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The Inducible Defense System: The Induction and Development of the Inducible Defence
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
Michael A. Hickey, Diane Wallace Taylor
As noted above, macrophages can be activated by contact with cytokine, bacterial compounds, and components of the complement cascade. They can also be activated by direct contact with activated T helper cells. In this interaction, the CD40L on the activated T helper cell binds to CD40 which is constitutively expressed on monocytes and macrophages (Figure 8.10). This interaction, plus a second signal activates macrophages. As noted above, activated macrophages are more efficient in killing both intracellular pathogens (e.g., the bacteria that cause tuberculosis and leprosy) and extracellar bacteria than are resting macrophages. Thus, the Th1 cell greatly enhances the cellular immune response.
The Immune System and Immune Modulation
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
François Hirsch, Guido Kroemer
On theoretical grounds, all cells from the body expressing MHC molecules can serve as APCs. However, certain APCs have specialized features, for instance, dentritic cells (discussed earlier). In addition, the interaction of B and T cells has attracted the interest of immunologists. One important receptor-counterreceptor pair involved in B-T interactions is CD40 and its ligand (CD40L). While CD40 is expressed on dendritic cells, B cells, and activated macrophages [23], CD40L is expressed on activated T cells [24]. Ligation of CD40-CD40L allows for B cell activation and differentiation as well as Ig class switching [25]. The neutralization of this interaction thus has potent immunosuppressive effects.
Mucosal manifestations of immunodeficiencies
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Scott Snapper, Jodie Ouahed, Luigi D. Notarangelo
Patients with CD40L deficiency are at increased risk of malignancies that often involve the gastrointestinal tract. Cholangiocarcinoma, hepatocellular carcinoma, peripheral neuroectodermal tumors, and lymphoma have been frequently reported. Epithelial tumors and dysplasia of the liver and bile ducts in patients with CD40L deficiency are often associated with sclerosing cholangitis, and with infections due to Cryptosporidium, cytomegalovirus, and hepatitis B or C viruses. Sclerosing cholangitis and tumors of the gastrointestinal tract are associated with poor outcomes in patients with CD40L deficiency. In the absence of immune reconstitution, attempts to treat Cryptosporidium-related sclerosing cholangitis with liver transplantation are usually not successful in patients with CD40L deficiency, due to reinfection and relapse of the liver disease. Successful outcome has been reported following combined liver transplantation and HCT in some patients, but even using this approach, disseminated C. parvum infection and death may occur before immune reconstitution is achieved.
Dysregulated translational factors and epigenetic regulations orchestrate in B cells contributing to autoimmune diseases
Published in International Reviews of Immunology, 2023
Ming Yang, Ping Yi, Jiao Jiang, Ming Zhao, Haijing Wu, Qianjin Lu
IL-6 and soluble CD40L (sCD40L) secreted by DCs and macrophages regulate the immune tolerance by inhibiting the antibody production of autoreactive B cells in response to pathogen-associated molecular pattern (PAMP)-induced Toll-like receptor (TLR)4 stimulation. Detailly, ERK serves as an integration point of three signaling pathways initiated by BCR, that is the Ras, the phosphoinositide 3-kinase (PI3K) and the phospholipase C-γ pathway, and low-level ERK signal is defined as tolerogenic ERK [76, 77]. Chronic BCR-mediated and acute IL-6R/CD40-mediated ERK signal restrict nuclear translocation of phosphorylated ERK (pERK) and downregulate the expression of TLR4-) induced Blimp1 and XBP1 to repress Ig production [76]. Besides, IL-21 secreted by Th2, Th17 cells and follicular helper CD4 T cells (Tfh), induces expression of Blimp1 and Bcl6, and reduces Pax5 in activated B cell [78]. CD40L functions as a survival factor of B cells in GC, similarly with B cell activating transcription factor (BAFF) and a proliferation-inducing ligand (APRIL). Type I interferon (TI IFN) could induce the expression of IFN-stimulated gene (ISG) BAFF, and IRF1/2 positively regulate transcription of BAFF, while IRF4 and IRF8 potently suppress it [79]. The translational factor network participated in terminal differentiation of B cells into plasma cells in GC, and their relative changes in the pathogenesis of autoimmune diseases are shown in Figure 2.
State of the art review: coronary artery disease in patients with inflammatory bowel disease: mechanisms, prevalence, and outcomes
Published in Acta Cardiologica, 2022
Faisal Masood, Eli D. Ehrenpreis, Gabrielle Rubin, James Russell, Siddartha Guru, Peter Luzzi
CD40-CD40L both belong to the tumour necrosis factor (TNF) family. CD40 is an integral membrane protein expressed mostly on antigen presenting cells including monocytes/macrophages, B cells, and dendritic cells but can also be found on endothelial cells, platelets, and other types of epithelial cells. CD40’s expression is regulated by proinflammatory cytokines including TNF-a, interferon gamma (IFN-y), CD40L, interleukin-1 (IL-1), and others [2]. CD40L has been found to be expressed on a broad range of haematopoietic cells including but not limited to T cells, basophils, B cells, platelets, endothelial cells, and smooth muscle cells and has been shown to exist in many structural forms including trimeric complexes on cell surfaces along with soluble fractions of CD40L detected in circulation. CD40-CD40L binding results in the recruitment of tumour necrosis factor receptor-associated factors (TRAFs), toll-like receptors (TLRs), and IL-1 receptors. These in turn activate the nuclear factor-kB (NF-kB), phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK), and phospholipase Cy pathways. The overall effect of CD40-CD40L binding includes inflammatory cytokine and chemokine expression, along with signals for cell survival and proliferation [2]. Moreover, CD40-CD40L interaction induces smooth muscle cells (SMCs) and endothelial cells (ECs) to release matrix metalloproteinases. These are molecules that destabilise atherosclerotic plaques [3]. As a result, CD40-40L interaction creates an inflammatory environment with destabilisation of atherosclerotic plaque that are more prone to rupture.
Rationale and clinical development of CD40 agonistic antibodies for cancer immunotherapy
Published in Expert Opinion on Biological Therapy, 2021
Karin Enell Smith, Adnan Deronic, Karin Hägerbrand, Per Norlén, Peter Ellmark
Several CD40 agonistic antibodies, as well as soluble CD40L, have been evaluated in the clinic over the years. Promising single-agent effects have been reported in clinical studies with dacetuzumab (also known as SGN-40) in patients with non-Hodgkin lymphoma [78,79]. In addition, selicrelumab (also known as CP-870,893) induced immune-activating effects, as well as signs of clinical activity, in a dose escalation study of single intravenous doses in 29 patients with advanced solid tumors [65]. Further, Beatty et al. demonstrated an increase in progression-free survival when administering selicrelumab once every three weeks to 22 patients with pancreatic adenocarcinoma [26,80]. Mitazalimab (also known as ADC-1013 or JNJ-64457107) demonstrated early signs of clinical activity in a phase 1 dose escalation study in solid tumors with one partial response [61]. Sotigalimab (also known as APX005M) and Chi Lob 7/4 reported stable disease as the best response in phase 1a studies [81–83]. In addition, a phase 1 study using recombinant human CD40L in cancer patients provided early signs of clinical activity [84].