th17.0, and Th17.1 cell subsets defined by CCR6, CCR4 and CXCR3 in blood samples. We compared the percentages of T-bet+ cells in RORγt+Th17.0 cells (defined as CCR6+CCR4+CXCR3-) based on subjects' PFT group. We also assessed the relationship between the direction of change in PFTs with the changes in %T-bet+ frequencies using mixed effects modeling. Results: We found that T-bet expression in subjects' RORγt+Th17.0 cells varied based on clinical outcome. The T-bet+ percentage of RORγt+Th17.0 cells was higher in the cases (subject group with PFT changes) as compared to controls (stable group) (27 vs. 16%, p = 0.0040). In comparisons before and after subjects' PFT changes, the T-bet+ frequency of RORγt+Th17.0 cells increased or decreased in the opposite direction of the PFT change. The percentage of these T-bet+ cells was also higher in those with greater numbers of involved organs. Serum levels of interferon-γ-induced chemokines, CXCL9, CXCL10, and CXCL11, and whole blood gene expression of IFN-γ-related genes including GBP1, TAP1, and JAK2 were independently positively associated with the T-bet+ frequencies of RORγt+Th17.0 cells. Conclusions: These data suggest that expression of T-bet in Th17.0 cells could reflect the extent of granulomatous inflammation in sarcoidosis patients because they represent a transition state leading to the Th17.1 cell phenotype. These findings indicate that Th17 plasticity may be part of the disease paradigm.

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الوصول الحر: https://escholarship.org/uc/item/922531z9Test

المؤلفون: Mohammadi, M Rezaa, Dehkordi-Vakil, Farideh, Ricks-Oddie, Joni, Mansfield, Robert, Kashimiri, Himala, Daniels, Mark, Zhao, Weian, Lakey, Jonathan Rt

مصطلحات موضوعية: Humans, Diabetes Mellitus, Type 1, Islets of Langerhans Transplantation, Cohort Studies, Adolescent, Adult, Aged, Middle Aged, Female, Male, Young Adult, Surveys and Questionnaires, biomaterials, implantable devices, islet transplantation, patients’ preferences, type 1 diabetes, patients' preferences, Autoimmune Disease, Diabetes, Bioengineering, Transplantation, Metabolic and endocrine, Neurology & Neurosurgery, Biological Sciences, Technology, Medical and Health Sciences

الوصف: Transplantation of pancreatic islets within a biomaterial device is currently under investigation in clinical trials for the treatment of patients with type 1 diabetes (T1D). Patients' preferences on such implants could guide the designs of next-generation implantable devices; however, such information is not currently available. We surveyed the preferences of 482 patients with T1D on the size, shape, visibility, and transplantation site of islet containing implants. More than 83% of participants were willing to receive autologous stem cells, and there was no significant association between implant fabricated by one's own stem cell with gender (χ 2 (1, n = 468) = 0.28; P = 0.6) or with age (χ 2 (4, n = 468) = 2.92; P = 0.6). Preferred location for islet transplantation within devices was under the skin (52.7%). 48.3% preferred microscopic disks, and 32.3% preferred a thin device (like a credit card). Moreover, 58.4% preferred the implant to be as small as possible, 25.4% did not care about visibility, and 16.2% preferred their implants not to be visible. Among female participants, 81% cared about the implant visibility, whereas this number was 64% for male respondents (χ 2 test (1, n = 468) = 16.34; P < 0.0001). 22% of those younger than 50 years of age and 30% of those older than 50 did not care about the visibility of implant (χ 2 test (4, n = 468) = 23.69; P < 0.0001). These results suggest that subcutaneous sites and micron-sized devices are preferred choices among patients with T1D who participated in our survey.

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الوصول الحر: https://escholarship.org/uc/item/4q59n52tTest

المؤلفون: Due‐Christensen, Mette, Bruun, L. D., Joensen, L. E., Norgaard, O., Andersen, T. H.

المصدر: Diabetic Medicine; May2023, Vol. 40 Issue 5, p1-14, 14p

مصطلحات موضوعية: CINAHL database, PSYCHOLOGY information storage & retrieval systems, MEDICAL information storage & retrieval systems, SYSTEMATIC reviews, TYPE 1 diabetes, PATIENTS' attitudes, PSYCHOSOCIAL factors, RESEARCH funding, PSYCHOLOGY of the sick, LITERATURE reviews, MEDLINE, PEOPLE with diabetes, ADULTS

مستخلص: Aim: To map existing research on psychosocial aspects of adult‐onset type 1 diabetes (T1D), including psychosocial health status, ways psychosocial aspects may affect management of T1D in everyday life, and interventions targeting management of adult‐onset T1D. Methods: We conducted a systematic search in MEDLINE, EMBASE, CINAHL and PsycInfo. Search results were screened with predefined eligibility criteria, followed by data extraction of the included studies. Charted data were summarized in narrative and tabular form. Results: We included 10 reports describing nine studies from the 7302 identified in the search. All studies were conducted in Europe. Participant characteristics were missing in several studies. Five of the nine studies incorporated psychosocial aspects as the main aim of the study. Limited information on psychosocial aspects was available in the remaining studies. We identified three overarching themes related to psychosocial aspects: (1) the impact of the diagnosis on everyday life, (2) the influence of psychosocial health on metabolic levels and adaptation, and (3) provision of self‐management support. Conclusions: Research focussing on psychosocial aspects of the adult‐onset population is scarce. Future research should involve participants across the adult life age span and from a wider geographical area. Sociodemographic information should be collected to explore different perspectives. Further exploration of suitable outcome measures considering adults' limited experience of living with the condition is needed. This would help to better understand how psychosocial aspects may affect management of T1D in everyday life and thus enable healthcare professionals to provide appropriate support to adults with new‐onset T1D. [ABSTRACT FROM AUTHOR]

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المؤلفون: Rodriguez, Fausto J, Graham, Mindy K, Brosnan-Cashman, Jacqueline A, Barber, John R, Davis, Christine, Vizcaino, M Adelita, Palsgrove, Doreen N, Giannini, Caterina, Pekmezci, Melike, Dahiya, Sonika, Gokden, Murat, Noë, Michael, Wood, Laura D, Pratilas, Christine A, Morris, Carol D, Belzberg, Allan, Blakeley, Jaishri, Heaphy, Christopher M

المصدر: Acta Neuropathologica Communications. 7(1)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Brain Cancer, Cancer, Neurofibromatosis, Brain Disorders, Neurosciences, Rare Diseases, Adult, Brain Neoplasms, Female, Glioma, Humans, Kaplan-Meier Estimate, Male, Mutation, Neurofibromatosis 1, Neurofibromin 1, Neurofibrosarcoma, Telomere, Telomere Homeostasis, Young Adult, NF1, ATRX, Alternative lengthening of telomeres, MPNST, Biochemistry and Cell Biology, Clinical Sciences, Biochemistry and cell biology

الوصف: The presence of Alternative lengthening of telomeres (ALT) and/or ATRX loss, as well as the role of other telomere abnormalities, have not been formally studied across the spectrum of NF1-associated solid tumors. Utilizing a telomere-specific FISH assay, we classified tumors as either ALT-positive or having long (without ALT), short, or normal telomere lengths. A total of 426 tumors from 256 NF1 patients were evaluated, as well as 99 MPNST tumor samples that were sporadic or of unknown NF1 status. In the NF1-glioma dataset, ALT was present in the majority of high-grade gliomas: 14 (of 23; 60%) in contrast to only 9 (of 47; 19%) low-grade gliomas (p = 0.0009). In the subset of ALT-negative glioma cases, telomere lengths were estimated and we observed 17 (57%) cases with normal, 12 (40%) cases with abnormally long, and only 1 (3%) case with short telomeres. In the NF1-associated malignant nerve sheath tumor (NF1-MPNST) set (n = 75), ALT was present in 9 (12%). In the subset of ALT-negative NF1-MPNST cases, telomeres were short in 9 (38%), normal in 14 (58%) and long in 1 (3%). In the glioma set, overall survival was significantly decreased for patients with ALT-positive tumors (p

الوصول الحر: https://escholarship.org/uc/item/8m62235kTest

المؤلفون: Ekhlaspour, Laya, Nally, Laura, El-Khatib, Firas, Ly, Trang, Clinton, Paula, Frank, Eliana, Tanenbaum, Molly, Hanes, Sarah, Selagamsetty, Rajendranath, Hood, Korey, Damiano, Edward, Buckingham, Bruce

المصدر: DST. 13(6)

مصطلحات موضوعية: artificial pancreas, bionic pancreas, closed-loop system, type 1 diabetes, Adult, Blood Glucose, Blood Glucose Self-Monitoring, Diabetes Mellitus, Type 1, Feasibility Studies, Female, Humans, Hypoglycemic Agents, Insulin, Insulin Infusion Systems, Male, Pancreas, Artificial, Treatment Outcome

الوصف: BACKGROUND: We tested the safety and performance of the insulin-only configuration of the bionic pancreas (BP) closed-loop blood-glucose control system in a home-use setting to assess glycemic outcomes using different static and dynamic glucose set-points. METHOD: This is an open-label non-randomized study with three consecutive intervention periods. Participants had consecutive weeks of usual care followed by the insulin-only BP with (1) an individualized static set-point of 115 or 130 mg/dL and (2) a dynamic set-point that automatically varied within 110 to 130 mg/dL, depending on hypoglycemic risk. Human factors (HF) testing was conducted using validated surveys. The last five days of each study arm were used for data analysis. RESULTS: Thirteen participants were enrolled with a mean age of 28 years, mean A1c of 7.2%, and mean daily insulin dose of 0.6 U/kg (0.4-1.0 U/kg). The usual care arm had an average glucose of 145 ± 20 mg/dL, which increased in the static set-point arm (159 ± 8 mg/dL, P = .004) but not in the dynamic set-point arm (154 ± 10 mg/dL, P = ns). There was no significant difference in time spent in range (70-180 mg/dL) among the three study arms. There was less time

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الوصول الحر: https://escholarship.org/uc/item/14r0166sTest

المؤلفون: Shumway, Martha, Fisher, Lawrence, Hessler, Danielle, Bowyer, Vicky, Polonsky, William H, Masharani, Umesh

المصدر: Journal of Diabetes and its Complications. 33(11)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Clinical Trials and Supportive Activities, Prevention, Autoimmune Disease, Diabetes, Clinical Research, Metabolic and endocrine, Adult, Anxiety, Cost-Benefit Analysis, Depression, Diabetes Mellitus, Type 1, Group Processes, Health Care Costs, Humans, Implementation Science, Middle Aged, Patient Acceptance of Health Care, Patient Education as Topic, Psychological Distress, Psychotherapy, Group, Self Care, Stress, Psychological, Type 1 diabetes, Costs, Cost analysis, Self-management, Patient education, Endocrinology & Metabolism, Clinical sciences

الوصف: AimsThis study evaluated the implementation costs of two group interventions, one focused on diabetes education (KnowIt) and one focused directly on diabetes distress (OnTrack), that reduced diabetes distress and HbA1C in adults with poorly controlled type 1 diabetes (T1DM) in the T1-REDEEM trial.MethodsResources used to provide interventions were enumerated using activity-based micro-costing methods. Costs were assigned to resources in 2017 US dollars. US median wage and benefit rates were used to calculate costs of staff time. Cost per unit change was calculated for diabetes distress and HbA1C.ResultsFor both interventions, per participant implementation costs were approximately $250 and cost per 1.0 percentage point (11 mmol/mol) change in HbA1C was $1400. Cost per unit change in diabetes distress was $364 for KnowIt and $335 for OnTrack. No statistically significant differences in costs were observed.ConclusionsThis is the first study to examine the costs of implementing interventions targeting diabetes distress in the context of T1DM. Both interventions had per participant implementation costs in the lower end of the range of previously examined diabetes self-management interventions ($219 to $5390). These inventions and their costs merit further attention because reducing diabetes distress may impact long term T1DM outcomes.Clinical trials registrationClinicalTrials.govNCT02175732.

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الوصول الحر: https://escholarship.org/uc/item/2nt5w61nTest

المؤلفون: Hotchkiss, Richard S, Colston, Elizabeth, Yende, Sachin, Crouser, Elliott D, Martin, Greg S, Albertson, Timothy, Bartz, Raquel R, Brakenridge, Scott C, Delano, Matthew J, Park, Pauline K, Donnino, Michael W, Tidswell, Mark, Mayr, Florian B, Angus, Derek C, Coopersmith, Craig M, Moldawer, Lyle L, Catlett, Ian M, Girgis, Ihab G, Ye, June, Grasela, Dennis M

المصدر: Intensive Care Medicine. 45(10)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Immunology, Sepsis, Clinical Research, Hematology, Clinical Trials and Supportive Activities, Prevention, Infectious Diseases, Evaluation of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Infection, Inflammatory and immune system, Adult, Aged, Biomarkers, Double-Blind Method, Female, HLA-DR Antigens, Humans, Immunologic Factors, Male, Middle Aged, Nivolumab, Programmed Cell Death 1 Receptor, Anti-PD-1, Immunosuppression, Phase 1, Immune checkpoint inhibition, Public Health and Health Services, Emergency & Critical Care Medicine, Clinical sciences

الوصف: PurposeSepsis-associated immunosuppression increases hospital-acquired infection and viral reactivation risk. A key underlying mechanism is programmed cell death protein-1 (PD-1)-mediated T-cell function impairment. This is one of the first clinical safety and pharmacokinetics (PK) assessments of the anti-PD-1 antibody nivolumab and its effect on immune biomarkers in sepsis.MethodsRandomized, double-blind, parallel-group, Phase 1b study in 31 adults at 10 US hospital ICUs with sepsis diagnosed ≥ 24 h before study treatment, ≥ 1 organ dysfunction, and absolute lymphocyte count ≤ 1.1 × 103 cells/μL. Participants received one nivolumab dose [480 mg (n = 15) or 960 mg (n = 16)]; follow-up was 90 days. Primary endpoints were safety and PK parameters.ResultsTwelve deaths occurred [n = 6 per study arm; 40% (480 mg) and 37.5% (960 mg)]. Serious AEs occurred in eight participants [n = 1, 6.7% (480 mg); n = 7, 43.8% (960 mg)]. AEs considered by the investigator to be possibly drug-related and immune-mediated occurred in five participants [n = 2, 13.3% (480 mg); n = 3, 18.8% (960 mg)]. Mean ± SD terminal half-life was 14.7 ± 5.3 (480 mg) and 15.8 ± 7.9 (960 mg) days. All participants maintained > 90% receptor occupancy (RO) 28 days post-infusion. Median (Q1, Q3) mHLA-DR levels increased to 11,531 (6528, 19,495) and 11,449 (6225, 16,698) mAbs/cell in the 480- and 960-mg arms by day 14, respectively. Pro-inflammatory cytokine levels did not increase.ConclusionsIn this sepsis population, nivolumab administration did not result in unexpected safety findings or indicate any 'cytokine storm'. The PK profile maintained RO > 90% for ≥ 28 days. Further efficacy and safety studies are warranted. TRIAL REGISTRATION NUMBER (CLINICALTRIALS.GOV): NCT02960854.

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الوصول الحر: https://escholarship.org/uc/item/5mr522btTest

المؤلفون: Baker, Ashley C, Wiebe, Deborah J, Kelly, Caitlin S, Munion, Ascher, Butner, Jonathan E, Swinyard, Michael T, Murray, Mary, Berg, Cynthia A

المصدر: Journal of Behavioral Medicine. 42(5)

مصطلحات موضوعية: Social and Personality Psychology, Psychology, Behavioral and Social Science, Autoimmune Disease, Prevention, Clinical Research, Diabetes, Pediatric, 7.1 Individual care needs, Management of diseases and conditions, Metabolic and endocrine, Good Health and Well Being, Adolescent, Adult, Communication, Diabetes Mellitus, Type 1, Disease Management, Female, Glycated Hemoglobin, Humans, Male, Models, Structural, Mother-Child Relations, Patient-Centered Care, Self Care, Self Efficacy, Transition to Adult Care, Treatment Adherence and Compliance, Young Adult, Patient-centered communication, Type 1 diabetes, Transition to adult care, Early emerging adulthood, Self-efficacy, Diabetes management, Medical and Health Sciences, Psychology and Cognitive Sciences, Clinical Psychology, Public health, Social and personality psychology

الوصف: Early emerging adulthood (ages 18-25) is a time of risk for type 1 diabetes (T1D) when relationships with parents and providers are changing. We examined whether individuals' high-quality relationships with mothers are associated with greater perceptions of patient-centered communication (PCC) with their doctor and whether PCC is associated with better adherence and glycemic control through diabetes-related self-efficacy. Additionally, we tested whether associations of PCC with self-efficacy and diabetes outcomes are stronger among those who had transferred to adult care. One-year post-high school, 217 individuals with T1D (60% women, 53% in adult care) reported perceptions of maternal relationship quality, PCC, self-efficacy, and adherence. Glycemic control was measured via HbA1c assay kits. Structural equation modeling indicated good model fit and revealed indirect paths linking higher maternal relationship quality to better adherence through higher PCC, and higher PCC to better HbA1c through adherence. Transfer status moderated the link between PCC and self-efficacy, suggesting PCC may be especially important when emerging adults transfer to adult care.

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الوصول الحر: https://escholarship.org/uc/item/3z06f2dpTest

المؤلفون: Roy, Soumyabrata, Coulon, Pierre-Gregoire, Prakash, Swayam, Srivastava, Ruchi, Geertsema, Roger, Dhanushkodi, Nisha, Lam, Cynthia, Nguyen, Vivianna, Gorospe, Elyssa, Nguyen, Angela M, Salazar, Stephanie, Alomari, Nuha I, Warsi, Wasay R, BenMohamed, Lbachir

المصدر: Journal of Virology. 93(18)

مصطلحات موضوعية: Prevention, Sexually Transmitted Infections, Immunization, Rare Diseases, Vaccine Related, Eye Disease and Disorders of Vision, Infectious Diseases, 2.1 Biological and endogenous factors, Aetiology, Infection, Good Health and Well Being, Adult, Animals, Antigens, CD, B7-H1 Antigen, CD8-Positive T-Lymphocytes, Cornea, Epitopes, T-Lymphocyte, Female, HLA Antigens, HLA-A2 Antigen, Herpes Simplex Virus Vaccines, Herpesvirus 1, Human, Histocompatibility Antigens, Histocompatibility Antigens Class II, Humans, Male, Middle Aged, Programmed Cell Death 1 Receptor, Rabbits, Trigeminal Ganglion, Vaccination, Virus Shedding, Lymphocyte Activation Gene 3 Protein, CD8(+) T cell, HSV-1, LAG-3, PD-1, disease, herpes, ocular, protection, rabbit, vaccine, CD8+ T cell, Biological Sciences, Agricultural and Veterinary Sciences, Medical and Health Sciences, Virology

الوصف: Chronic viruses such as herpes simplex virus 1 (HSV-1) evade the hosts' immune system by inducing the exhaustion of antiviral T cells. In the present study, we found that exhausted HSV-specific CD8+ T cells, with elevated expression of programmed death ligand-1 (PD-1) and lymphocyte activation gene-3 (LAG-3) receptors were frequent in symptomatic patients, with a history of numerous episodes of recurrent corneal herpetic disease, compared to asymptomatic patients who never had corneal herpetic disease. Subsequently, using a rabbit model of recurrent ocular herpes, we found that the combined blockade of PD-1 and LAG-3 pathways with antagonist antibodies significantly restored the function of tissue-resident antiviral CD8+ TRM cells in both the cornea and the trigeminal ganglia (TG). An increased number of functional tissue-resident HSV-specific CD8+ TRM cells in latently infected rabbits was associated with protection against recurrent herpes infection and disease. Compared to the PD-1 or LAG-3 blockade alone, the combined blockade of PD-1 and LAG-3 appeared to have a synergistic effect in generating frequent polyfunctional Ki-67+, IFN-γ+, CD107+, and CD8+ T cells. Moreover, using the human leukocyte antigen (HLA) transgenic rabbit model, we found that dual blockade of PD-1 and LAG-3 reinforced the effect of a multiepitope vaccine in boosting the frequency of HSV-1-specific CD8+ TRM cells and reducing disease severity. Thus, both the PD-1 and the LAG-3 exhaustion pathways play a fundamental role in ocular herpes T cell immunopathology and provide important immune checkpoint targets to combat ocular herpes.IMPORTANCE HSV-specific tissue-resident memory CD8+ TRM cells play a critical role in preventing virus reactivation from latently infected TG and subsequent virus shedding in tears that trigger the recurrent corneal herpetic disease. In this report, we determined how the dual blockade of PD-1 and LAG-3 immune checkpoints, combined with vaccination, improved the function of CD8+ TRM cells associated with a significant reduction in recurrent ocular herpes in HLA transgenic (Tg) rabbit model. The combined blockade of PD-1 and LAG-3 appeared to have a synergistic effect in generating frequent polyfunctional CD8+ TRM cells that infiltrated both the cornea and the TG. The preclinical findings using the established HLA Tg rabbit model of recurrent herpes highlight that blocking immune checkpoints combined with a T cell-based vaccine would provide an important strategy to combat recurrent ocular herpes in the clinic.

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الوصول الحر: https://escholarship.org/uc/item/7c33m4nxTest

المؤلفون: Ashouri, Judith F, Hsu, Lih-Yun, Yu, Steven, Rychkov, Dmitry, Chen, Yiling, Cheng, Debra A, Sirota, Marina, Hansen, Erik, Lattanza, Lisa, Zikherman, Julie, Weiss, Arthur

المصدر: Proceedings of the National Academy of Sciences of the United States of America. 116(37)

مصطلحات موضوعية: Synovial Membrane, CD4-Positive T-Lymphocytes, Animals, Mice, Transgenic, Humans, Mice, Arthritis, Experimental, Arthritis, Rheumatoid, Zymosan, Green Fluorescent Proteins, Receptors, Antigen, T-Cell, Interleukin-6, Interleukin-17, Biopsy, Signal Transduction, Cell Differentiation, Down-Regulation, Genes, Reporter, Adult, Aged, Middle Aged, Female, Male, Nuclear Receptor Subfamily 4, Group A, Member 1, Th17 Cells, Suppressor of Cytokine Signaling 3 Protein, Synovectomy, Nur77, T cells, antigen receptor signaling, autoimmunity, rheumatoid arthritis, Transgenic, Arthritis, Experimental, Rheumatoid, Receptors, Antigen, T-Cell, Genes, Reporter, Nuclear Receptor Subfamily 4, Group A, Member 1

الوصف: How pathogenic cluster of differentiation 4 (CD4) T cells in rheumatoid arthritis (RA) develop remains poorly understood. We used Nur77-a marker of T cell antigen receptor (TCR) signaling-to identify antigen-activated CD4 T cells in the SKG mouse model of autoimmune arthritis and in patients with RA. Using a fluorescent reporter of Nur77 expression in SKG mice, we found that higher levels of Nur77-eGFP in SKG CD4 T cells marked their autoreactivity, arthritogenic potential, and ability to more readily differentiate into interleukin-17 (IL-17)-producing cells. The T cells with increased autoreactivity, nonetheless had diminished ex vivo inducible TCR signaling, perhaps reflective of adaptive inhibitory mechanisms induced by chronic autoantigen exposure in vivo. The enhanced autoreactivity was associated with up-regulation of IL-6 cytokine signaling machinery, which might be attributable, in part, to a reduced amount of expression of suppressor of cytokine signaling 3 (SOCS3)-a key negative regulator of IL-6 signaling. As a result, the more autoreactive GFPhi CD4 T cells from SKGNur mice were hyperresponsive to IL-6 receptor signaling. Consistent with findings from SKGNur mice, SOCS3 expression was similarly down-regulated in RA synovium. This suggests that despite impaired TCR signaling, autoreactive T cells exposed to chronic antigen stimulation exhibit heightened sensitivity to IL-6, which contributes to the arthritogenicity in SKG mice, and perhaps in patients with RA.

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الوصول الحر: https://escholarship.org/uc/item/406077cbTest