Abstract：
:The immunopathogenesis of rheumatoid arthritis (RA) spans decades, beginning with the production of autoantibodies against post-translationally modified proteins (checkpoint 1). After years of asymptomatic autoimmunity and progressive immune system remodeling, tissue tolerance erodes and joint inflammation ensues as tissue-invasive effector T cells emerge and protective joint-resident macrophages fail (checkpoint 2). The transition of synovial stromal cells into autoaggressive effector cells converts synovitis from acute to chronic destructive (checkpoint 3). The loss of T cell tolerance derives from defective DNA repair, causing abnormal cell cycle dynamics, telomere fragility and instability of mitochondrial DNA. Mitochondrial and lysosomal anomalies culminate in the generation of short-lived tissue-invasive effector T cells. This differentiation defect builds on a metabolic platform that shunts glucose away from energy generation toward the cell building and motility programs. The next frontier in RA is the development of curative interventions, for example, reprogramming T cell defects during the period of asymptomatic autoimmunity.
journal_name
Nat Immunoljournal_title
Nature immunologyauthors
Weyand CM,Goronzy JJdoi
10.1038/s41590-020-00816-xsubject
Has Abstractpub_date
2021-01-01 00:00:00pages
10-18issue
1eissn
1529-2908issn
1529-2916pii
10.1038/s41590-020-00816-xjournal_volume
22pub_type
杂志文章,评审abstract：:We define here the specificity and significance of proteases in the endoplasmic reticulum (ER) that generate peptides for presentation by major histocompatibility complex (MHC) class I molecules. We show that aminopeptidases efficiently trimmed all residues except proline that flank the NH2-termini of antigenic precur...
journal_title：Nature immunology
pub_type： 杂志文章
doi：10.1038/89800
更新日期：2001-07-01 00:00:00
abstract：:Despite their central function in orchestrating immunity, dendritic cells (DCs) can respond to inhibitory signals by becoming tolerogenic. Here we show that galectin-1, an endogenous glycan-binding protein, can endow DCs with tolerogenic potential. After exposure to galectin-1, DCs acquired an interleukin 27 (IL-27)-d...
journal_title：Nature immunology
pub_type： 杂志文章
doi：10.1038/ni.1772
更新日期：2009-09-01 00:00:00
abstract：:EAE can refer either to experimental autoimmune encephalomyelitis or experimental allergic encephalomyelitis. Although EAE is classically a prototypic T helper 1 (TH1) cell-mediated autoimmune disease, it can also be induced by TH2 cells. Characteristically, the most severe manifestation of allergy, anaphylaxis, is as...
journal_title：Nature immunology
pub_type： 杂志文章
doi：10.1038/85266
更新日期：2001-03-01 00:00:00
abstract：:Innate lymphoid cells (ILCs) of the ILC22 type protect the intestinal mucosa from infection by secreting interleukin 22 (IL-22). ILC22 cells include NKp46(+) and lymphoid tissue-inducer (LTi)-like subsets that express the aryl hydrocarbon receptor (AHR). Here we found that Ahr(-/-) mice had a considerable deficit in I...
journal_title：Nature immunology
pub_type： 杂志文章
doi：10.1038/ni.2187
更新日期：2011-11-20 00:00:00
abstract：:Ingested antigens lead to the generation of effector T cells that secrete interleukin 4 (IL-4) rather than interferon-gamma (IFN-gamma) and are capable of influencing naive T cells in their immediate environment to do the same. Using chimeric mice generated by aggregation of two genotypically different embryos, we fou...
journal_title：Nature immunology
pub_type： 杂志文章
doi：10.1038/ni1077
更新日期：2004-06-01 00:00:00
abstract：:The importance of protein glycosylation in the migration of immune cells throughout the body has been extensively appreciated. However, our awareness of the impact of glycosylation on the regulation of innate and adaptive immune responses is relatively new. An increasing number of studies reveal the relevance of glyco...
journal_title：Nature immunology
pub_type： 杂志文章,评审
doi：10.1038/ni.f.203
更新日期：2008-06-01 00:00:00
abstract：:Nedd4 and Itch are E3 ubiquitin ligases that ubiquitinate similar targets in vitro and thus are thought to function similarly. T cells lacking Itch show spontaneous activation and T helper type 2 polarization. To test whether loss of Nedd4 affects T cells in the same way, we generated Nedd4(+/+) and Nedd4(-/-) fetal l...
journal_title：Nature immunology
pub_type： 杂志文章
doi：10.1038/ni.1670
更新日期：2008-12-01 00:00:00
abstract：:The ubiquitin-editing enzyme A20 is a critical negative regulator of inflammation and cytokine-mediated activation of the transcription factor NF-kappaB; however, little is known about the mechanisms of A20-mediated inactivation of signaling intermediates such as RIP1. Here we demonstrate that the regulatory molecule ...
journal_title：Nature immunology
pub_type： 杂志文章
doi：10.1038/ni1563
更新日期：2008-03-01 00:00:00
abstract：:Chronic infection is difficult to overcome because of exhaustion or depletion of cytotoxic effector CD8(+) T cells (cytotoxic T lymphoytes (CTLs)). Here we report that signaling via Toll-like receptors (TLRs) induced intrahepatic aggregates of myeloid cells that enabled the population expansion of CTLs (iMATEs: 'intra...
journal_title：Nature immunology
pub_type： 杂志文章
doi：10.1038/ni.2573
更新日期：2013-06-01 00:00:00
abstract：:As a result of decades of research-driven breakthroughs in basic and clinical science and recent advances in the broad-scale implementation of interventions for the prevention and treatment of infection with HIV, a turning point has been reached in the global HIV-AIDS pandemic. To end the pandemic and achieve the goal...
journal_title：Nature immunology
pub_type： 杂志文章
doi：10.1038/ni.2735
更新日期：2013-11-01 00:00:00
abstract：:Notch molecules are well conserved from Drosophila melanogaster to mammals and regulate a broad spectrum of various cell lineage commitment processes. Recent studies using inhibitors, transgenic mice and conditional loss-of-function approaches have demonstrated essential roles for Notch signaling in the differentiatio...
journal_title：Nature immunology
pub_type： 杂志文章,评审
doi：10.1038/ni1453
更新日期：2007-05-01 00:00:00
abstract：:Fc epsilon RI activation of mast cells is thought to involve Lyn and Syk kinases proximal to the receptor and the signaling complex organized by the linker for activation of T cells (LAT). We report here that Fc epsilon RI also uses a Fyn kinase-dependent pathway that does not require Lyn kinase or the adapter LAT for...
journal_title：Nature immunology
pub_type： 杂志文章
doi：10.1038/ni817
更新日期：2002-08-01 00:00:00
abstract：:B cells are activated by two temporally distinct signals, the first provided by the binding of antigen to the B cell antigen receptor (BCR), and the second provided by helper T cells. Here we found that B cells responded to antigen by rapidly increasing their metabolic activity, including both oxidative phosphorylatio...
journal_title：Nature immunology
pub_type： 杂志文章
doi：10.1038/s41590-018-0156-5
更新日期：2018-08-01 00:00:00
abstract：:Chronic inflammation is a common feature of obesity, with elevated cytokines such as interleukin-1 (IL-1) in the circulation and tissues. Here, we report an unconventional IL-1R-MyD88-IRAK2-PHB/OPA1 signaling axis that reprograms mitochondrial metabolism in adipocytes to exacerbate obesity. IL-1 induced recruitment of...
journal_title：Nature immunology
pub_type： 杂志文章
doi：10.1038/s41590-020-0750-1
更新日期：2020-10-01 00:00:00
abstract：:Members of the Toll-like receptor (TLR) family are key regulators of both innate and adaptive immune responses. The function of TLRs in various human diseases has been investigated by comparison of the incidence of disease among people having different polymorphisms in genes that participate in TLR signaling. These st...
journal_title：Nature immunology
pub_type： 杂志文章,评审
doi：10.1038/ni1116
更新日期：2004-10-01 00:00:00
abstract：:More than 20 years after the first successful engraftment of human leukocytes and hematopoietic organs in mice, scientists met for the 2nd International Workshop on Humanized Mice to discuss progress and to highlight expectations in this dynamic field. ...
journal_title：Nature immunology
pub_type： 杂志文章,评审
doi：10.1038/ni1009-1039
更新日期：2009-10-01 00:00:00
abstract：:Kinases of the Jak ('Janus kinase') family and transcription factors (TFs) of the STAT ('signal transducer and activator of transcription') family constitute a rapid membrane-to-nucleus signaling module that affects every aspect of the mammalian immune system. Research on this paradigmatic pathway has experienced brea...
journal_title：Nature immunology
pub_type： 杂志文章,评审
doi：10.1038/ni.3691
更新日期：2017-03-22 00:00:00
abstract：:Myelin basic protein-specific CD8(+) T cells can induce central nervous system autoimmunity; however, immune tolerance prevents these autoreactive cells from causing disease. To define the mechanisms that mediate tolerance, we developed two T cell receptor-transgenic mouse lines with different affinities for the H-2K(...
journal_title：Nature immunology
pub_type： 杂志文章
doi：10.1038/ni1073
更新日期：2004-06-01 00:00:00
abstract：:Tyrosine kinases couple the T cell receptor (TCR) to discrete signaling cascades, each of which is capable of inducing a distinct functional outcome. Precisely how TCR signals are channeled toward specific targets remains unclear. TCR stimulation triggers 'alternative' activation of the mitogen-activated protein kinas...
journal_title：Nature immunology
pub_type： 杂志文章
doi：10.1038/ni1422
更新日期：2007-02-01 00:00:00
abstract：:High-throughput 3' single-cell RNA-sequencing (scRNA-seq) allows cost-effective, detailed characterization of individual immune cells from tissues. Current techniques, however, are limited in their ability to elucidate essential immune cell features, including variable sequences of T cell antigen receptors (TCRs) that...
journal_title：Nature immunology
pub_type： 杂志文章
doi：10.1038/s41590-019-0544-5
更新日期：2019-12-01 00:00:00
abstract：:Store-operated Ca2+ entry through calcium release-activated calcium channels is the chief mechanism for increasing intracellular Ca2+ in immune cells. Here we show that mouse T cells and fibroblasts lacking the calcium sensor STIM1 had severely impaired store-operated Ca2+ influx, whereas deficiency in the calcium sen...
journal_title：Nature immunology
pub_type： 杂志文章
doi：10.1038/ni1574
更新日期：2008-04-01 00:00:00
abstract：:In the version of this article initially published, the Supplementary Note was missing. The Supplementary Note has now been provided online and is cited in the Methods section of the article. The error has been corrected in the HTML and PDF version of the article. ...
journal_title：Nature immunology
pub_type： 杂志文章,已发布勘误
doi：10.1038/s41590-018-0104-4
更新日期：2018-06-01 00:00:00
abstract：:Phagocytosis has essential functions in immunity. Here we highlight the presence of a subcellular level of self-non-self discrimination in dendritic cells that operates at the level of individual phagosomes. We discuss how engagement of Toll-like receptor signaling controls distinct programs of phagosome maturation. A...
journal_title：Nature immunology
pub_type： 杂志文章,评审
doi：10.1038/ni1006-1029
更新日期：2006-10-01 00:00:00
abstract：:CD25(+)CD4(+) regulatory T cells in normal animals are engaged in the maintenance of immunological self-tolerance. We show here that glucocorticoid-induced tumor necrosis factor receptor family-related gene (GITR, also known as TNFRSF18)--a member of the tumor necrosis factor-nerve growth factor (TNF-NGF) receptor gen...
journal_title：Nature immunology
pub_type： 杂志文章
doi：10.1038/ni759
更新日期：2002-02-01 00:00:00
abstract：:Germinal center B cells (GCBCs) are critical for generating long-lived humoral immunity. How GCBCs meet the energetic challenge of rapid proliferation is poorly understood. Dividing lymphocytes typically rely on aerobic glycolysis over oxidative phosphorylation for energy. Here we report that GCBCs are exceptional amo...
journal_title：Nature immunology
pub_type： 杂志文章
doi：10.1038/s41590-020-0598-4
更新日期：2020-03-01 00:00:00
abstract：:Feedback regulatory circuits provided by regulatory T cells (T(reg) cells) and suppressive cytokines are an intrinsic part of the immune system, along with effector functions. Here we discuss some of the regulatory cytokines that have evolved to permit tolerance to components of self as well as the eradication of path...
journal_title：Nature immunology
pub_type： 杂志文章,评审
doi：10.1038/ni.2406
更新日期：2012-10-01 00:00:00
abstract：:The balance of myeloid populations and lymphoid populations must be well controlled. Here we found that osteopontin (OPN) skewed this balance during pathogenic conditions such as infection and autoimmunity. Notably, two isoforms of OPN exerted distinct effects in shifting this balance through cell-type-specific regula...
journal_title：Nature immunology
pub_type： 杂志文章
doi：10.1038/ni.3791
更新日期：2017-09-01 00:00:00
abstract：:Myxoma virus, a member of the poxvirus family, causes lethal infection only in rabbits, but the mechanism underlying the strict myxoma virus species barrier is not known. Here we show that myxoma virus infection of primary mouse embryo fibroblasts elicited extracellular signal-regulated kinase (Erk) signaling, which w...
journal_title：Nature immunology
pub_type： 杂志文章
doi：10.1038/ni1132
更新日期：2004-12-01 00:00:00
abstract：:Although Moraxella catarrhalis and Neisseria meningitidis are important human pathogens, they often colonize the human respiratory tract without causing overt clinical symptoms. Both pathogens express structurally unrelated proteins that share the ability to stimulate the adhesion molecule CEACAM1 expressed on human c...
journal_title：Nature immunology
pub_type： 杂志文章
doi：10.1038/ni.1661
更新日期：2008-11-01 00:00:00
abstract：:The lung is inhabited by resident alveolar and interstitial macrophages as well as monocytic cells that survey lung tissues. Each cell type plays distinct functional roles under homeostatic and inflammatory conditions, but mechanisms establishing their molecular identities and functional potential remain poorly unders...
journal_title：Nature immunology
pub_type： 杂志文章
doi：10.1038/s41590-019-0582-z
更新日期：2020-02-01 00:00:00
