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Clinical Applications of Gene Therapy for Immuno-Deficiencies
Published in Yashwant Pathak, Gene Delivery, 2022
Khushboo Faldu, Sakshi Gurbani, Jigna Shah
X-SCID is an X-linked disorder that mutates the common cytokine receptor gamma chain [interleukin 2 receptor subunit gamma (IL2RG) gene], prevents normal development and functioning of the lymphocytes, and produces deficits in cellular and humoral immunity. Infants suffering from severe infections are the first signs of clinical presentation. Treatment involves alloHSCT or HSC-GT for the prevention of mortality [40]. γRV vectors were initially utilized, which provided successful immune reconstitution and persistence of gene-marked cells, but led to the development of T-cell lymphoblastic leukemia [41, 42]. To overcome insertional mutagenesis, SIN- γRV and SIN-LV vectors were developed. HSC-GT is being evaluated in numerous clinical studies for X-SCID.
Dissecting Importance of B Cells versus T Cells in Rotavirus Vaccine-Induced Immunity Using Gene Knockout Gn Pigs
Published in Lijuan Yuan, Vaccine Efficacy Evaluation, 2022
In the current study, we had a low number of HCKO pigs in some treatment groups because using somatic cell nuclear transfer (SCNT) and cloning technology to generate genetically modified pigs, such as the HCKO pigs, can be challenging at times. These processes are labor-intensive and inefficient. In addition, pigs generated through SCNT often show developmental defects, which is the reason for the high mortality rate at birth observed in HCKO pigs in this study (data not shown) and other studies with genetically modified pigs using SCNT. However, in recent years the explosive development in porcine gene-editing technologies based on meganucleases (Zinc Finger Nucleases, Tal effector nucleases, CRISPR/Cas9) has provided new tools that may help to get around the need for SCNT for developing genetically modified pigs with much higher efficiency at lower costs (Lee et al., 2014; Sato et al., 2014; Wei et al., 2013). Genetically modified pigs are becoming more readily available for the study of mechanisms of protective immunity against human viral diseases. In addition to using the B cell-deficient HCKO Gn pigs, future studies using other genetically modified pigs, such as IgA-deficient, IgG-deficient, CD8-deficient (CD8α–/–), αβ T cell–deficient (αβ TCR –/–), γδ T cell–deficient (γδ TLR –/–), αβ and γδ T cell–deficient (αβ/γδ TLR –/–), and SCID pig (Rag2 –/– and IL2RG –/–) will greatly further advance the understanding of mechanisms of rotavirus protective immunity and the field of viral immunity research in general. After this study using HCKO Gn pigs, we have also used RAG2-/IL2RG– Gn pigs that were generated with CRISPR/Cas9 technology in a study of HuNoV infection and immunity (Lei et al., 2016b).
Leukaemias of Mature B- and T/NK-Cells
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
PLL is a rare, aggressive form of a mature leukaemia which is distinct from CLL, and comprises of B-cell (B-PLL) and T-cell (T-PLL) subtypes. Though similar, each subtype has characteristic morphologic, phenotypic, cytogenetic and molecular features (Figure 9.18). It probably accounts for <2% of the mature lymphoid leukaemias affecting adults, and less than 1% of CLL patients who transform into PLL. Most patients present with constitutional symptoms characterized by symptomatic splenomegaly, lymphadenopathy, erythematous or nodular rashes, and about 25% have pleuro-peritoneal effusions; lymphocytosis, often >100 × 109/L, is not uncommon. In T-PLL, inv(14)(q11q23) and t(14;14)(q11q23) are observed in about 70% and t(x;14)(q28q11) in 20% of patients; abnormalities in chromosome 8 are also common. Rearrangements between the TCR gene (on chromosome 14) and the TCL-1, TCL-1B or MTCP-1 (on chromosome X) result in oncoproteins via activation of AKT and may be important in the molecular pathogenesis of the disease. About 75% of patients with T-PLL harbour abnormalities in the ATM gene, and in the JAK-STAT pathway, in particular IL2RG, JAK-1, JAK-3 and STAT-5B. Rare mutations involving EZH2, FBXW10 and CHEK2 have also been observed, in addition to a unique case report involving the SEPT9-ABL1 fusion. In contrast, about half of the patients with B-PLL have abnormal cytogenetics, in particular (8;14) or del(17p), and molecular genetics, with TP53 mutations or deletions, and MYC abnormalities. There is some genetic overlap between B-PLL and other B-lymphoid malignancies in the MCL, SMZL and HCL variants.
Diagnostic signature and immune characteristic of aging-related genes from placentas in Preeclampsia
Published in Clinical and Experimental Hypertension, 2022
Xiufang Wang, Andong He, Ka Cheuk Yip, Xiaoting Liu, Ruiman Li
The imbalances of immune function and angiogenetic-antiangiogenetic system are long known to be involved in PE (29). Based on aging-related DEGs, we classified the PE samples into three subtypes and investigated the potential roles of immune characteristics and angiogenesis in the pathogenesis of PE. The enriched pathways, including HIF-1 and MAPK pathway, indicated that hypoxic stimulation and abnormal cell behavior may exist during placental aging in PE. Although placental hypoxia, oxidative stress, and placental aging may be one of the essential features of PE, the molecular association between them requires more experimental validation. According to the present results, several immune cells, such as activated CD8 T cell, T follicular helper cell, and Type 17 T helper cell, may be associated with placental aging, and IL2RG may be a potential important aging-related gene in PE. IL2RG plays an essential role in the T-cell development, so this gene may have a close relationship with immune function (30). Notably, we noticed that IL2RG has been identified in PE in another study (31), although the exact role of it in this disease remains unknown. Additionally, some proteins, such as Alpha klotho, may play roles in vascular-mediated placental aging (32), and we identified several aging-related genes, including STC1, VEGFA, TIMP1, PRG2, and LUM, may be involved in angiogenesis in PE. The associations between placental aging and angiogenesis may deserve further exploration.
Identification of IL2RG and CYBB mutations in two Chinese primary immunodeficiency patients by whole-exome sequencing
Published in Immunological Investigations, 2018
Shanshan Xu, Qiyuan Li, Jinzhun Wu, Guobing Chen, Bizhen Zhu, Weiyue Gu
In patient 1, we found a novel mutation in IL2RG gene. The mutation c.794T>A (p.I265N) had not yet been reported in the Human Gene Mutation Database, the 1000 Genomes Database, or the NHLBI GO Exome Sequencing Project Database at the time of writing. The novel missense mutation c.794T>A (p.I265N) was predicted to be “probably damaging” with a score of 0.936 by the PolyPhen-2 software, to “affect protein function” with a score of 0.01 by the SIFT software, and was placed in the “disease-causing” class by the Mutation Taster software. The potential 3D structure changes in the protein induced by the novel missense mutation were predicted by Swiss PDB Viewer. The wild-type and mutant IL2RG protein 3D structure models are illustrated in Figure 3.
Long Term Follow-Up of the Patients with Severe Combined Immunodeficiency After Hematopoietic Stem Cell Transplantation: A Single-Center Study
Published in Immunological Investigations, 2022
Duygu Demirtas, Deniz Cagdas, Tuba Turul Ozgur, Baris Kuskonmaz, Duygu Uckan Cetinkaya, Ozden Sanal, Ilhan Tezcan
In the United States, IL2RG genetic defect was found in 19% of SCID patients who were diagnosed by newborn screening whereas it is nearly half in published cohorts (Kwan et al. 2014). The IL2RG ratio in the genetic defects detected in our study is 20.6%. The most common genetic defects are; RAG1/2 (38.2%) and Artemis (23.5%). Genetic defects related to molecules involved in DNA repair mechanisms inherited as autosomal recessive trait are frequently seen in our population. This may be attributed to the high consanguineous marriage frequency in Turkey (18.5%) (Kaplan et al. 2016). Although consanguineous marriage is a disadvantage for the occurrence of autosomal recessive SCID, it also provides increased chance to find a HLA identical donor in the family.