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Vasculitis
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
Michelle L. Robinette, Eli Miloslavsky, Zachary S. Wallace
Other monogenic syndromes with associated vasculitis include interferonopathies, inflammasopathies, and relopathies (15). Among these, vasculitis occurs most frequently among some interferonopathies, which mechanistically share increased type I interferon signatures but can diverge in phenotype (36–38). For example, heterozygous gain-of-function mutations in TMEM173, encoding stimulator of interferon genes (STING) downstream of several cytosolic DNA sensors, cause early-onset cutaneous leukocytoclastic vasculitis in STING-associated vasculopathy with onset in infancy (SAVI). In COPA syndrome, autosomal dominant mutations in the coatomer protein complex subunit alpha (COPA) similarly result in prolonged function of activated STING. However, this syndrome presents with a different vascular phenotype than SAVI and is characterized by pediatric-onset pulmonary capillaritis that mimics isolated pulmonary AAV as well as teenage-onset glomerular disease with multiple histopathologic subtypes (39). Additionally, a variety of disease-associated mutations occur in the DNA exonuclease TREX1 and can cause cutaneous vasculopathy reminiscent of SAVI and DADA2 or CNS vasculopathy, with clinically divergent but overlapping phenotypes and inheritance patterns among the four named disease entities (40).
Fibroblast and Immune Cell Cross Talk in Cardiac Repair
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Stelios Psarras, Georgina Xanthou
The cardiac injury caused by MI also involves the cGAS/STING danger signal pathway. In this case, DNA released by necrotic myocardium is being sensed in macrophages by the cyclic GMP-AMP synthase (cGAS) PRR (60). This in turn leads to activation of the stimulator of interferon genes (STING) pathway and to elevated expression of interferon-stimulated genes, including those encoding inducible nitric oxide synthase (iNOS) and CXCL10 (74). Conversely, inhibition of the cGAS-STING axis protects from cardiac rupture (60) associated with a switch in macrophage pheno-type from pro-inflammatory toward a reparative one. This switch is accompanied by the increased formation of myofibroblasts and dense collagen deposition in the infarct areas. The myofibroblast formation could be also facilitated by fibronectin, whose expression is elevated in reparative macrophages (74) (Figure 5.2). Interestingly, ex vivo generation of M2b alternatively activated macrophages and injection to the infarcted zones ameliorated MI repair by reducing platelet-derived growth factor–dependent (PDGF) activation of cardiac fibroblasts (75) (Figure 5.2).
Mitochondrial Dysfunction, Immune Systems, Their Diseases, and Possible Treatments
Published in Shamim I. Ahmad, Handbook of Mitochondrial Dysfunction, 2019
Elise Jacquin, Eric Hervouet, Michaël Boyer-Guittaut
Mitochondrial dynamics (fission and fusion events) have been shown to play important roles in immune cell responses to infection. Indeed, activation of MAVS following viral infection promotes mitochondrial elongation through Mitofusin-1 (Mfn1). This change in mitochondrial dynamics in turn favors interaction between activated MAVS and the endoplasmic reticulum protein STING (stimulator of interferon genes), thus inducing type I IFN and pro-inflammatory cytokine production.7 Deletion of Drp1 (a protein involved in mitochondria fission) and aberrant mitochondria elongation in macrophages has been shown to lead to NRLP3 activation, caspase 1 cleavage as well as IL-1β secretion and aberrant inflammation.8 Furthermore, Mitofusin-2 (Mfn2), involved in mitochondria fusion, has been shown to interact with NRLP3 and drive inflammasome formation and secretion of mature IL-1β following viral infection.9 Mitochondria metabolism is also regulated during immune cell stimulation. Activated M1 macrophages, as well as dendritic cells (DCs) present a decrease of oxidative phosphorylation in mitochondria together with an increase in glycolysis (for a review, see10). Upon activation with LPS, macrophages switch their metabolism from OXPHOS to glycolysis leading to the accumulation of tricarboxylic acid cycle (TCA) intermediates, such as succinate. This metabolite promotes the expression and secretion of the pro-inflammatory cytokine IL-1β by stabilizing the transcription factor HIF1α, thus enhancing the pro-inflammatory functions of M1 macrophages.11
What are the challenges involved in the strategies for future antibody-drug conjugate discovery and development for oncology?
Published in Expert Opinion on Drug Discovery, 2023
Sajeli Ahil Begum, Ahmed Kamal
Chemotherapeutic drugs, which are cytotoxic at sub-nanomolar concentrations, are selected for conjugation with antibodies as payloads. Cytotoxic agents that were found to be unsuitable for systemic delivery as free drugs turned out to be suitable for ADCs. The payload class found in the so-far FDA-approved ADCs include calicheamicin (ozogamicin), auristatin (monomethyl auristatin E and F), maytansinoid (DM1), camptothecin (irinotecan metabolite SN-38, DXd), and PBD dimer (SG3199) [1,7]. Although several cytotoxic drugs acting through various mechanisms are known, payloads of ADCs explored so far are majorly tubulin inhibitors and DNA damaging agents. Recently, immune-stimulating antibody conjugates are designed and found to exhibit promising tumor regression and long-term anti-tumor immunity as these conjugates incorporate the antibody-navigated targeting precision and small molecule-based modulation power of the innate and adaptive immune systems. Also, newer payloads such as toll-like receptor (TLR) agonists (TLR7 and/or TLR8 activation) and stimulator of interferon genes (STING) agonists are currently under development [23]. ADCs containing metal (Pt/Au)-based cytotoxic payloads are also emerging [24], and their translation to the clinic will be based on efficacy vs toxicity and performance in the case of Pt-resistant recurrent cancers [25].
The STING-IRF3 pathway contributes to paraquat-induced acute lung injury
Published in Toxicology Mechanisms and Methods, 2022
Na Wang, Xiaofeng Wang, Yuhua Li, Haitao Shen, Zhenning Liu, Zhongliang Ma, Qiuhe Li, Min Zhao
Recently, the effect of activated STING (stimulator of interferon genes protein) signaling upon innate immune responses and inflammation has attracted increasing attention (Qiao et al. 2018; Zhao et al. 2018; Hu et al. 2019). Initial studies focused on the role of the STING signaling pathway in antiviral infection in immune cells. These studies revealed that STING can recognize pathogenic DNA in the cytoplasm through DNA sensors to initiate innate immune responses. However, subsequent studies found that ‘mislocalized’ self-DNA can have a similar effect on the activation of STING as pathogenic DNA (Ahn et al. 2014). Self-DNA (Benmerzoug et al. 2019), including nuclear DNA (nDNA) fragments and mitochondrial DNA (mtDNA), leak into the cytoplasm after DNA damage, and act as danger signals that drive sterile inflammation (Li and Chen 2018). Once STING signaling is activated by self-DNA, it can activate IFN regulatory factor 3 (IRF3) and many other downstream factors, promoting the release of inflammatory mediators and cytokines to result in immune responses and inflammation (Ahn et al. 2012; Mao et al. 2017).
Making cold malignant pleural effusions hot: driving novel immunotherapies
Published in OncoImmunology, 2019
Pranav Murthy, Chigozirim N. Ekeke, Kira L. Russell, Samuel C. Butler, Yue Wang, James D. Luketich, Adam C. Soloff, Rajeev Dhupar, Michael T. Lotze
Adaptive immunotherapies that involve the selection, activation, and expansion of T cells to elicit a tumor specific response with immunological memory hold much promise in treating MPE. Though many MPEs share similar characteristics, the primary site of disease appears to influence the composition of the effusion as demonstrated when comparing MM and breast/lung cancer patients.166 In addition to T cells, the pleural space harbors other immunomodulatory elements that vary within patients, suggesting a personalized approach to restoring a functional ‘hot’ immune tumor microenvironment, amenable to immunotherapy. In general, ‘hot’ immune infiltrated tumors are those within which intimate contact between T cells can be observed in the tumor. Dysfunctional T cells found within effusions are dispersed, like tumor cells, in the pleural fluid.167 Local administration of agents such as TLR-9 agonists (CpG’s), stimulator of interferon genes (STING) agonists, or installation of oncolytic viruses would seem to be logical approaches and need to be evaluated. Sequential studies of the pleural fluid should enable detailed mechanistic studies in this setting.