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Therapeutic Challenges in COVID-19
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Alaa A. A. Aljabali, Murtaza M. Tambuwala, Debmalya Barh, Kenneth Lundstrom
-B*15:27, -B*46:01, -C*01:02, an-C*07:29 alleles correlate with COVID-19 susceptibility, and HLA-A*02:02, -B*15:03, and -C*12:03 may have a protective role. Genetic polymorphisms that affect ACE2 and TMPRSS2 expression also increase the risk of infection, and variations in cytokine genes such as IL6, ILR, TNF etc. could be associated with cytokine storm affecting disease severity. In the GWAS (Genome-Wide Association Study), two loci are found associated with COVID-19 severity. These are 3p21.31 harboring genes such as FYCO1, SLC6A20, CCR9, LZTFL1, XCR1, and CXCR6, and 9q34.2, where the ABO genes are located [63]. It has also been reported that people with blood group A are more susceptible to SARS-CoV-2 infections [64]. Furthermore, inborn errors of type I IFN immunity are associated with very severe COVID-19 [65].
Role of dendritic cells in integrating immune responses to luminal antigens
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Brian L. Kelsall, Maria Rescigno
cDC1 cells have been shown in mouse models to have specific effects on the induction, differentiation, and survival of TH1 cells in vivo. The induction of MLN TH1 cells is reduced, and small intestinal LP CD4+ T cells express lower levels of IFN-γ mRNA in Xcr1-DTA mice treated with diphtheria toxin (DT) to selectively eliminate cCD1 cells. In Cd11c-cre.Irf8fl/fl mice, TH1 cells are significantly reduced in the intestinal and colonic LP. cDC1 cell IL-12 contributes to intestinal TH1 responses during Toxoplasma gondii infection and to intestinal T-cell release of IFN-γ, which protects epithelial cells against damage induced by dextran sodium sulfate (DSS).
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].
A safe and highly efficient tumor-targeted type I interferon immunotherapy depends on the tumor microenvironment
Published in OncoImmunology, 2018
Anje Cauwels, Sandra Van Lint, Geneviève Garcin, Jennyfer Bultinck, Franciane Paul, Sarah Gerlo, José Van der Heyden, Yann Bordat, Dominiek Catteeuw, Lode De Cauwer, Elke Rogge, Annick Verhee, Gilles Uzé, Jan Tavernier
To address the impact of perilesional AFN treatment on the DC activation status in the tumor draining lymph node, B16-mCD20 melanoma bearing mice were injected with BCII10-AFN, mCD20-AFN (5000 IU) or PBS. 24 hours post injection, tumor-draining lymph nodes were dissected and processed for flow cytometry. Cell suspensions were stained with CD16/CD32 to block Fc receptors, followed by CD3-AlexaFluor-700, CD19-AlexaFluor-700, Ly6C-PECy7, CD11b-APCCy7, CD86-eFluor450, PDL1-PE, CD40-APC, CD80-APC, CD11c-PEeFluor610, MHCI-FITC (all eBioscience), XCR1-BV650 (BioLegend). After exclusion of T and B cells and Ly6Chi monocytes, DCs were identified based on their expression of CD11c and MHCII. XCR1+ cDC1s were identified based on their XCR1+ CD11b− MHCIIint-hi CD11cint-hi phenotype, whereas CD11b+ cDC2s were identified based on their XCR1− CD11b+ MHCIIint-hi CD11cint-hi phenotype. Samples were acquired on a BD LSR Fortessa (5-laser) and analyzed using FlowJo software.
A Comprehensive Profile of Chemokine Gene Expression in the Tissues of the Female Reproductive Tract in Mice
Published in Immunological Investigations, 2020
Fiona M. Menzies, Rachel S. Oldham, Carolann Waddell, Scott M. Nelson, Robert J. B. Nibbs
CCR10, along with CCR8, might also direct T cell homing to the uterus: they have both been implicated in the trafficking of leukocytes, particularly T cells, into and within the skin of humans and mice during homeostasis and inflammation (Gombert et al., 2005; Homey et al., 2002; Islam et al., 2011; McCully et al., 2015, 2012; Nagao et al., 2012; Qu et al., 2004; Reiss et al., 2001; Schaerli et al., 2004; Sigmundsdottir et al., 2007; Soler et al., 2003). Our data show that uterus expresses Ccl1 and Ccl8 at a level equivalent to skin. To our knowledge, there have been no studies exploring the function of CCR8 and its ligands in the uterus. This is also the case for XCL1. XCR1 is the only receptor for XCL1 and has no other known ligands. It is highly restricted to a subset of DCs that cross-present antigens to CD8+ T cells to initiate immune responses to viruses or tumours (Crozat et al., 2010, 2011; Dorner et al., 2009). Mice lacking XCR1 or XCL1 show diminished CD8+ T cell responses to infection (Dorner et al., 2009). The XCL1/XCR1 axis also maintains intestinal homeostasis by controlling T cell and DC abundance in the tissue (Ohta et al., 2016). We speculate that XCL1/XCR1 serves a similar homeostatic function in the uterus, and will contribute to anti-viral immune responses in the FRT. Interestingly, male antigens in seminal fluid can be cross-presented to CD8+ T cells (Moldenhauer et al., 2009) and generate tolerogenic CD4+ Tregs (Guerin et al., 2011; Robertson et al., 2009), so XCL1 might play important roles in preparing the uterus for implantation. CCL21 is also likely to be important in this regard. Acting through CCR7, it directs DC egress from tissues into lymphatic vessels (Girard et al., 2012), after which the DCs travel to lymph nodes where they activate or tolerise naïve T cells.
Vaccine-induced CD8 T cells are redirected with peptide-MHC class I-IgG antibody fusion proteins to eliminate tumor cells in vivo
Published in mAbs, 2020
Cornelia Fischer, Michael W. Munks, Ann B. Hill, Richard A. Kroczek, Stefan Bissinger, Verena Brand, Martina Schmittnaegel, Sabine Imhof-Jung, Eike Hoffmann, Frank Herting, Christian Klein, Hendrik Knoetgen
Vaccination was performed by targeting peptide to XCR1+ dendritic cells, as described previously.23 The MCMV M38 peptide (SSPPMFRV) was fused to the C-terminus of the anti-XCR1 antibody MARX10 by enzymatic sortase coupling.24,25 C57BL/6 N mice were immunized (i.v.) with 5 µg of anti-XCR1-M38 and 10 µg of poly(I:C) (InvivoGen). Five days later, antigen-specific CD8 T cells were amplified by administration of autologous peptide antigen-presenting cells and IL-2 cytokine receptor stimulation was started on day six (data not shown).