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Critical Reviews™ in Immunology

Publicou 6 edições por ano

ISSN Imprimir: 1040-8401

ISSN On-line: 2162-6472

The Impact Factor measures the average number of citations received in a particular year by papers published in the journal during the two preceding years. 2017 Journal Citation Reports (Clarivate Analytics, 2018) IF: 1.3 To calculate the five year Impact Factor, citations are counted in 2017 to the previous five years and divided by the source items published in the previous five years. 2017 Journal Citation Reports (Clarivate Analytics, 2018) 5-Year IF: 2.6 The Eigenfactor score, developed by Jevin West and Carl Bergstrom at the University of Washington, is a rating of the total importance of a scientific journal. Journals are rated according to the number of incoming citations, with citations from highly ranked journals weighted to make a larger contribution to the eigenfactor than those from poorly ranked journals. Eigenfactor: 0.00079 The Journal Citation Indicator (JCI) is a single measurement of the field-normalized citation impact of journals in the Web of Science Core Collection across disciplines. The key words here are that the metric is normalized and cross-disciplinary. JCI: 0.24 SJR: 0.429 SNIP: 0.287 CiteScore™:: 2.7 H-Index: 81

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A Common Druggable Defect in Regulatory T Cells from Patients with Autoimmunity

Volume 40, Edição 3, 2020, pp. 185-193
DOI: 10.1615/CritRevImmunol.2020034631
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RESUMO

We identified a druggable defect in IL-2 receptor (IL-2R) signaling by comparing the response of regulatory T cells (Tregs) of autoimmune disease patients to that of healthy controls. This defect was in the inhibition of Treg desensitization and was shared across various autoimmune diseases. Low-dose IL-2 stimulation results in maintained pSTAT5 expression for > 4 h, allowing the Treg transcriptome for "function" to be transcribed. Tregs of autoimmune Tregs of autoimmune disease patients more rapidly terminate IL-2R signaling through STAT5. Prolonged pSTAT5 expression following IL-2R activation is mediated by blocking proteasomal degradation of pJAKl, which is associated with the IL-2RP chain. In Tregs of controls, this is accomplished by inhibiting a requisite-activating post-translational modification (neddylation) of the SOCS3/Cul5 cullin ring ligase (CRL), which normally ubiquitinates pJAKl. Many receptor-associated tyrosine kinases are desensitized by a CRL. Tregs uniquely constitutively express an E3 ligase known as the gene related to anergy in lymphocytes (GRAIL), which ubiquinates the exact lysine on the Cul5 protein that needs to be neddylated as a condition for the activation and consequent ubiquitination of pJAKl. There is a defect in this GRAIL-associated pathway of competitive inhibition of neddylation in the Tregs of autoimmune disease patients. This defect can be mitigated by the application of a small-molecule drug known as a neddylation activating enzyme inhibitor (NAEi). Low-dose IL-2 and an NAEi as a protein-drug conjugate was found to be much more effective than simply using low-dose IL-2 or a combination of low-dose IL-2 and an NAEi systemically in treating animal models of autoimmune diseases.

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