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Immunology
Published in M. Alan Menter, Caitriona Ryan, Psoriasis, 2017
IL-23 is composed of two chains: the unique p19 (IL-23R) chain and the p40 (IL-12Rβ1) chain which is shared with IL-12. IL-23p19 and IL-12/23p40 messenger RNA (mRNA) are strongly unregulated in psoriatic lesions, and variants in the genes for the IL-23 receptor and the p19 subunit are linked to psoriasis susceptibility in genome-wide association studies.2,50,51 IL-23 induces differentiation of Th17 cells and Th22 cells, and abundant IL-23 is produced by both BDCA-1- inflammatory DCs and BDCA-1+ resident DCs, as well as macrophages in psoriatic lesions.2,38,52
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).
Human Genetic Variability and Susceptibility to Infectious Diseases
Published in Thomas R. O’Brien, Chemokine Receptors and AIDS, 2019
Idiopathic disseminated infections with weakly pathogenic mycobacterias, such as NTM and the attenuated strain of M bovis used for vaccination (BCG), are very rare and severe conditions. Familial forms of this condition, along with the high rates of parental consanguinity among affected children, strongly suggest the involvement of a recessive genetic disorder [reviewed in (114)]. Using a linkage study based on homozygosity mapping (115) in affected children from two consanguineous families, two groups located a genetic defect on chromosome region 6q22-q23, and identified mutations in the IFNGR1 gene that encodes the IFN-γ-receptor ligand-binding chain (IFN-γR1) (116, 117). In the first family, four Maltese children infected with NTM were homozygous for a nonsense mutation (116), and in the second, one child with disseminated BCG infection was homozygous for a frameshift deletion (117). Several in vitro experiments established the causative relationship between the presence of two mutated IFNGR1 alleles and the impaired response to IFN-γ by the cells of these patients [reviewed in (114)]. Another child was found to be a compound heterozygote for two null IFNGR1 mutations (118), and additional patients with complete IFN-γR1 deficiency were reported (119). Subsequently, a missense homozygous mutation causing partial, as opposed to complete, IFN-γR1 deficiency was identified in a child with tuberculoid BCG infection (120). This finding suggested a correlation between IFNGR1 genotype and cellular, histopathological and clinical phenotypes (121). More recently, a hotspot (i.e., sequence with an abnormally high frequency of mutations) for small deletions in IFNGR1 that confer dominant susceptibility to NTM and BCG was reported in 12 independent families (122). Homozygous mutations causing these disseminated infections have also been found in three other genes involved in IFN-γ mediated immunity. These mutations are: a null mutation in the IFNGR2 gene, which encodes the IFN-γ receptor signalling chain (IFN-γR2) (123); a large deletion in the IL12B gene, which encodes the p40 subunit of IL-12 (a potent IFN-γ-inducing heterodimeric cytokine secreted by phagocytes and dendritic cells) (124); and several mutations in the IL12RB1 gene, which encodes the βΐ subunit of the IL-12 receptor (IL-12Rpl) that is expressed on NK and T cells (125,126).
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
Cytometric determination of the expression of IL-12Rβ1 (CD212)/IL-12Rβ2 on activated T-lymphocytes and NK cells serves as a diagnostic method to detect AR IL-12Rβ1 and IL-12Rβ2 deficiency. This can be performed on PBMCs after 72 hours of stimulation with phytohemagglutinin (PHA) at 37°C in humidified 5% CO2 incubator. While IL12RB1 defects show an absence of CD212 expression, IL12RB2 defects show an absence of IL-12Rβ2 expression. However, detection of receptor expression on the cell surface may not rule out the underlying disorder (expression of a nonfunctional receptor). In such scenarios, a functional assessment of the cellular responses to IL-12 is required. Although receptor expression analysis can identify almost all IL12RB1 mutations and is easy to perform; a few variants (e.g. 700 + 362_1619-944del, c.21 G > A) can lead to a detectable expression of IL-12Rβ1 protein (nonfunctional) on the plasma membrane [71,72].
Laboratory evaluation of the IFN-γ circuit for the molecular diagnosis of Mendelian susceptibility to mycobacterial disease
Published in Critical Reviews in Clinical Laboratory Sciences, 2018
Ana Esteve-Solé, Ithaisa Sologuren, María Teresa Martínez-Saavedra, Àngela Deyà-Martínez, Carmen Oleaga-Quintas, Rubén Martinez-Barricarte, Andrea Martin-Nalda, Manel Juan, Jean-Laurent Casanova, Carlos Rodriguez-Gallego, Laia Alsina, Jacinta Bustamante
Interestingly, specific clinical manifestations have been associated with specific gene defects: the correlation of pathogens and/or clinical forms with all described genetic etiologies of MSMD was nicely reviewed by Bustamante et al. [2]. Briefly, patients with IFN-γ production defects caused by mutations in IL12RB1 and IL12B (encoding IL-12Rβ1 and IL-12p40, respectively) commonly also suffer from disease caused by Salmonella (recurrent or not) and, to a lesser extent, by Candida. Patients with IFN-γ production defects do not usually present with viral infections. Regarding IFN-γ response defects, the presence of multifocal osteomyelitis should raise the suspicion of a partial autosomal dominant (AD) IFN-γR1, partial AR, or AD STAT1 loss of function (LOF) [36,47–53]. Patients with complete deficiency in IFN-γR1 and IFN-γR2, abolishing IFN-γ response, are more prone to viral diseases such as cytomegalovirus, respiratory syncytial virus and varicella-Zoster virus, among others [2].
Select animal models of colitis and their value in predicting clinical efficacy of biological therapies in ulcerative colitis
Published in Expert Opinion on Drug Discovery, 2021
Janine Bilsborough, Marie F Fiorino, Bradley W Henkle
IL-12 is a heterodimeric protein consisting of a p40 (IL-12p40) and p35 (IL-12p35) subunit. The receptor for IL12 (IL-12R) is a heterodimeric protein comprising IL-12Rβ1 and IL-12Rβ2 Figure 1. Signaling through the receptor induces activation of Janus kinase 2 (JAK2) and tyrosine kinase 2 (TYK2), subsequently activating signal transducer and activator of transcription (STAT) 4. IL-12 is a proinflammatory cytokine primarily produced by antigen presenting cells and modulates T and NK cells to produce IFNγ[75].