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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
Issues with apoptosis can be found in the FAS (Fas cell-surface death receptor) or FASL (Fas ligand) genes. Mice studies have identified these genes involved in regulation of activation-induced cell death leading to SLE-like disease in mice. Similarly, mutations in protein kinase C delta (PKCδ), which is involved in apoptosis, proliferation, and B cell negative selection, can lead to SLE-like disease.80RAG2 mutation can cause impaired T cell and B cell tolerance, thus leading to self-reactivity.50
Autoimmune Lymphoproliferative Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The FASLG gene on chromosome 1q24.3 spans 8 kb with four exons, and encodes a 281 aa, 31.4 kDa type II transmembrane protein (FASLG, FAS ligand, TNFSF6, or CD95L) belonging to the tumor necrosis factor family. FASLG binds to FAS, and activates the FAS/FASLG signaling pathway, causing activation-induced cell death (AICD) of T cells and cytotoxic T lymphocyte induced cell death [10].
Inflammation and immunology
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
Christopher Bellamy, Stephen J. Jenkins, Henry J. McSorley, David A. Dorward, Timothy J. Kendall
Tolerance may be bypassed by several mechanisms. Activation-induced cell death may be bypassed if Fas-induced apoptosis fails. This seems to increase with age as the efficiency of intrathymic elimination decreases. T-cell anergy is circumvented if cells that normally do not express co-stimulatory molecules such as MHC class II are induced to do so. Thus, in the pancreas, induction of MHC class II molecules on the β cells of the islets triggers an immune response against self-antigens on these cells and the induction of both cell-mediated and antibody-mediated β-cell elimination, with consequent type 1 diabetes mellitus (Figure 4.16). Molecular mimicry occurs when a microbial antigen encountered by the patient is sufficiently similar to a self-antigen that cross-reactivity with the self-antigen occurs. In rheumatic heart disease after a throat infection with certain streptococcal strains the antibody formed to the bacterium cross-reacts with an antigen present in the heart wall. The resulting antibody-mediated attack damages the myocardium and endocardium, leading to chronic valvular disease and potentially life-threatening long-term sequelae (see Chapter 7). In some circumstances, particularly exposure to Gram-negative endotoxin, there is a polyclonal and relatively non-specific activation of B cells. These B cells may be reactive against several different antigens including some self-antigens.
Defining potency of CAR+ T cells: Fast and furious or slow and steady
Published in OncoImmunology, 2019
Ivan Liadi, Harjeet Singh, Gabrielle Romain, Badrinath Roysam, Laurence JN Cooper, Navin Varadarajan
The ability of T cells to mediate antitumor response and to persist in vivo is one of the hallmarks of therapeutic success.9 Since T cells can undergo apoptosis upon functional activation, we investigated the frequency and kinetics of them undergoing apoptosis. Remarkably, the frequency and kinetics of activation-induced cell death (AICD) was dependent on functional activation through multiple tumor cell lysis events. Although it is known that T cell populations undergo activation, expansion, and subsequent contraction, our results provide direct linkage to functional activation at the single-cell level modulating T-cell fate, in vitro (Fig. 1B). Comparisons of the CAR8 cells and CAR4 cells demonstrated that CAR8 cells underwent AICD faster than CAR4 cells, upon antigen limitation. Together, these data are consistent with observations made in the clinic, where CAR+ T cells regulate their numbers based on the tumor bioburden i.e. they proliferate to greater numbers after infusion to respond to a large number of tumor cells, and then decreased in numbers as tumor cells were killed by the CAR+ T cells.2,10 Overall, our short TIMING data (12 h) suggest that multi-killing, GzB content, and resistance to AICD may serve as critical components in determining the functional attributes of the inoculum that contribute to overall therapeutic success.
Facing the future: challenges and opportunities in adoptive T cell therapy in cancer
Published in Expert Opinion on Biological Therapy, 2019
Isabelle Magalhaes, Claudia Carvalho-Queiroz, Ciputra Adijaya Hartana, Andreas Kaiser, Ana Lukic, Michael Mints, Ola Nilsson, Hans Grönlund, Jonas Mattsson, Sofia Berglund
IL-2 is the most extensively used cytokine, and well known to efficiently promote proliferation of cultured T cells. It is, however, also known to stimulate to differentiation, especially in high concentrations and with longer culture time [75], while lower concentrations and short-term culture result in maintenance of less differentiated phenotypes [20,75,82]. The high IL-2 concentrations used in the REP TIL protocol (6000 IU/ml culture medium) were found to result in downregulation of CD62L and CD27, and to a lesser extent CD28, indicating loss of less differentiated memory T cells [20] (Table 1). IL-2 has been associated with activation-induced cell death as well. This has resulted in a change of strategy toward exchanging or combining IL-2 with other cytokines, such as IL-4, IL-7, IL-15, and IL-21 [78,83–91], or toward altering the concentration and timing of IL-2 administration [82,92,93]. Different strategies are summarized in Table 1.
Tumor mutational burden is a determinant of immune-mediated survival in breast cancer
Published in OncoImmunology, 2018
Alexandra Thomas, Eric D. Routh, Ashok Pullikuth, Guangxu Jin, Jing Su, Jeff W. Chou, Katherine A. Hoadley, Cristin Print, Nick Knowlton, Michael A. Black, Sandra Demaria, Ena Wang, Davide Bedognetti, Wendell D. Jones, Gaurav A. Mehta, Michael L. Gatza, Charles M. Perou, David B. Page, Pierre Triozzi, Lance D. Miller
Intriguingly, we identified significant and reproducible copy number gains in PID tumors involving genes on chromosome 1q associated with immune regulation. While amplification events at the gene-dense 1q locus occur in 50% or more of breast tumors,40 “driver” genes with immune regulatory functions have not been proposed. In our analysis, amplified immune genes were identified by the significant enrichment of immune-related ontology terms. Interleukin-10 (encoded by the IL10 gene) is an immunosuppressive cytokine known to inhibit tumor-specific type 1 immune responses.41 Fas ligand (FASLG) promotes activation-induced cell death (AICD) of activated T and B cells42 and is believed to confer immune privilege to tumors by inducing apoptosis in tumor infiltrating lymphocytes.43 Serpin Family C Member 1 (SERPINC1), also known as Antithrombin III, is a known inhibitor of T cell-derived Granzyme A.44,45 The reproducible PID-enriched amplification of these genes suggests the possibility that amplification of one or more of these genes, alone or in combination, may play a functional role in immune escape that contributes to the immunologically cold phenotype of the PID immune subclass.