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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
CD40 ligand (CD40L, CD154) is a cell-surface molecule predominantly expressed by activated CD4+ T lymphocytes. Interaction of CD40L with its counter-receptor CD40 on the surface of B cells is essential for germinal center formation and class-switch recombination. Furthermore, CD40 is also expressed on dendritic cells, macrophages, and activated endothelial and epithelial cells. Interaction of CD40L-expressing CD4+ T cells with these cell types promotes B- and T-cell priming triggering protective responses against intracellular pathogens. Mutations in the CD40LG gene, mapping at Xq26, result in X-linked hyper-IgM syndrome (also known as type 1 hyper-IgM syndrome), a combined immunodeficiency characterized by an increased occurrence of bacterial and opportunistic infections, neutropenia, a high incidence of liver and biliary tract disease, increased risk of malignancies, and a high mortality rate.
T Cells:Regulation and Cellular Immunity
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
Membrane phosphatidylethanolamine is converted to phosphatidylcholine which is subsequently metabolized to arachidonic acid. This enters the lipoxygenase pathway with production of leukotrienes and activation of guanylate cyclase. A combination of all of these mechanisms along with calcium fluxes leads to altered patterns of gene expression. CD40L is expressed, and binds to CD40 on the surface of the antigen-presenting cell. This induces the APC to express B7 (CD80), the ligand for CD28. Activation of the genes for IL-2 and other lymphokines is calcium-dependent, while activation of the IL-2Ra gene is not. Establishment of a particular pattern of cytokine synthesis depends on unknown factors (see Figure 6–11 for some possibilities). The surface markers which are up-regulated in activated T cells are listed in Table 6–VI.
Influencing tumor-associated macrophages in malignant melanoma with monoclonal antibodies
Published in OncoImmunology, 2022
Rebecca Adams, Gabriel Osborn, Bipashna Mukhia, Roman Laddach, Zena Willsmore, Alicia Chenoweth, Jenny L C Geh, Alastair D MacKenzie Ross, Ciaran Healy, Linda Barber, Sophia Tsoka, Victoria Sanz-Moreno, Katie E Lacy, Sophia N Karagiannis
CD40 is a target of significant interest in many solid cancers, including melanoma. CD40 is expressed on antigen presenting cells, including macrophages. Once bound by CD40 ligand on T cells, it can stimulate macrophages to produce pro-inflammatory cytokines, as well as to engage in direct target cell killing.96 Several clinical trials have looked at the potential of CD40 agonists as a monotherapy for treatment-resistant solid tumors. For example, a trial of selicrelumab, a human IgG2 agonistic mAb against CD40, in 15 patients with melanoma, demonstrated a partial response in 4 patients, some of which were long-lasting responses.97 More recently, selicrelumab in combination with CTLA-4 inhibition showed an overall response rate of 27.3% compared with 10.7% in the anti-CTLA-4 only arm.98–100 There are currently no ongoing trials further exploring selicrelumab in melanoma. APX005M and SEA-CD40 are both humanized IgG1 agonistic CD40 mAbs currently tested in melanoma in multiple phase 2 trials, in combination with pembrolizumab (NCT02706353, NCT04337931, NCT04993677, see Table 2). Furthermore, CDX-1140 is a human IgG2 mAb being trialed in combination with a melanoma peptide vaccine and a TLR agonist (NCT04364230). Results from these trials are awaited.
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.
IRAK1 Gene Polymorphism in Rheumatoid Arthritis
Published in Immunological Investigations, 2021
Najme Hosseini, Mohammad Taher Tahoori, Adel Mohammadzadeh, Hossein Zarei Jaliani, Morteza Bitaraf Sani, Hosein Soleimani Salehabadi
Several investigations have indicated the essential role of CD40 in a large number of chronic inflammatory and autoimmune diseases. CD40 involvement in RA pathogenesis has been investigated for several years and its overexpression has been reported in CD4+ and CD8+ T-cells and monocytes in synovial fluid of RA patients. Also, it is now known that CD40 engagement in RA patients and healthy subjects generate IgM anti-cyclic citrullinated peptide antibodies by B-cells. CD40 also induces the expression of vascular endothelial growth factor (VEGF) and receptor activator of nuclear factor kappa-Β ligand (RANKL) in synovial fibroblasts, which potentiate the progression and severity of RA. Moreover, the expression of RANKL results in bone erosion mediated by osteoclasts (Román-Fernández et al. 2016).