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Anti-infectious innate and adaptive immune responses
Published in Gabriel Virella, Medical Immunology, 2019
Carl Atkinson, Gabriel Virella
The effective response involves activation of CD4+ Th1 lymphocytes and, particularly, the release of IL-12. The role of IL-12 appears to be critical, because IL-12 receptor deficiency is associated with the predisposition to develop tuberculosis, a classical example of intracellular infection. When properly activated by IL-12, Th1 lymphocytes release a variety of lymphokines, particularly interferon-γ, which activates macrophages and enhances their ability to kill intracellular organisms, and GM-CSF, which promotes differentiation and release of granulocytes and monocytes from the bone marrow. As a consequence of the delivery of activation signals, macrophages and lymphocytes enter into a complex cycle of self and mutual activation involving a variety of cytokines.
Immunology (primary Immunodeficiency Syndromes
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Stephan Strobel, Alison M. Jones
Defects in the interferon-gamma (IFNγ)/IL-12 pathway result in increased susceptibility to intracellular pathogens, especially non-tuberculous mycobacterial infection and Salmonella species. Mutations in several genes can be responsible, including IFNγ receptor, IL-12 receptor beta1 (IL-12Rbeta1) and IL-12 p40 genes.
Ustekinumab
Published in John Y. M. Koo, Ethan C. Levin, Argentina Leon, Jashin J. Wu, Alice B. Gottlieb, Moderate to Severe Psoriasis, 2014
IL-23 is the key cytokine involved in the survival and proliferation of Th17 cells (Figure 13.1) [15,16]. IL-23 is a heterodimeric protein that consists of a unique p19 subunit that is paired with a second subunit called p40 (Figure 13.2). IL-12 is a related heterodimer consisting of p40 and a unique subunit called p35, and it promotes development of Th1 cells (Figure 13.2) [3]. The IL-23 receptor is also a heterodimer consisting of IL-12Rβ1 and IL-23R subunits, whereas the IL-12 receptor is composed of IL-12Rβ1 and IL-12Rβ2 subunits (Figure 13.2).
Biologic treatment of psoriasis in oncologic patients
Published in Expert Opinion on Biological Therapy, 2022
Lluís Rusiñol, Gemma Camiña-Conforto, Luis Puig
As regards ustekinumab – targeting the p40 subunit common to both IL-12 and IL-23 – , its data sheet alerts about its use on patients with previous cancer[21], and IL-12 is considered to induce tumor suppression promoting tumor infiltration by cytotoxic T cells[56]. On the other hand, IL-23 knock-out mice show resistance to tumor induction compared to wild-type mice,(53) and mice genetically deficient in IL-12/23p40 show no increased lifetime risk of developing tumors compared to normal mice[57]. Mice with IL-12Rβ2 (the specific IL-12 receptor subunit) deficiency were found to be more prone to develop node plasmacytoma and lung carcinoma compared to wild-type mice[58]. In summary, IL-12 promotes T helper (Th)1 immunity, with tumor-inhibitory effects, whereas IL-23 promotes Th17 immunity, with tumor-promoting effects, and the balance between IL-12 and IL-23 is important in carcinogenesis; where tumor initiation, growth, and metastasis are concerned, IL-12 may act independently of interferon (IFN)-γ, and IL-23 independently of IL-17A[52,56–58]. Furthermore, IL-23 purportedly has a key role in gut tumorigenesis[59,60].
An updated review on Mendelian susceptibility to mycobacterial diseases– a silver jubilee celebration of its first genetic diagnosis
Published in Expert Review of Clinical Immunology, 2021
Jhumki Das, Aaqib Zaffar Banday, Jitendra Shandilya, Madhubala Sharma, Pandiarajan Vignesh, Amit Rawat
T-helper 1 (Th1) response plays a crucial role in immunity against intracellular microbes with IL-12/IL-23 and IFN-γ being the key cytokines involved in this pathway [8]. The pattern recognition receptors (PRRs) are activated by the bacterial pathogen-associated molecular patterns (PAMPs) when the antigen-presenting cells (APCs) interact with bacteria [9,10]. The consequent activation of APCs induces production of important cytokines like tumor necrosis factor-α (TNF-α), IL-12, and IL-23 [11]. IL-12 aids in the differentiation of naïve T cells into Th1 subpopulation and aids in activation of natural killer (NK) cells and T cells. The IL-12 receptor along with the downstream Janus kinases (JAK2, TYK2) and signal transducer and activator of transcription (STAT)-4 molecules mediate the immunological effects of IL-12. Consequently, IFN-γ secretion is upregulated which activates macrophages and enhances the immune response against intracellular pathogens. Monogenic defects in genes involved in the IL-12/23–IFN-γ circuit result in impaired immunity against intracellular pathogens resulting in clinical phenotypes of MSMD (Figure 2).
Treatment of inflammatory bowel disease from the immunological perspective
Published in Immunological Medicine, 2020
IL-12 and IL-23 are produced by antigen-presenting cells (APCs) during intestinal inflammation [17]. Dendritic cells and macrophages showed increased production of IL-12 (which is composed of the p35 and p40 subunits) and IL-23 (which is composed of the IL-12 p40 subunit and a p19 subunit) during inflammation. IL-12 signals through signal transducers and activator of transcription (STAT) 4 and the central role of this transcription factor plays in skewing naïve Th cells toward the Th1 phenotype has been well documented. IL-23 triggers the heterodimerization of IL-12Rβ1 and IL-23R. Subsequently, signal transduction pathways, including Tyk2 and JAK2/STAT4 and 3, are activated. IL-23 plays an important role in expanding and maintaining the Th-17 cell population. Preclinical studies have implicated IL-12 and IL-23 in the pathophysiology of CD [18]. Ustekinumab is a fully human IgG1k monoclonal antibody that binds to the p40 subunit common to IL-12 and IL-23. As a result, these two cytokines cannot bind to the IL-12 receptor present on the membrane surface of T cells and NK cells.