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Brooke–Spiegler Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
By removing lys63-linked ubiquitin chains from several specific substrates, CYLD deubiquitinates several NF-kappa-B regulators (e.g., TRAF2, TRAF6, NEMO [IKBKG], and BCL3), and negatively regulates the nuclear factor-kappa B and c-Jun N-terminal kinase pathways [6]. Therefore, inhibition or loss of CYLD deubiquitinating activity enhances constitutive activation of transcription factor NF-kappa-B, increases resistance to apoptosis, and contributes to hyperproliferation and tumorigenesis. Indeed, reduced CYLD level induces B-cell lymphoma-3/p50/p52-dependent nuclear factor-κB activation and triggers the expression of genes encoding cyclin D1 and N-cadherin. In turn, elevated levels of cyclin D1 and N-cadherin promote melanoma proliferation and invasion [7,8].
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
The nuclear factor kappa B (NF-κB) is a multimeric transcription factor that regulates a variety of cellular processes, including innate and adaptive immune responses. Activation of NF-κB is regulated by a complex consisting of two catalytic protein subunits with kinase activity (IKKα and IKKβ) and a regulatory component, IKKγ (also known as NF-κB essential modulator, or NEMO), which function to phosphorylate and deactivate IκB, an inhibitor of NF-κB. NEMO is encoded by a gene (IKBKG) located on the X chromosome. In humans, null IKBKG gene mutations lead to incontinentia pigmenti in heterozygous females, and result in embryonic lethality in males. In contrast, hypomorphic mutations in males result in X-linked immunodeficiency with ectodermal dystrophy. Typical manifestations of the disease include scanty hair, defective tooth formation with conical teeth, nail defects, hypohidrosis, increased susceptibility to recurrent infections (including mycobacterial disease), and aberrant inflammatory responses. Most patients show hypogammaglobulinemia, with reduced IgG levels and defective antibody responses. Impaired T-cell priming and defective cytolytic function of NK cells are also present. There is significant variability in the severity of the clinical phenotype. Treatment is based on immunoglobulin replacement therapy and prompt treatment of infections.
Approach to hypopigmentation
Published in Electra Nicolaidou, Clio Dessinioti, Andreas D. Katsambas, Hypopigmentation, 2019
Clio Dessinioti, Andreas D. Katsambas
Incontinentia pigmenti (IP) is a rare, hereditary, X-linked dominant disorder that may present with hypopigmentation in adult life. IP is usually lethal in males, so female patients are almost exclusively recognized (92%). IKBKG (previously NEMO) is the gene known to be associated with IP.15 Stages of skin changes in IP include stage 1 (vesiculo-bullous stage), stage 2 (verrucous stage), and stage 3 (hyperpigmented stage). The fourth stage (atrophic/hypopigmented stage) may present in approximately 13% of patients with IP. Hypopigmentation presents as swirls of atrophic hypopigmented or depigmented bands of streaks along the Blaschko lines, which are also hypohydrotic and hairless. Reduction of melanin in the epidermis has been described. The hypopigmented lesions present in adult life. Extracutaneous abnormalities are frequent3 (Table 2.2). Diagnostic criteria have been proposed.15
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
NEMO deficiency, which X-linked disease caused by mutations in the IKBKG gene, presents two clinically different diseases, incontinentia pigmenti (IP) and anhidrotic ectodermal dysplasia, with immunodeficiency (EDA-ID). EDA-ID patients are hemizygous for a NEMO mutation and always in males. While the complete LOF mutation of NEMO is prenatally lethal in males and causes IP in females because of random X-chromosome inactivation. NEMO deficiency is characterized by antibody deficiency, low NK cell function, and normal T cell numbers and function, and some patients have elevated IgM and IgA [56–58]. EDA-ID suffers from infections most caused by mycobacteria, invasive pyogenic bacteria, and sometimes viruses, parasites, and fungi [59]. Patients with homozygous loss-of-function mutations in IKBKB have the manifestation of hypogammaglobulinemia, an abundance of naïve B and T cells. These patients may have bacterial, viral, or fungal infections with or without exhibiting clinical EDA signs and occasionally CID depending on mutation [60]. Patients with the IkB alpha (IKBA) deficiency experienced variable degrees of EDA-ID as well as a higher risk of developing atypical mycobacterial infections. These patients have similar immunologic profiles of NEMO deficiency [61].
Curcumin mediates autophagy and apoptosis in granulosa cells: a study of integrated network pharmacology and molecular docking to elucidate toxicological mechanisms
Published in Drug and Chemical Toxicology, 2022
Zhen Lin, Huazhong Liu, Chunyan Yang, Haiying Zheng, Yu Zhang, Weiming Su, Jianghua Shang
KEGG Mapper tool further substantiated the biological regulation of Cur target proteins and screened out three key targets that regulate apoptosis, namely IKK (CHUK, IKBKB, IKBKG), NF-κB (NFKB1), and Proto-oncogene c-Fos (FOS). These three molecules are distributed in two branches with opposite functions of pro-survival and pro-apoptosis, both of which were regulated by the MAPK signaling pathway (Eferl and Wagner 2003, Hayden and Ghosh 2004). Molecular docking verified that Cur could stably bind to two catalytic subunits CHUK and IKBKB. Moreover, the interaction between Cur and amino acids around the binding site was similar to the positive ligands. Previous studies have shown that Cur has inhibitory effects on IKK/NF-κB downstream of the MAPK signal pathway, which is a double-edged sword that can inhibit and promote apoptosis (Duarte et al.2010, Wang et al.2020).
Transcriptional regulation of B cell class-switch recombination: the role in development of noninfectious complications
Published in Expert Review of Clinical Immunology, 2022
Stelios Vlachiotis, Hassan Abolhassani
Other clinical phenotypes that have been demonstrated by patients with CSR defects are noninfectious, non-autoimmune enteropathies that are most likely due to the local function of these proteins in the mucosal layers of the gastrointestinal tract. Gene defects with these presentations constitute Tfh co-stimulation defects (ICOS/ICOSL and CTLA4/LRBA/DEF and RIPK1 deficiencies), NF-κB pathway defects (NF-κB1/2 and IKBKG deficiencies), and cytokine stimulations (IL21/R and BACH2 deficiencies) [52,133–137]. Many unsolved CSR-defect patients presenting with common variable immunodeficiency with normal peripheral B cells but decreased levels of IgG, IgA, and/or IgM also display this phenotype that can be a consequence of lack of IgA in the mucosal layer, microbiota dysbiosis, initiation of systemic inflammatory responses, specific human leukocyte antigen (HLA) genotypes, and also specific innate immune cell interactions [138–140]. Atopy including allergic manifestations, hypersensitivity reactions, and asthma can be also detected in a minority of patients mainly with cytokine stimulation (IL-6 and STAT3 deficiencies) and PI3K signaling (mainly PIK3CG and PLCG2 deficiencies) defects [52,137,141]. Finally, other functional defects can be observed in connective tissues, cardiovascular and dermatologic systems with CSR-defect patients that have been listed in Table 1 [52,141].