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Genetics and genomics of exposure to high altitude
Published in Andrew M. Luks, Philip N. Ainslie, Justin S. Lawley, Robert C. Roach, Tatum S. Simonson, Ward, Milledge and West's High Altitude Medicine and Physiology, 2021
Andrew M. Luks, Philip N. Ainslie, Justin S. Lawley, Robert C. Roach, Tatum S. Simonson
Putatively adaptive copies of the THRB gene region, as well as PPARA and EPAS1 identified in Tibetans (Simonson et al. 2010), show relationships with hemoglobin concentration in Amhara Ethiopians (Scheinfeldt et al. 2012). EDNRB (endothelial receptor B), previously reported as a top selection candidate in Andeans (Bigham et al. 2010), is also reported in Amhara Ethiopians, and knockdown of this gene increases hypoxia tolerance in mice (Udpa et al. 2014). The gene family member EDNRA is also a top candidate gene in Tibetans (Simonson et al. 2010). BHLHE41, although not associated with hemoglobin, is a key HIF pathway gene and top selection candidate in Amhara, Oromo, and Tigray Ethiopians (Huerta-Sánchez et al. 2013). In addition to these hypoxia-associated genes, three others (VAV3, which encodes vav guanine nucleotide exchange factor 3, and RORA that encodes the RAR-related orphan receptor A) are reported as top candidates in Amhara Ethiopians (Scheinfeldt et al. 2012). Whole-genome sequence analyses indicate three genes contained within the same region of chromosome 19 identified as adaptive targets in Oromo and Simen Ethiopians, CIC, LIPE, and PAFAH1B3 (that encode capicua transcriptional repressor, lipase E hormone-sensitive type, and platelet- activating factor acetylhydrolase 1b catalytic subunit 2, respectively) have orthologs in Drosophila that afford tolerance to hypoxia (Udpa et al. 2014).
Role of regulatory T cells in mucosal immunity
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Foxp3+ Treg cells show a significant degree of phenotypic plasticity to adapt to specific microenvironments and to suppress different types of immune responses (“specification” in Figure 9.4). Treg cells accomplish this functional adaptation by employing the same transcriptional machinery that directs the differentiation of effector TH cells. For example, interferon regulatory factor IRF4, and an AP-1 transcription factor BATF, can be activated in response to TCR signals and environmental cues and cooperatively direct the differentiation of multiple TH cell subsets; they can also drive Treg cells to differentiate into various effector states. Conventional effector CD4+ T cells can differentiate into TH1, TH2, TH17, or TFH cell subsets, defined by expression of their signature transcription factors T-bet, GATA3, RAR-related orphan receptor γ-t (RORγt), and Bcl6. In a similar fashion, effector Treg cells are also heterogeneous and consist of subsets distinguished by expression of TH cell signature transcription factors, chemokine receptors, and cytokine receptors. For example, T-bet-expressing Treg cells, which are induced under conditions of TH1 inflammation, express CXCR3, accumulate at sites of TH1 inflammation, and exhibit the ability to specifically regulate TH1 responses. Bcl6-expressing Treg cells, which are termed follicular regulatory T (TFR) cells, express CXCR5, and migrate into lymphoid follicles where they control TFH-cell-dependent germinal center reactions. In the mucosa, Treg cells contain high frequencies of the RORγt+ and GATA3+ subsets. By differentiating into those diverse effector subsets with distinctive migratory, functional, and homeostatic characteristics, Treg cells can influence a broad range of cell populations and exert suppressive activities in a variety of anatomical locations and immune environments.
Zinc finger protein 189 promotes the differentiation of lamina propria T helper 17.1 cells in dextran sulfate sodium-induced colitis
Published in Autoimmunity, 2023
Zhihong Xia, Bo Hu, Min Yang, Wenjie He
IL-17A-EGFP transgenic mice were fed with DSS-containing water to induce acute colitis (Supplementary Figure S1). To determine ZFP189 expression in IL-17A-expressing CD4+ T cells, we isolated immune cells from mouse mLNs and LP after colitis induction and conducted flow cytometry to find IL-17A-expressing CD4+ T cells. As shown in Figure 1A, single cells were gated according to the forward scatter A and forward scatter H. CD3+CD4+ T cells were then recognised among single cells. IL-17A+CCR6+ T cells were found in CD3+CD4+ T cells isolated from the LP and mLNs, respectively. These IL-17A+CCR6+ T cells expressed RAR-related orphan receptor gamma t (RORγt) (Figure 1B). ZFP189 protein was expressed at a low level in mLN IL-17A+CCR6+ T cells and was moderately up-regulated in LP IL-17A+CCR6+ T cells (Figure 1C and D).
T helper cells in depression: central role of Th17 cells
Published in Critical Reviews in Clinical Laboratory Sciences, 2022
Raghumoy Ghosh, Prasenjit Mitra, P. V. S. N. Kiran Kumar, Taru Goyal, Praveen Sharma
Among transcription factors, RAR-related orphan receptor γt (RORγT), encoded by the RORC gene, is the master regulator of Th17 cell differentiation. IL-6 and TGF-β are known to stimulate the expression of RORγT, and overexpression of RORγT heralds the Th1/Th2 independent differentiation of Th17 cells. The transcription factor STAT3, induced by IL-6 and IL-21, controls RORα expression. RORα and RORγT work synergistically toward the completion of Th17 differentiation, and both these factors have to be knocked out in mice for complete resistance to MOG-induced EAE and Th17 cell deficiency in mice [83]. Other important transcription factors include the activating transcription factor (ATF)-like basic leucine zipper transcription factor (BATF), runt-related transcription factor-1 (RUNX1), aryl hydrocarbon receptor (Ahr), interferon regulatory factor 4 (IRF4), and STAT5 [84].
The impact of the interleukin 12/23 inhibitor ustekinumab on the risk of infections in patients with psoriatic arthritis
Published in Expert Opinion on Drug Safety, 2020
Alen Zabotti, Delia Goletti, Ennio Lubrano, Fabrizio Cantini
In a model of immunity proposed by Gérard Eberl, the healthy immune system is always active and in a state of dynamic equilibrium between pro-inflammatory and anti-inflammatory immune responses, maintaining the organism in a state of homeostasis [12]. When this balance is disturbed, the resulting state of disequilibrium weakens protective immunity, potentially leading to inflammatory pathologies such as PsA. For example, increased production of IL-23 stimulated by infection or injury can drive the expression of the RAR-related orphan receptor (ROR)-γt, which further induces the expression of pro-inflammatory cytokines [12]. It has been suggested that the action of IL-23 on ROR-γt+ CD3+ CD4–CD8 – entheseal resident T-cells can induce spondyloarthropathy, such as occurs in PsA [13]. In addition to IL-12 and IL-23, the immune response mediated by IL-17 plays a pivotal role in PsA [14,15] and are target candidates for PsA treatment [16,17].