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Sjögren's Disease
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
Epstein-Barr virus (EBV) has been the most studied etiologic agent in SjD. It is a human double-stranded DNA virus with tropism for B cells and epithelial cells. Most people are infected in early life and develop a latent infection in memory B cells. Reactivation can occur later in life (106). Compared to controls, SjD patients demonstrated the presence of EBV nucleic acids in blood and salivary glands and higher serum titers of anti-EBV antibodies (107–111). EBV-encoded small RNA binds to the SSB/La antigen, forming immune complexes released by EBV-infected cells, which in turn activate toll-like receptor 3 (TLR3), leading to production of type I interferon (112). B cell lines from SjD patients produced EBV at a higher frequency and in larger amounts than did B cell lines from RA and SLE patients (113). IgG antibodies against EBV early antigen, a marker of past exposure, have a higher prevalence among SjD patients when compared to controls and correlate with anti-SSA/Ro and anti-SSB/La antibodies (114). Despite this evidence, it remains to be determined if a causal relationship exists between EBV virus and SjD.
Herpes simplex viruses
Published in Avindra Nath, Joseph R. Berger, Clinical Neurovirology, 2020
Israel Steiner, Felix Benninger
Toll-like receptor 3 (TLR3) is a pattern recognition receptor triggered by viral double-stranded RNA and leading to the activation of specific transcription factors, which stimulate the production of cytokines that induce a complex program of innate immune responses that facilitate viral, including HSV, clearance [39]. The importance of innate immunity in the control of human HSE was suggested through studies of HSE in children with genetic defects that shared the common feature of encoding proteins involved in TLR3-interferon signaling pathways. Indeed mutations in TLR3 were associated with recurrent HSE [40,41]. Recently, TLR3 receptor pathway defects have been shown to be more prevalent also in adults with HSV encephalitis [42]. Being present in only a fraction of patients with HSE, do these findings have a broader implication [43]? In one patient with a deleterious TLR3 mutation, the first HSE episode took place at 8 months and the second at age 35 years, and in a second patient, 3 episodes happened at 2.5, 22, and 28 years of age. Clearly, something else is required to enable HSE besides a TLR3 abnormality. These may include environmental, pathogen, and host factors, alone or in concert. The studies identifying TLR3-interferon signaling defects as a host susceptibility factor in HSE focus almost exclusively on pediatric populations, and it remains to be determined if the results also apply to adult and elderly patients in whom the prevalence of HSV increases progressively as a cause of encephalitis of identified etiology.
RNA interference: a potential therapy for posterior pole diseases
Published in A Peyman MD Gholam, A Meffert MD Stephen, D Conway MD FACS Mandi, Chiasson Trisha, Vitreoretinal Surgical Techniques, 2019
While any dsRNA can be processed into siRNA to mediate RNAi, siRNA acts as a true intermediary and can be used alone as an activator of the RNAi machinery.5 dsRNA can be manufactured and used to mediate RNAi. The downside of using long dsRNA is that dsRNA molecules greater than 60 nucleotide base-pairs in length are recognized by another cellular defense mechanism called the interferon response. The interferon response, which is mediated potentially by double-stranded RNA interacting with Toll-like receptor 3, can shut down cellular function and may result in toxicity.6 It is believed that siRNA molecules are small enough not to be recognized by this defense mechanism and thus have an advantage over unprocessed long dsRNA. While siRNA has been shown to potentially activate the interferon response in vitro, recent in vivo studies have shown the ability of nonmodified siRNA to mediate RNAi without inducing the interferon response in a mouse model.7,8
Expression of interferon-stimulated gene 20 (ISG20), an antiviral effector protein, in glomerular endothelial cells: possible involvement of ISG20 in lupus nephritis
Published in Renal Failure, 2023
Takao Karasawa, Riko Sato, Tadaatsu Imaizumi, Masashi Fujita, Tomomi Aizawa, Koji Tsugawa, Deborah Mattinzoli, Shogo Kawaguchi, Kazuhiko Seya, Kiminori Terui, Kensuke Joh, Hiroshi Tanaka
In some forms of glomerulonephritis, innate immunity in resident renal cells is thought to play a role in the pathogenesis of kidney inflammation, in addition to the antiviral response [1]. In this process, activated Toll-like receptors (TLRs) on circulating immune cells and resident renal cells induce the production of type I interferons (IFNs) and subsequently that of pro-inflammatory cytokines/chemokines [2,3]. Among the pro-inflammatory chemokines, CX3CL1/fractalkine and CXCL10/IFN-γ-induced protein 10 are representative chemokines that could initiate activated leukocyte infiltration into glomerular cells [4–6]. Although Toll-like receptor 3 (TLR3)/type I IFN signaling plays a major role in antiviral innate immunity [7], it can be induced by noninfectious stimuli such as endogenous ligands, including damage-associated molecular patterns (DAMPs). Therefore, it is postulated that TLR3/type I IFN signaling may be involved in the pathogenesis of some forms of glomerulonephritis, particularly lupus nephritis (LN) [8–11]. The TLR3, TLR4, TLR7, and TLR9 signaling pathways play important roles in LN pathogenesis [8–13]. Regarding the TLR3, a unique concept of the ‘pseudoviral’ immunity that focuses on the excess activation of regional TLR3 signaling has been proposed as additional pathogenetic factors of LN [8–11,14–16], although this remains controversial. As TLR3 signaling is unique [7,8], we previously determined the detailed mechanisms of TLR3 signaling in resident renal cells [9–11]. However, the role of TLR3 activation in LN remains largely unknown [9].
A review on the reciprocal interactions between neuroinflammatory processes and substance use and misuse, with a focus on alcohol misuse
Published in The American Journal of Drug and Alcohol Abuse, 2023
Anny Gano, Terrence Deak, Ricardo Marcos Pautassi
Another important member of the TLR family is the toll-like receptor 3, which identifies double-stranded RNA in endosomes, and subsequently promotes a concerted antiviral action, which includes the secretion of proinflammatory cytokines. In the present special issue, Gano et al. (16) probed the role of that receptor in alcohol drinking in mice that were relatively naïve to alcohol or in counterparts that had been chronically exposed to ethanol via vapor exposure. Unlike the gene deletion used in Guerri’s studies, Gano and coworkers (16) used a pharmacological approach, administering the viral mimetic Poly I:C to the mice. The results indicated a modest, albeit significant, effect of Poly I:C in naïve animals. The promoting effect of the viral mimetic on alcohol intake, however, was stronger and long lasting in the mice that had been chronically exposed to ethanol.
Gut microbiota in Celiac Disease: microbes, metabolites, pathways and therapeutics
Published in Expert Review of Clinical Immunology, 2020
Katherine L Olshan, Maureen M Leonard, Gloria Serena, Ali R Zomorrodi, Alessio Fasano
Given that CD is a disease characterized by inflammation in the small intestine, it is reasonable to postulate that the local microenvironment, which is heavily influenced by the microbiota, plays a significant role in disease pathogenesis and loss of tolerance to dietary gluten. There are many proposed mechanisms through which the gut microbes are implicated in the pathogenesis of CD. Some bacteria express epitopes that mimic gliadin, and thus may potentially trigger a host immune response [46]. Lipopolysaccharide, a molecule expressed in the outer membrane of gram-negative bacteria, may also trigger both the innate and adaptive immune systems through IL-15 production [7]. Other bacteria, such as Pseudomonas aeruginosa, may synergize with gluten to cause increased mucosal inflammation [47]. Gastrointestinal viral infections may activate the innate immune system through toll-like receptor 3 [48]. The microbiota may also modify the digestion of gluten, producing either immunogenic or tolerogenic gluten peptides, and thus influences antigen development. Additionally, the microbiome can directly affect intestinal permeability through zonulin release, and by promoting epithelial mucosal maturation. Intestinal microbes also modulate the immune system through the production of proinflammatory or anti-inflammatory peptides, metabolites, and cytokines [49].”