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https://www.readbyqxmd.com/read/28931755/combination-central-tolerance-and-peripheral-checkpoint-blockade-unleashes-antimelanoma-immunity
#1
Pearl Bakhru, Meng-Lei Zhu, Hsing-Hui Wang, Lee K Hong, Imran Khan, Maria Mouchess, Ajay S Gulati, Joshua Starmer, Yafei Hou, David Sailer, Sandra Lee, Fengmin Zhao, John M Kirkwood, Stergios Moschos, Lawrence Fong, Mark S Anderson, Maureen A Su
Blockade of immune checkpoint proteins (e.g., CTLA-4, PD-1) improves overall survival in advanced melanoma; however, therapeutic benefit is limited to only a subset of patients. Because checkpoint blockade acts by "removing the brakes" on effector T cells, the efficacy of checkpoint blockade may be constrained by the limited pool of melanoma-reactive T cells in the periphery. In the thymus, autoimmune regulator (Aire) promotes deletion of T cells reactive against self-antigens that are also expressed by tumors...
September 21, 2017: JCI Insight
https://www.readbyqxmd.com/read/28906131/effects-of-immunomodulators-on-the-response-induced-by-vaccines-against-autoimmune-diseases
#2
Dante J Marciani
A promising treatment for T-cell-mediated autoimmune diseases is the induction of immune tolerance by modulating the immune response against self-antigens, an objective that may be achieved by vaccination. There are two main types of vaccines currently under development. The tolerogenic vaccines, composed of proteins formed by a cytokine fused to a self-antigen, which usually induce tolerance by eliminating the T-cells that are immune reactive against the self-antigen. The immunogenic vaccines, comprised of a self-antigen plus a sole Th2 adjuvant either free or conjugated, that alleviate autoimmunity by switching the immune response against the self-antigen, from a damaging pro-inflammatory Th1/Th17 to an anti-inflammatory Th2 immunity...
September 14, 2017: Autoimmunity
https://www.readbyqxmd.com/read/28900679/ctla-4-an-essential-immune-checkpoint-for-t-cell-activation
#3
Shunsuke Chikuma
The response of peripheral T lymphocytes (T cell) is controlled by multiple checkpoints to avoid unwanted activation against self-tissues. Two opposing costimulatory receptors, CD28 and CTLA-4, on T cells bind to the same ligands (CD80 and CD86) on antigen-presenting cells (APCs), and provide positive and negative feedback for T-cell activation, respectively. Early studies suggested that CTLA-4 is induced on activated T cells and binds to CD80/CD86 with much stronger affinity than CD28, providing a competitive inhibition...
September 13, 2017: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/28892471/dynamic-regulation-of-t-follicular-regulatory-cell-responses-by-interleukin-2-during-influenza-infection
#4
Davide Botta, Michael J Fuller, Tatiana T Marquez-Lago, Holly Bachus, John E Bradley, Amy S Weinmann, Allan J Zajac, Troy D Randall, Frances E Lund, Beatriz León, André Ballesteros-Tato
Interleukin 2 (IL-2) promotes Foxp3(+) regulatory T (Treg) cell responses, but inhibits T follicular helper (TFH) cell development. However, it is not clear how IL-2 affects T follicular regulatory (TFR) cells, a cell type with properties of both Treg and TFH cells. Using an influenza infection model, we found that high IL-2 concentrations at the peak of the infection prevented TFR cell development by a Blimp-1-dependent mechanism. However, once the immune response resolved, some Treg cells downregulated CD25, upregulated Bcl-6 and differentiated into TFR cells, which then migrated into the B cell follicles to prevent the expansion of self-reactive B cell clones...
September 11, 2017: Nature Immunology
https://www.readbyqxmd.com/read/28887429/nfm-cross-reactivity-to-mog-does-not-expand-a-critical-threshold-level-of-high-affinity-t-cells-necessary-for-onset-of-demyelinating-disease
#5
Lori Blanchfield, Joseph J Sabatino, Laurel Lawrence, Brian D Evavold
Of interest to the etiology of demyelinating autoimmune disease is the potential to aberrantly activate CD4(+) T cells due to cross-recognition of multiple self-epitopes such as has been suggested for myelin oligodendrocyte glycoprotein epitope 35-55 (MOG35-55) and neurofilament medium protein epitope 15-35 (NFM15-35). NFM15-35 is immunogenic in C57BL/6 mice but fails to induce demyelinating disease by polyclonal T cells despite having the same TCR contact residues as MOG35-55, a known encephalitogenic Ag...
September 8, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28878770/changes-in-reactivity-in-vitro-of-cd4-cd25-and-cd4-cd25-t-cell-subsets-in-transplant-tolerance
#6
Bruce M Hall, Catherine M Robinson, Karren M Plain, Nirupama D Verma, Giang T Tran, Masaru Nomura, Nicole Carter, Rochelle Boyd, Suzanne J Hodgkinson
Transplant tolerance induced in adult animals is mediated by alloantigen-specific CD4(+)CD25(+) T cells, yet in many models, proliferation of CD4(+) T cells from hosts tolerant to specific-alloantigen in vitro is not impaired. To identify changes that may diagnose tolerance, changes in the patterns of proliferation of CD4(+), CD4(+)CD25(+), and CD4(+)CD25(-) T cells from DA rats tolerant to Piebald Virol Glaxo rat strain (PVG) cardiac allografts and from naïve DA rats were examined. Proliferation of CD4(+) T cells from both naïve and tolerant hosts was similar to both PVG and Lewis stimulator cells...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28877735/priming-astrocytes-with-tnf-enhances-their-susceptibility-to-trypanosoma-cruzi-infection-and-creates-a-self-sustaining-inflammatory-milieu
#7
Andrea Alice Silva, Rafael Rodrigues Silva, Daniel Gibaldi, Rafael Meyer Mariante, Jessica Brandão Dos Santos, Isabela Resende Pereira, Otacílio Cruz Moreira, Joseli Lannes-Vieira
BACKGROUND: In conditions of immunosuppression, the central nervous sty 5ystem (CNS) is the main target tissue for the reactivation of infection by Trypanosoma cruzi, the causative agent of Chagas disease. In experimental T. cruzi infection, interferon gamma (IFNγ)(+) microglial cells surround astrocytes harboring amastigote parasites. In vitro, IFNγ fuels astrocyte infection by T. cruzi, and IFNγ-stimulated infected astrocytes are implicated as potential sources of tumor necrosis factor (TNF)...
September 6, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28864471/peripheral-deletion-of-cd8-t-cells-requires-p38-mapk-in-cross-presenting-dendritic-cells
#8
Trevor Smith, Xiaotian Lin, Marielle Mello, Kristi Marquardt, Jocelyn Cheung, Binfeng Lu, Linda A Sherman, Grégory Verdeil
Peripheral tolerance mechanisms exist to prevent autoimmune destruction by self-reactive T cells that escape thymic deletion. Dominant tolerance imposed by CD4(+)Foxp3(+) T regulatory cells can actively control autoaggressive T cell responses. Tolerance mechanisms that act endogenous to the T cell also exist. These mechanisms include T cell inactivation (anergy) and deletion. A major difference between anergic T cells and T cells undergoing peripheral deletion is the capacity of the latter to still signal through MAPKs upon TCR stimulation, suggesting these signals may be required for T deletion...
September 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28861084/autoantibody-repertoire-in-apeced-patients-targets-two-distinct-subgroups-of-proteins
#9
Dmytro Fishman, Kai Kisand, Christina Hertel, Mike Rothe, Anu Remm, Maire Pihlap, Priit Adler, Jaak Vilo, Aleksandr Peet, Antonella Meloni, Katarina Trebusak Podkrajsek, Tadej Battelino, Øyvind Bruserud, Anette S B Wolff, Eystein S Husebye, Nicolas Kluger, Kai Krohn, Annamari Ranki, Hedi Peterson, Adrian Hayday, Pärt Peterson
High titer autoantibodies produced by B lymphocytes are clinically important features of many common autoimmune diseases. APECED patients with deficient autoimmune regulator (AIRE) gene collectively display a broad repertoire of high titer autoantibodies, including some which are pathognomonic for major autoimmune diseases. AIRE deficiency severely reduces thymic expression of gene-products ordinarily restricted to discrete peripheral tissues, and developing T cells reactive to those gene-products are not inactivated during their development...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28860950/t-cell-s-sense-of-self-a-role-of-self-recognition-in-shaping-functional-competence-of-na%C3%A3-ve-t-cells
#10
REVIEW
Hee-Ok Kim, Jae-Ho Cho
Post-thymic naïve T cells constitute a key cellular arm of adaptive immunity, with a well-known characteristic of the specificity and robustness of responses to cognate foreign antigens which is presented as a form of antigen-derived peptides bound to major histocompatibility complex (MHC) molecules by antigen-presenting cells (APCs). In a steady state, however, these cells are resting, quiescent in their activity, but must keep full ranges of functional integrity to mount rapid and robust immunity to cope with various infectious pathogens at any time and space...
August 2017: Immune Network
https://www.readbyqxmd.com/read/28842400/increased-effector-memory-insulin-specific-cd4-t-cells-correlate-with-insulin-autoantibodies-in-recent-onset-type-1-diabetic-patients
#11
Justin A Spanier, Nathanael L Sahli, Joseph C Wilson, Tijana Martinov, Thamotharampillai Dileepan, Adam L Burrack, Erik B Finger, Bruce R Blazar, Aaron W Michels, Antoinette Moran, Marc K Jenkins, Brian T Fife
Type 1 diabetes (T1D) results from T-cell mediated destruction of insulin producing beta cells. Insulin represents a key self-antigen in disease pathogenesis as recent studies identified proinsulin responding T-cells from inflamed pancreatic islets of recent onset T1D organ donors. These cells respond to an insulin B chain epitope presented by human leukocyte antigen (HLA) DQ8 molecule associated with high T1D risk. It is now critical to understand insulin specific T-cell frequency and phenotype in peripheral blood...
August 25, 2017: Diabetes
https://www.readbyqxmd.com/read/28835461/ectopic-expression-of-self-antigen-drives-regulatory-t-cell-development-and-not-deletion-of-autoimmune-t-cells
#12
Thomas Lee, Maran L Sprouse, Pinaki Banerjee, Maria Bettini, Matthew L Bettini
Type 1 diabetes is a T cell-mediated autoimmune disease that is characterized by Ag-specific targeting and destruction of insulin-producing β cells. Although multiple studies have characterized the pathogenic potential of β cell-specific T cells, we have limited mechanistic insight into self-reactive autoimmune T cell development and their escape from negative selection in the thymus. In this study, we demonstrate that ectopic expression of insulin epitope B:9-23 (InsB9-23) by thymic APCs is insufficient to induce deletion of high- or low-affinity InsB9-23-reactive CD4(+) T cells; however, we observe an increase in the proportion and number of thymic and peripheral Foxp3(+) regulatory T cells...
October 1, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28830733/the-mechanisms-of-t-cell-selection-in-the-thymus
#13
REVIEW
Hiroyuki Takaba, Hiroshi Takayanagi
T cells undergo positive and negative selection in the thymic cortex and medulla, respectively. A promiscuous expression of a wide array of self-antigens in the thymus is essential for the negative selection of self-reactive T cells and the establishment of central tolerance. Aire was originally thought to be the exclusive factor regulating the expression of tissue-restricted antigens, but Fezf2 recently emerged as a critical transcription factor in this regulatory activity. Fezf2 is selectively expressed in thymic medullary epithelial cells, regulates a large number of tissue-restricted antigens and suppresses the onset of autoimmune responses...
August 19, 2017: Trends in Immunology
https://www.readbyqxmd.com/read/28827353/foxp3-independent-mechanism-by-which-tgf-%C3%AE-controls-peripheral-t-cell-tolerance
#14
Soyoung A Oh, Ming Liu, Briana G Nixon, Davina Kang, Ahmed Toure, Michael Bivona, Ming O Li
Peripheral T cell tolerance is promoted by the regulatory cytokine TGF-β and Foxp3-expressing Treg cells. However, whether TGF-β and Treg cells are part of the same regulatory module, or exist largely as distinct pathways to repress self-reactive T cells remains incompletely understood. Using a transgenic model of autoimmune diabetes, here we show that ablation of TGF-β receptor II (TβRII) in T cells, but not Foxp3 deficiency, resulted in early-onset diabetes with complete penetrance. The rampant autoimmune disease was associated with enhanced T cell priming and elevated T cell expression of the inflammatory cytokine GM-CSF, concomitant with pancreatic infiltration of inflammatory monocytes that triggered immunopathology...
August 21, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28820075/t-regulatory-cell-subsets-in-children-with-type-1-diabetes-mellitus-relation-to-control-of-the-disease
#15
Mabrouk Ghonaim, Rawhia El-Edel, Wafaa Abo El Fotoh, Samar Kamal Eldein, Samar Salman
BACKGROUND: Type 1 diabetes mellitus described as a chronic metabolic disorder characterized by aggressive immune β-cell destruction. There are numbers of varied immune mechanisms for sustaining self-tolerance in opposition to the autoimmune disorders. A recessive tolerance accomplished by thymic gland via a negative assortment of different clones while a dominant tolerance accomplished by the regulatory T cells (Treg) in the periphery. Treg (CD4+CD25+FOXP3+) are subsets of T cells which have an essential role in maintaining tolerance...
August 17, 2017: Endocrine, Metabolic & Immune Disorders Drug Targets
https://www.readbyqxmd.com/read/28806642/circulating-follicular-helper-t-cells-presented-distinctively-different-responses-toward-bacterial-antigens-in-primary-biliary-cholangitis
#16
Zun-Qiang Zhou, Da-Nian Tong, Jiao Guan, Mei-Fang Li, Qi-Ming Feng, Min-Jie Zhou, Zheng-Yun Zhang
Primary biliary cholangitis (PBC) is a chronic and progressive cholestatic liver disease with unknown causes. The initiation of PBC is associated with bacterial infections and abnormal immune correlates, such as the presence of self-reactive anti-mitochondrial antibodies and shifted balance of T cell subsets. In particular, the CD4(+)CXCR5(+) follicular helper T (Tfh) cells are highly activated in PBC patients and are significantly associated with PBC severity, but the underlying reasons are unknown. In this study, we found that the circulating CD4(+)CXCR5(+) T cells were enriched with the interferon (IFN)-γ-secreting Th1-subtype and the interleukin (IL)-17-secreting Th17-subtype, but not the IL-4-secreting Th2 subtype...
August 11, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28801345/molecular-basis-for-increased-susceptibility-of-indigenous-north-americans-to-seropositive-rheumatoid-arthritis
#17
Stephen W Scally, Soi-Cheng Law, Yi Tian Ting, Jurgen van Heemst, Jeremy Sokolove, Aaron J Deutsch, E Bridie Clemens, Antonis K Moustakas, George K Papadopoulos, Diane van der Woude, Irene Smolik, Carol A Hitchon, David B Robinson, Elizabeth D Ferucci, Charles N Bernstein, Xiaobo Meng, Vidyanand Anaparti, Tom Huizinga, Katherine Kedzierska, Hugh H Reid, Soumya Raychaudhuri, René E Toes, Jamie Rossjohn, Hani El-Gabalawy, Ranjeny Thomas
OBJECTIVE: The pathogenetic mechanisms by which HLA-DRB1 alleles are associated with anticitrullinated peptide antibody (ACPA)-positive rheumatoid arthritis (RA) are incompletely understood. RA high-risk HLA-DRB1 alleles are known to share a common motif, the 'shared susceptibility epitope (SE)'. Here, the electropositive P4 pocket of HLA-DRB1 accommodates self-peptide residues containing citrulline but not arginine. HLA-DRB1 His/Phe13β stratifies with ACPA-positive RA, while His13βSer polymorphisms stratify with ACPA-negative RA and RA protection...
August 11, 2017: Annals of the Rheumatic Diseases
https://www.readbyqxmd.com/read/28754892/a-cell-based-high-throughput-screening-assay-system-for-inhibitor-compounds-of-antigen-presentation-by-hla-class-ii-molecule
#18
Nobuo Watanabe, Yusuke Suzuki, Takahisa Yonezu, Yuki Nakagawa, Takashi Shiina, Noriaki Hirayama, Sadaki Inokuchi, Shigeaki Inoue
A number of autoimmune diseases are associated with the genotypes of human leukocyte antigen class II (HLA), some of which present peptides derived from self-proteins, resulting in clonal expansion of self-reactive T cells. Therefore, selective inhibition of self-peptide loading onto such disease-associated HLA could ameliorate the diseases. To effectively identify such compounds, in this study, we established, for the first time, a cell- and 96-well microplate-based high-throughput screening system for inhibitors of antigen presentation...
July 28, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28751760/il28b-rs12979860-genotype-as-a-predictor-marker-of-progression-to-bkvirus-associated-nephropathy-after-kidney-transplantation
#19
Roee Dvir, Vera Paloschi, Filippo Canducci, Giacomo Dell'Antonio, Sara Racca, Rossana Caldara, Giuseppe Pantaleo, Massimo Clementi, Antonio Secchi
BK virus (BKV) associated nephropathy (BKVAN) is still an important cause of allograft dysfunction after kidney transplantation (KT). Recent data have shown that the new interferon (IFN)-λ family has been ascribed antiviral properties similar to IFNα, and that the response to IFNλ in kidney is restricted to epithelial cells, suggesting that the IFNλ system evolves as specific protection of the epithelia. We aimed to test the hypothesis of correlation between a single nucleotide polymorphism (C/T dimorphism rs12979860) in the genomic region of IL28B and BKVAN, in patients after KT...
July 27, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28745239/therapeutic-interventions-of-tissue-specific-autoimmune-onset-in-systemic-lupus-erythematosus
#20
Subhajit Dasgupta
Systemic lupus erythematosus (SLE) is a female predominant autoimmune disease. The onset of SLE has been found to affect kidney, bone, cardiovascular and central nervous system. Auto activation of B cells and T helper cells together are known to develop self-reactive immune responses in SLE. The therapy still includes corticosteroids to prevent allergic manifestations and inflammatory immune responses. Recent observations suggested that, mycophenolate mofetil and cyclophosphamide treatment in combination with corticosteroids have benefit to control disease manifestations...
July 25, 2017: Mini Reviews in Medicinal Chemistry
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