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Systemic Lupus Erythematosus
Published in Jason Liebowitz, Philip Seo, David Hellmann, Michael Zeide, Clinical Innovation in Rheumatology, 2023
Vaneet K. Sandhu, Neha V. Chiruvolu, Daniel J. Wallace
For many years, the understanding of SLE pathophysiology was highly focused on autoantibodies, which expectedly led to therapeutic targeting of antibody production. However, this explained only part of disease pathogenesis. In addition to the adaptive immune response, the innate immune response also plays an important role. Multiple studies have identified the role of IFN-I, particularly IFN-α, in the pathogenesis of SLE. Prior to this, IFN had been well studied in antiviral defense. Elevated IFN in sera of SLE patients was first noted in 1979. This was followed by cumulative evidence of elevated IFN-1 receptor activation in SLE. Recent research in gene signaling has supported this observation, showing activation of genes involved in IFN-1 signaling. As opposed to viral infections where IFN-1 levels are elevated only during infection, studies have shown that IFN-1 levels are chronic in SLE patients, but there is poor evidence of correlation with disease flares. Plasmacytoid dendritic cells (pDC) are the prime IFN-α-producing cells, and there is evidence of their role in inflammation in SLE. Furthermore, it seems that immune complexes with nucleic acid, specifically RNA (Ro, La, Sm, RNP), can trigger IFN production through toll-like receptor 7 (TLR7).
Depigmenting Agents
Published in Vineet Relhan, Vijay Kumar Garg, Sneha Ghunawat, Khushbu Mahajan, Comprehensive Textbook on Vitiligo, 2020
Imiquimod is a novel imidazoquinolinone immune response modifier frequently used for topical treatment of anogenital warts and basal cell carcinomas [32]. Imiquimod increases production of proinflammatory cytokines, mainly interferon (IFN)-α, tumor necrosis factor (TNF)-α, and IL-6, IL-8, IL-10, and IL-12, all of which augment the type 1 helper T-cell (TH1) response which is found to be prominent in the pathogenesis of vitiligo [4]. Imiquimod also stimulates CD8 cells to become cytotoxic, and enhances antigen presentation [33]. Recently, it was reported that human melanocytes express toll-like receptor 7 (TLR7). When applied topically, imiquimod binds to TLR7, followed by stimulation of various cytokines which induce the previously-mentioned T lymphocytic response [34]. Imiquimod also has a direct action on melanocytes via apoptosis of melanocytes. This action is related to reduction of expression of Bcl-2 and/or an increase in the proapoptotic stimulus (cytotoxic T lymphocytes, natural cytotoxic T cells/killer cells, granzyme B, Fas, TNF, Bax, etc.) [35]. Imiquimod (5%) application may be followed by erythema, which gradually turns to depigmented patches over a period of 3 months. No repigmentation has been seen until 6 months after the depigmentation. Also, depigmentation did not extend to areas that had not been treated with imiquimod [36]. The most common side effects of imiquimod are burning, itching, pain, erythema, erosions, and scabbing/crusting at the target site, which occur more frequently with twice-daily application [4].
Celiac disease
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Most of the established loci harbor candidate genes with immune functions. These genes can be classified into different pathways. Many of the genes belong to pathways of T- and B-cell costimulation. Such genes include CTLA4, CD80, SH2B3, PTPN2, TAGAP, ICOSLG, and CD247. Also frequently represented are cytokine and cytokine receptor genes, including IL2/IL21, IL12A, and IL18RAP; genes involved in migration of immune cells such as the chemokine receptors CCR3/CCR5/CCR1 and CCR4; and the integrin gene ITGA4. Another interesting pathway involves molecules important for T-cell development in the thymus, such as THEMIS, which plays a role in both positive and negative T-cell selection during late thymocyte development, and RUNX3, which is involved in CD8+ T-cell differentiation. One network includes genes involved in nuclear factor (NF)-κB signaling, such as REL, which encodes a component of the NF-κB complex, and TNFAIP3, which encodes a molecule that inhibits NF-κB activity. Finally, a pathway involving molecules implicated in innate immune detection such as toll-like receptor 7 (TLR7), TLR8, and IRF4 has been identified. Both TLR7 and TLR8 recognize viral RNA, whereas IRF4 is a transcriptional activator that is part of the TLR7 pathway. This latter finding suggests involvement of viruses in the pathogenesis of celiac disease, likely initial events important for inducing the antigluten CD4+ T-cell response.
The molecular basis of immuno-radiotherapy
Published in International Journal of Radiation Biology, 2023
Ioannis M. Koukourakis, Dina Tiniakos, Vassilis Kouloulias, Anna Zygogianni
A large number of additional IC-pathways have been identified (Marin-Acevedo et al. 2021). Inhibitory pathways include: 1) LAG-3 (CD223) and TIGIT expressed by T-cells and NK-cells, 2) Adenosine A2aR/P1-R receptor on T-cells and the CD39 and CD73 expressed by lymphocytes and CCs promoting the production of immunosuppressive adenosine molecules, and 3) Killer immunoglobulin-like receptors KIR/CD158 expressed mainly by NK-cells. Co-stimulatory pathways include: 1) OX40/CD134 expressed by activated CD4 and CD8 T-cells, that also inhibits the suppressive activity of Tregs, 2) Glucocorticoid-induced TNF receptor family-related protein GITR that enhances cytotoxic T-cell activity, 3) Inducible co-stimulator (ICOS) that has a similar function to CD28 enhancing T-cell cytotoxicity, 4) CD27/CD70 pathway that induces T-cell differentiation to effector and memory cells, and 5) CD40/CD154 pathway that induces secretion of cytokines by B-cells and activates cytotoxic T-cells. TIM-1 expressed by T-cells, and TIM-3 and 4 expressed by NK-cells and macrophages (and CCs) have a distinct still unclear or even dual role as stimulatory or inhibitory molecules of tumor immune surveillance (Das et al. 2017). Toll-like receptors TLR7/8 and TLR9 are also involved in the induction of anti-tumor T-cell activity (Paulos et al. 2007). Arginase and inducible iNOS, enzymes highly expressed by CCs that deplete the aminoacid arginine essential for T-cell activation and proliferation, are also targets for immunotherapy (Timosenko et al. 2017; So et al. 2019).
A case of topical imiquimod induced fatigue
Published in Journal of Dermatological Treatment, 2022
Justin Raman, Elizabeth Bisbee, Tricia A. Missall, Sami K. Saikaly
Imiquimod is an immunomodulator with US Food and Drug Administration approval for the treatment of superficial basal cell carcinoma (BCC), actinic keratoses (AK), and anogenital warts (1). It has also been used off-label for the treatment of many cutaneous diseases including melanoma in-situ (MIS), molluscum contagiosum, keloids, and morphea (1). Preparations include a 2.5%, 3.75% and 5% topical cream (2). As an immunomodulator, it impacts both innate and adaptive immune responses (2). Although the exact mechanism of action is unclear, it is a toll-like receptor 7 and 8 agonist, inducing proinflammatory cytokines (1). Imiquimod is considered a safe topical medication with a minor side effect profile (1). Here we present a case of severe fatigue induced by 5% imiquimod used for a pigmented lesion that was likely an early MIS, per dermoscopic findings and confocal microscopic imaging.
Gut non-bacterial microbiota contributing to alcohol-associated liver disease
Published in Gut Microbes, 2021
Wenkang Gao, Yixin Zhu, Jin Ye, Huikuan Chu
Furthermore, people have also found the interaction between archaea and the human immune system. When stimulating the immune system with M. stadtmanae,154 high levels of proinflammatory cytokines including interleukin and interferon were released.166,167 Only recently was it demonstrated that RNA from M. stadtmanae was a potent immune stimulator, and toll-like receptor 7 (TLR7) and TLR8 were identified as the involved pattern recognition receptors. Moreover, this molecular interaction induced TLR8-dependent NLRP3 inflammasome activation.168 The proinflammatory ability of archaea also varies from species to species. For example, M. stadtmanae is capable of inducing a stronger immune response than both M. smithii and M. luminyensis.166,169 There are some speculations attempting to explain the mild response induced by M. smithii stating that M. smithii has the capacity to produce glycans which is similar to those found in the gut,170 and thus may help M. smithii escape from the host immune system. In conclusion, understanding the molecular mechanisms of how archaea induce inflammation in the body is thus an important step in uncovering how such diseases might develop.