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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
With progressively decreasing costs of sequencing technologies, migration away from SNP arrays to whole exome or whole genome sequencing will undoubtedly facilitate the identification of additional genetic causes of vasculitis. We envision these will include additional rare germline variants, such as unrecognized mosaicism of known and novel variants, as well as somatic mutations most likely to be enriched in the vasculitides associated with hematologic malignancies and aging, namely, PAN, GCA, and late-onset Behchet’s (68). In some cases, these may occur in low-variant allele frequency, as recently described in inflammation, neutropenia, bone marrow failure, and lymphoproliferation caused by TLR8 (INFLTR8) syndrome (116). Like known monogenic mutations, a “genetics-first” approach may identify genetic variants that do not segregate with vessel size or pathology but include vasculitis as a manifestation along with other atypical clinical features such as bone marrow failure syndromes and treatment refractoriness. While genetic variants have and will continue to provide insight into mechanisms of disease pathogenesis, we suspect that rare variants will only explain disease in a small portion of patients with vasculitis. However, pathways implicated in the development of vasculitis in patients with rare variants may be common in non-variant-associated forms of the disease, triggered by a variety of other stimuli. As such, integration of genomic and transcriptional data from cohorts via a network medicine approach is likely to predict further disease-causing nodes and identify novel treatment targets (117).
Plant-Based Adjunct Therapy for Tuberculosis
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Lydia Gibango, Anna-Mari Reid, Jonathan L. Seaman, Namrita Lall
TLRs have been identified in both humans (10 TLRs) and mice (12 TLRs). In humans, TLR2 is found on the cell membrane as a surface receptor and dimerizes with TRL1 or TLR6. The heterodimer formed between TLR1 and TLR2 is responsible for detecting triacylated lipopeptides from mycoplasma or gram-negative bacteria. The heterodimer formed between TLR2 and TLR6 could sense diacylated lipopeptides from mycoplasma or gram-positive bacteria (Circelli et al., 2017). TLR3 is a receptor found in the endosome and has the ability to recognize double-stranded RNA (dsRNA). TLR4 recognizes lipopolysaccharide (LPS), a component found in the outer membrane of gram-negative bacteria (Kawai and Akira, 2010). The only TLR4 agonist used as a cancer vaccine adjuvant that is approved is monophosphoryl lipid A (MPL), which has undergone many clinical trials to prove its safety and probability to elicit an immune response (Cluff, 2010). Both TLR7 and TLR8 are endosomal receptors that recognize single-stranded RNA (ssRNA); TLR7, Imiquimod, is the only approved ligand for use in the treatment of precancerous skin lesions (Vacchelli et al., 2012). TLR9 can identify unmethylated CpG dinucleotides of bacterial DNA origin (Kawai and Akira, 2010). TLRs that have had the ability to steer a Th1 elicited immune response include Poly:IC (TLR3), 3-O-desacyl-4’-monophosphoryl lipid A (MPLA: TLR4) or CpG oligonucleotides (TLR9). They have the ability to activate these specific TLRs and induce a downstream IL-12 response, which is important for the activation of a Th1 response (Stewart et al., 2019).
Peptide Vaccines in Cancers
Published in Mesut Karahan, Synthetic Peptide Vaccine Models, 2021
Öznur Özge Özcan, Rümeysa Rabia Kocatürk, Fadime Canbolat
PLGA is also FDA approved for humans, biocompatible, and polymeric NPs. Highly stable in PLGA saline buffer, it is very suitable for skin and intramuscular injections in cancer peptide vaccine applications (Kim, Griffith, and Panyam 2019). Transition-like receptor (TLR) 7/8 agonists are among the important adjuvant groups in cancer vaccines to demonstrate strong T cell responses by promoting DC uptake and are also a citcon enhancer in cellular immune response. Although TLR7 agonists were successful in in vitro cancer vaccination studies, they resulted in their accumulation at the injection site in preclinical and clinical studies. As a solution, although it is thought that by applying subcutaneous and intramuscular applications, TLR7 and TLR8 agonists will be provided with advantage in terms of transmission to DCs that can produce the desired immune response. It has been used with PLGA polymeric NPs that can overcome these problems such as enhancing the DC uptake and lymphatic drainage; PLGA NPs overcome these problems by providing high clearance protection for adjuvant formulations (Silva et al. 2013). Since peptides identified by cancer type and biology are not sufficient to increase T cell stimulation, an immunostimulant is also needed to increase the immunogenicity of the vaccine. For this reason, to increase the immunogenicity of peptide vaccines in cancer, IL-12, granulocyte-macrophage colony stimulating factor (GM-CSF), and TLRs agonists have been actively studied as vaccine adjuvants so far (Lehner et al. 2007; Simons and Sacks 2006; Napolitani et al. 2005).
Emergence of mRNA vaccines in the management of cancer
Published in Expert Review of Vaccines, 2023
Mohamad Irfan Mohamad Razif, Nabilah Nizar, Nur Hannah Zainal Abidin, Syasya Nasuha Muhammad Ali, Wan Nurul Najihah Wan Zarimi, Junaidi Khotib, Deny Susanti, Muhammad Taufiq Mohd Jailani, Muhammad Taher
A self-adjuvant type of mRNA vaccine can initiate the innate immune response after being administered in vivo. Initially, APCs identify mRNA, which then activates PRRs which are mostly abundant in the cell’s endolysosomal region. PRRs include toll-like receptor (TLR) family such as TLR3, TLR7, and TLR8. mRNA vaccines that are available in the cytosol can be recognized by these receptors [32]. dsRNA triggers the innate immune response by the recognition of TLR3, meanwhile, ssRNA is recognized by TLR7 and TLR8. The downstream pathway activated by TLR7 and TLR8 results in the synthesis of IFN-1 and induces proinflammatory cytokines such as tumor necrosis factor α (TNF-α), respectively [33,34]. The production of IFN-1, proinflammatory cytokines, and other inflammatory molecules increases when APCs engage the downstream pathway, which in turn activates the tumor necrosis factor response [32]. Degradation and inhibition of mRNA translation can occur as a result of interferons or proinflammatory cytokine release [17]. Both benefits and drawbacks come with the mRNA vaccines’ ability to act as their own adjuvant as it can unintentionally inhibit the mechanism of adaptive immune response toward the vaccines [32].
Regulatory Effects of Clock and Bmal1 on Circadian Rhythmic TLR Expression
Published in International Reviews of Immunology, 2023
Xu-li Fan, Ying Song, Dong-Xu Qin, Pei-Yao Lin
MyD88 is an adaptor protein related to almost all TLR-mediated signal transduction, including TLR2/TLR1/6, TLR4, TLR5, TLR7/TLR8, and TLR9 [38]. The MyD88-dependent pathway mainly recruits and activates various kinases (IRAK4, IRAK1/2, TBK1, and IKK) and ubiquitin ligase (TRAF6 and Pellino 1) through the interaction between MyD88 and interleukin-1 (IL-1) related protein kinase family (IRAK), which in turn leads to the activation of p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) MAPK pathways [39, 40]. TRIF (TIR-domain-containing adapter-inducing interferon beta) containing the Toll/IL-1 receptor (TIR) domain, also known as TICAM-1 (TIR domain-containing adaptor molecular 1), has been confirmed to play a role in the MyD88-independent pathway of TLRs; the TIR domain can activate TAK1 by directly binding to TRAF6, leading to the activation of the IKK complex [35, 41]. The MyD88-dependent pathway activates AP-1, and the TRIF pathway mediates IFN response [42], both of which can lead to NF-κB activation [43] (Figure 3).
Myocarditis following COVID-19 vaccination: incidence, mechanisms, and clinical considerations
Published in Expert Review of Cardiovascular Therapy, 2022
John R. Power, Lucas K. Keyt, Eric D. Adler
This unique mechanism of vaccine-induced immunity has generated the hypothesis that excessive innate immune activation by both lipid nanoparticle and RNA components of COVID-19 vaccines can cause vaccine-associated myocarditis. COVID-19 mRNA vaccines mark one of the first clinical applications of in vitro transcribed (IVT) mRNA, a technology that has been under development since 1990 [80]. The rollout of IVT mRNA was initially hampered by inherent immunogenicity and instability of mRNA molecules. Endosomal toll-like receptors TLR3, TLR7, and TLR8 in immune cells and cytosolic receptors RIG-I and MDA5 in nonimmune cells act as a natural defense to foreign RNA but can cross-react with IVT RNA [81]. Activation of these receptors triggers an inflammatory cascade, resulting in the assembly of inflammasome platforms, production of type I interferons, and nuclear translocation of NF-kB [82]. Similarly, lipid nanoparticles have been used in these vaccines to prevent IVT mRNA degradation and to facilitate mRNA delivery but have been linked with TLR-mediated release of proinflammatory cytokines as well as complement activation-related hypersensitivity reactions [83–85]. Thus, perturbed adaptive immune response, which is believed to be at the root of many autoimmune diseases, may also drive myocarditis with mRNA vaccines [86].