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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 Immunomodulatory Features of Mesenchymal Stromal Cells Derived from Wharton’s Jelly, Amniotic Membrane, and Chorionic Villi In Vitro and In Vivo Data
Published in Ornella Parolini, Antonietta Silini, Placenta, 2016
Marta Magatti, Mohamed H. Abumaree, Antonietta R. Silini, Rita Anzalone, Salvatore Saieva, Eleonora Russo, Maria Elena Trapani, Giampiero La Rocca, Ornella Parolini
Another costimulatory molecule that belongs to the B7 family is the B7-H3 (CD276) protein. Flow cytometry and immunohistochemical analyses have shown that it is expressed by hWJMSCs (La Rocca et al. 2013b), hAECs (Petroff and Perchellet 2010), and hCVMSCs (Abumaree et al. 2013b). In addition, the molecule has been shown to be expressed not only in naive hWJMSCs but also in their in vitro–differentiated (toward osteogenic, adipogenic, and chondrogenic lineages) counterparts, a characteristic described above also for HLA-G, -E, and -F (La Rocca et al. 2013b). B7-H3 is an important T cell–immunosuppressive molecule that has been reported to consistently downregulate human T cell cytokine production and proliferation (Leitner et al. 2009). Finally, in contrast to PD-L1, PD-L2, and B7-H3, B7-H2 (CD275 or ICOS-L), the ligand for ICOS and provider of positive costimulatory effects promoting T cell activation, differentiation, and effector responses (Coyle et al. 2000; Petroff and Perchellet 2010; Yoshinaga et al. 1999), is not expressed by hAECs (Petroff and Perchellet 2010), hAMSCs (Kronsteiner et al. 2011b), and hCVMSCs (Abumaree et al. 2013b).
An update of targeted therapeutic options for primary Sjögren syndrome: current status and future development
Published in Expert Opinion on Pharmacotherapy, 2021
Soledad Retamozo, Antoni Sisó-Almirall, Alejandra Flores-Chávez, Manuel Ramos-Casals, Pilar Brito-Zerón
The co-stimulatory molecule ligand (ICOS-L) is a member of the co-stimulatory B7 family expressed on antigen-presenting cells such as B cells, macrophages, or dendritic cells [44]. ICOSL is abnormally expressed on epithelial cells of salivary glands in pSS patients; like CD28, ICOS/ICOS-L activation is involved in T-cell dependent B-cell activation and has been related to the development of ectopic GC [35]. Prezalumab (AMG557/MEDI5872) is a non-depleting anti-ICOSL monoclonal antibody that has been tested in 32 patients with pSS. The preliminary results of a phase II RCT [45] has showed a decrease of 3.8 points of the ESSDAI score at day 99 vs 2.3 points in the placebo group, a difference that was not statistically significant (Table 2). While individual blocking of ICOSL seems to be not totally effective, some preliminary in vitro data seems to suggest a potential better efficacy using dual CD28/ICOS antagonists ALPN-101 [46].
Lack of MHC class II molecules favors CD8+ T-cell infiltration into tumors associated with an increased control of tumor growth
Published in OncoImmunology, 2018
Nada Chaoul, Alexandre Tang, Belinda Desrues, Marine Oberkampf, Catherine Fayolle, Daniel Ladant, Alexander Sainz-Perez, Claude Leclerc
CD39 expression was also significantly increased on tumor Tregs, but since CD73 is significantly reduced, these results suggest that tumor Tregs do not exert their immunosuppressive activity through the up-regulation of intracellular AMP via the CD39-CD73 pathway. Recent studies have shown that highly suppressive Tregs that accumulate in tumors are characterized by increased expression of ICOS.24,25 Since we also observed increased expression of ICOS on tumor and dLN Tregs, this finding suggests that inhibition of the ICOS-ICOS-L pathway could be a promising strategy for enhancing the anti-tumor immune response. Similar results were obtained for the CD103 molecule, which was significantly increased on tumor and dLN Tregs. CD103 was shown to be a hallmark of tumor-infiltrating Tregs.23 However, this integrin, which is required for T-cell homing to the intestinal mucosa, is also expressed by T lymphocytes in epithelial tissues59 and by tissue-resident innate lymphoid cells and innate-like T cells.60 Importantly, resident memory cells (Trm), defined by the expression of CD103 and CD69, were recently shown to play a key role in the efficacy of cancer vaccine to inhibit tumor growth.61 In agreement with these findings, the expression of CD103 was also significantly increased on tumor-infiltrating Teffs.
Role of Inducible Co-Stimulator (ICOS) in cancer immunotherapy
Published in Expert Opinion on Biological Therapy, 2020
Florent Amatore, Laurent Gorvel, Daniel Olive
The expression of ICOSL was demonstrated to be boosted by inflammatory cytokines including TNF-α [15]. Therefore, the upregulation of ICOSL on endothelial cells provides the recruitment of effector T-cells into tissues under inflammatory conditions [16]. For example, during human cardiac allograft rejection, endothelial ICOSL expression is increased leading to EC-mediated CD8+ T cell co-stimulation [63] and CD8+ memory T-cell activation [64]. Interestingly, ICOS can deliver a reverse signal through ICOSL. First, the engagement of ICOSL produces a stimulatory synergistic effect, as shown for NOD2 (nucleotide-binding oligomerization domain 2)-driven cytokine secretion [65]. Moreover, signaling through ICOSL has a direct effect on DCs, promoting the secretion of IL-6 [66] via the phosphorylation of p38-MAPK. Furthermore, the Fc fragment of ICOS can stimulate monocyte-derived dendritic cells (MDDCs) through ICOSL during lipopolysaccharide-driven maturation and exacerbates IL-23, IL-10 secretion, which promoted Th17 polarization in mixed lymphocyte culture [67]. The expression of ICOS or ICOS-L by tumor cells is logically more the prerogative for hematologic diseases. However, the expression of ICOS-L has been found on glioma cells (but not in adjacent normal central nervous system tissues) [68], colorectal cancer [47] and melanoma [52]. Indeed, ICOS-L is expressed by malignant melanoma cells, which promotes the expansion of ICOS+ IL-10-secreting Tregs via ICOS/ICOSL pathway [52]. The expression of ICOS-L by melanoma cells and pDCs have been described to be type 1 IFN dependent [51,52]. Thereby, ICOS-L expression by melanoma tumor cells could favor immune escape by driving Treg expansion and survival.