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Constraints on the Hydropathicity and Sequence Composition of HCDR3 are Conserved Across Evolution
Published in Maurizio Zanetti, J. Donald Capra, The Antibodies, 2002
Ivaylo Ivanov, Jason Link, Gregory C. Ippolito, Harry W. Schroeder
the reading frame that contains termination codons. RF3 also typically contains hydrophobic amino acids, sometimes even more than RF2. The reading frames by inversion (iRFs), exhibit characteristic hydropathicities as well. iRF1 typically contains charged amino acids, whereas the hydropathicities of iRF2 and iRF3 parallel the hydropathicities of their corresponding reading frames by deletion (iRF2 is hydrophobic and iRF3 contains termination codons). The hydropathicities of the 6 RFs of some of the most highly used D segments from three species are shown in Table 1.
Innate Immune System in Cardiovascular Diseases
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Benjamin J. Kopecky, Kory J. Lavine
Compared to macrophages, dendritic cells are a rare innate immune cell population in the heart [23, 24, 41, 42]. Macrophages and dendritic cells share some cell surface markers (i.e., CD11c, MHC-II) with both sets of markers dynamically changing during an evolving immune response. Dendritic cells are composed of four subsets and can be distinguished from cardiac macrophages on the basis of the transcription factor ZBTB46 [43, 44]. Dendritic cells are classified as conventional/classical DC type 1 (cDC1), conventional/classical DC type 2 (cDC2), plasmacytoid DC (pDC), and monocyte-derived dendritic cells (mDCs). The latter subset shares features of macrophages and dendritic cells [45–47]. cDC1s and cDC2s require FLT3L signaling for their development. Committed precursor dendritic cells (CD103+ and CD11b+) migrate from the bone marrow to peripheral tissue, where they complete their differentiation into either cDC1s or cDC2s. cDC1s are dependent on IRF8, ID2, and BatF3 transcriptional activity, whereas cDC2s are dependent on IRF4, RelB, RBP-J, and IRF2 transcriptional activity [11, 48]. Under steady-state conditions, the heart contains cDC1s (Clec9a+ CD103+ CD24+ XCR1+) and cDC2s (CD11b+ CD172a+). As opposed to conventional DCs, which complete development in peripheral tissues, pDCs complete development in the bone marrow and express CD11c, CCR9, CD317, B220, and Siglec-H [46, 49]. pDCs have lower expression of MHC-II than do cDCs and less capacity for antigen presentation. pDCs are able to produce strong cytokine responses and influence T-regulatory cell development. Dendritic cells generally suppress self-reactive CD4+ T-cells through modulation of T-regulatory cells [50], participate in viral clearance [51], and modulate left-ventricular (LV) remodeling [49]. Cardiac dendritic cells are short lived and are replenished from blood monocytes, and bone marrow-derived progenitors [52, 53].
Genetic Control of Endotoxin Responsiveness: The Lps Gene Revisited
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Stefanie N. Vogel, Nayantara Bhat, Danielle Malo, Salman T. Qureshi
Previous studies demonstrated that Lpsd macrophages exhibit a reduced capacity to produce IFN, as evidenced by increased susceptibility to vesicular stomatitis virus infection in vitro or a more rapid decay in the capacity to transfer antiviral activity in tissue culture supernatants (reviewed in Ref. 2). Although Lps is clearly distinct from Ifa and Ifb loci (11,34,35), the differential expression of IFN may provide insights into the increased susceptibility phenotype of Lpsd mice to a variety of pathogens. Using nuclear run-on transcription assays, resident peritoneal macrophages from Lpsd mice were shown to transcribe low levels of IFN-βmRNA, even though they could not transfer an antiviral state (36). Treatment of Lpsn macrophages with cycloheximide resulted in a marked accumulation of IFN-βmRNA, in contrast to the lack of IFN-βmRNA accumulation in C3H/HeJ macrophages. Stabilization of IFN-βmRNA in the LPS-responsive macrophages was correlated with an increase in the accumulation of cytoplasmic factors that interact with the AU-rich sequences in the 3’ untranslated region of IFN-βmRNA. The authors concluded that C3H/HeJ macrophages exhibit an impaired capacity to stabilize IFN-βmRNA, thus resulting in a low expression of antiviral activity (37). In subsequent studies, semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) was utilized to demonstrate much lower basal expression of not only IFN-β, but also IFN-α and IFN-γ steady-state mRNA in C3H/HeJ peritoneal exudate macrophages when compared to C3H/OuJ macrophages (38,39), with the most profound difference being in levels of IFN-γ mRNA. Basal mRNA levels of IFN regulatory factor (IRF)-1, a well-characterized, IFN-inducible nuclear transactivating factor, were approximately 15-fold greater in LPS-responsive macrophages. In contrast, C3H/HeJ macrophage steady-state mRNA levels for IRF-2, an IFN-inducible transrepressive nuclear bind ing protein that is highly homologous to IRF-1, was approximately 18-fold greater than in LPS-responsive macrophages. Thus, the balance between the IRFs may represent yet an additional pathway in the complex response to LPS. Finally, C3H/HeJ macrophages failed to be “primed” by LPS to produce augmented levels of IFN bioactivity when subsequently stimulated by poly I:C, in contrast to the normal response of these cells to exogenous IFN-α or IFN-γ as the priming agent (39). Taken collectively, these data suggest the possibility that LPS-induced IFNs may act in an autocrine fashion to provide a replenishable source of “primed” macrophages that are functionally more responsive to “triggering” signals in the form of bacterial or viral challenge. Thus, the failure of environmental LPS to stimulate basal IFN levels in C3H/HeJ macrophages may well underlie the increased susceptibility to infection exhibited by this strain.
Five years of lenvatinib in hepatocellular carcinoma: are there any predictive and/or prognostic factors?
Published in Expert Review of Anticancer Therapy, 2023
Mara Persano, Andrea Casadei-Gardini, Valentina Burgio, Mario Scartozzi, Stefano Cascinu, Margherita Rimini
Recently, a study published by Myojin and colleagues demonstrated that Lenvatinib eliminated HCC cell lines expressing FGF19 and that Sorafenib eliminated those expressing MET and NRAS. Furthermore, it has been observed that resistance to Lenvatinib therapy in HCC cell lines was determined by down regulation of FGF19 expression, resulting from chronic exposure to the drug. From the analyses carried out on 79 patients undergoing surgery for HCC, it was found that ST6 β-galactoside α-2,6-sialyltransferase 1 (ST6GAL1) was a protein secreted by cancer cells and whose serum levels increased with the expression of FGF19. Patients with ST6GAL1 high serum levels showed better survival when treated with Lenvatinib than with Sorafenib (p < 0.05) [68]. Another potential factor of resistance to Lenvatinib is represented by β catenin, which is part of the Wnt signaling pathway. A preclinical study of HCC cell lines showed that interferon regulatory factor (IRF) 2 induced the β catenin production, thus promoting cell proliferation and inhibiting apoptosis. These factors were overexpressed in cells exposed to Lenvatinib. In particular, increase in IRF2 was correlated with a reduced sensitivity to Lenvatinib, representing a potential mechanism of resistance on which it could be interesting to intervene to improve therapeutic outcomes [69].
Dual role of ARPC1B in regulating the network between tumor-associated macrophages and tumor cells in glioblastoma
Published in OncoImmunology, 2022
Tianqi Liu, Chen Zhu, Xin Chen, Jianqi Wu, Gefei Guan, Cunyi Zou, Shuai Shen, Ling Chen, Peng Cheng, Wen Cheng, Anhua Wu
The interferon regulatory factor (IRF) proteins family were the crucial factors in immunoregulation, cell proliferation regulation and cellular response which was involved in tumorigenesis.46,47 Database analysis predicted IRF2, a member of the interferon regulatory factor (IRF) family, as a TF of ARPC1B, which was confirmed to regulate IFNγ-stimulated ARPC1B expression. Western blotting showed that IRF2 deficiency blocked the upregulation of ARPC1B caused by IFNγ treatment, suggesting that IRF2 also plays an oncogenic role in glioma progression. Several studies indicated the potential oncogenic roles of IFNγ through enrichment of IRF2.48 Moreover, IRF2 was associated with a more advanced pathological grade and worse outcomes in glioma patients.49 These results point to a role of IRF2 not only in the IFNγ-mediated regulation of ARPC1B expression but also in glioma progression.
IRF1 expression might be a biomarker of CD8+ T cell infiltration in cutaneous melanoma
Published in Expert Review of Clinical Immunology, 2022
Shijie Zhou, Chunli Lu, Gan Liu, Qinsheng Hu, Jinliang Yang
Several studies indicated that CTLA‐4 and PD‐1 inhibitors could elevate IFN-γ production in the TME, which has both pro- and anti-tumoral activities [3,21,22]. These effects might be distinguished by IFN-γ signaling in immune cells or tumor cells [23]. One recent study based on single-cell RNA-seq data revealed that the IFN-stimulated genes related to immunotherapeutic resistance (ISG.RS) were mainly expressed by cancer cells [23]. In comparison, IFN-γ hallmark gene set (IFNG. GS) (which did not overlap with ISG.RS) is mainly expressed by immune cells (such as T cells, NK cells, and macrophages) in tumors [23]. More importantly, the low ratio of IFNG.GS/ISG.RS was associated with the resistance to ICIs, while high IFNG. GS/ISG.RS ratio was linked to increased infiltration of CD8 + T cells, NK cell activation, and a better response to PD-1 immunotherapy [23]. Another recent study examined 101 patients with advanced melanoma who received nivolumab (anti-PD-1) monotherapy or combined with ipilimumab (anti-CTLA-4). T cell-induced IFN-γ is highly correlated with clinical response to the therapies [24]. Currently, however, it is not clinically practical to measure T cell-induced IFN-γ as a predictor for the response to ICIs due to cost and technological limitations. Among the IRF family members, IRF1, IRF2, IRF4, IRF5, IRF8, and IRF9 belong to the IFNG hallmark gene set, while IRF7 is in the ISG.RS gene set [23].