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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.
B Cells and Humoral Immunity
Published in Constantin A. Bona, Francisco A. Bonilla, Textbook of Immunology, 2019
Constantin A. Bona, Francisco A. Bonilla
CD40 is a receptor for CD40 ligand (CD40L), a protein found on the surface of activated T cells. CD40 plays a central role in antigen-dependent B cell development in lymphoid tissues (see below). The interaction of CD40 with its ligand prevents B cell death in germinal centers, and promotes Ig class-switching of activated B cells. Binding of CD40 in the presence of interleukin-4 results in an increase in class-switching to IgG and IgE. In the presence of transforming growth factor-β, switching to IgA is promoted. The absence of CD40L on the T cell surface due to a genetic defect results in a form of immune deficiency known as the X-linked hyper-IgM syndrome. Patients with this condition have normal or high levels of IgM and little or no IgG and IgA. These patients often have recurrent bacterial infections, particularly of the upper and lower respiratory tract.
Tolerance and autoimmunity
Published in Gabriel Virella, Medical Immunology, 2019
George C. Tsokos, Gabriel Virella
Thus, the sum of experimental data suggests that B-cell tolerance can result both from clonal anergy and clonal deletion, and the choice of mechanism depends on whether the antigen is soluble or membrane bound. Clonal deletion involves apoptosis of the self-reactive cells, but we do not know why only membrane-bound antigens appear to trigger apoptosis. B-cell anergy, conversely, is associated with a block in the transduction of the activating signal resulting from the binding of antigen to the membrane immunoglobulin, probably consequent to the lack of costimulatory signals usually delivered by activated Th2 cells. Experimental data suggest that the signal delivered to CD40+ B cells by interacting with the CD40 ligand expressed by T cells is critically important for B-cell differentiation. In the absence of CD40 signaling, B cells are easy to tolerize.
How do nuclear factor kappa B (NF-κB)1 and NF-κB2 defects lead to the incidence of clinical and immunological manifestations of inborn errors of immunity?
Published in Expert Review of Clinical Immunology, 2023
Nazanin Fathi, Hanieh Mojtahedi, Marzieh Nasiri, Hassan Abolhassani, Mahsa Yousefpour Marzbali, Marzie Esmaeili, Fereshte Salami, Furozan Biglari, Nima Rezaei
Antibody CSR is critical for more effective responses of the humoral immune. Although mature naive B cells make IgM antibodies or exhibit IgM as a surface BCR, IgM’s effector capabilities are very constrained. IgG and IgA are isotype-switched antibodies that can neutralize toxins and restrict infectious considerably more effectively than IgM. Current vaccines frequently develop isotype-switched antibodies, which have protective effects. The BCR cannot produce CSR without co-stimulation, according to the prevalent theory of Class-switch recombination (CSR) induction. For T-cell dependent (TD) antigens, CD40 ligand (CD40L) provides co-stimulatory signals, which are forwarded by activated T cells, or TLR ligands, which are either expressed by pathogens or adjuvants for antigens that are T-cell independent (TI). Stimulation of the BCR results in the activation of the transcription factor NF-κB1. NF-κB1 p50/RelA also stimulates the transcription of NF-κB2 p100. The p50/RelA and p52/RelB complex, together with other factors, induce activation-induced deaminase (AID) transcription. Notably, activation of NF-κB2 is required for the BCR signaling that induces CSR but not necessarily for TLR4 or CD40 [54]. So, the collaboration of both NF-κB1 and NF-κB2 leads to AID expressions. Defects in the components of these pathways, such as NF-κBs, could lead to hypogammaglobulinemia, as the experimental model showed that p50−/− primary mouse showed defects in B cells in AID expression and CSR [55].
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.
The discovery and development of oncolytic viruses: are they the future of cancer immunotherapy?
Published in Expert Opinion on Drug Discovery, 2021
Shunchuan Zhang, Samuel D Rabkin
In addition to ICI, co-stimulatory checkpoints can also be targeted for immunotherapy, using ligands or agonistic antibodies [30]. CD40 ligand (CD40L), encoded in CGTG-401 (Table 2), was used to treat a small number of patients with advanced solid tumors, who then displayed immune-mediated effects [119]. OX40L and GITRL were also encoded in oAd Delta-24-RGD (DNX-2240 and Delta-24-GREAT, respectively) (Table 2). Compared to Delta-24-RGD, DNX-2240 treatment of orthotopic tumors increased activated TILs and significantly extended survival, but not in immunodeficient mice, which was further extended by anti-PD-L1 treatment [120]. In a metastatic melanoma model, Delta-24-RGDOX injection of a subcutaneous tumor also inhibited an intracerebral tumor, an abscopal effect [121]. Treatment induced systemic increases in effector CD4+ and CD8 + T cells and reduced the frequency of exhausted TILs and regulatory T cells [121]. Delta-24-GREAT elicited similar anti-tumor efficacy in the same glioma model and both oAds protected ‘cured’ mice from tumor rechallenge [121,122]. To enhance efficacy, two co-stimulatory ligands (trimerized-CD40L and 4–1BBL) were encoded by oAd LOAd-703 and evaluated in clinical trials (Table 2). Because LOAd doesn’t infect or replicate in mouse cells, preclinical studies were performed mostly in human cells in vitro, with no striking differences detected between LOAd-703 and LOAd or LOAd-CD40L [123,124].