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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
Regulatory T cells (Tregs) prevent autoimmunity as they control immune response to self-antigens. IPEX syndrome develops due to the defects in transcription factor fork head box P3 (FoxP3) that are essential for the normal development and functioning of Tregs. IPEX syndrome clinically presents itself as eczema, enteropathy, and type I diabetes mellitus. Treatment involves prolonged immunosuppression and alloHSCT, but immune-mediated complications can limit its efficacy [83]. The T-cell approach lacks capability for the generation of an adequate amount of Tregs to improve clinical phenotype [84]. HSC-GT is challenging as FoxP3 expression in HSCs prevents proliferation and differentiation of the stem cells. The SIN-LV vector incorporating the endogenous FoxP3 promoter and regulatory elements has shown favourable results that induced lineage-specific expression in progeny of transduced HSCs [84–86].
T lymphocyte populations within the lamina propria
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Thomas T. MacDonald, Antonio Di Sabatino
Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a very rare X-linked disease where mutations in Foxp3 lead to defective regulatory T-cell activity. It is often used as an example of how regulatory T-cell defects cause colitis. Virtually all of these children have small bowel inflammation, and some have colitis. The gut manifestations, however, go alongside chronic inflammation in the pancreas and other endocrine organs, kidneys, liver, and skin; there is often anemia and/or thrombocytopenia, autoantibodies, and a generalized lymphadenopathy. It is therefore possible that children with IPEX have a general autoreactivity to self-antigens, with the gut tissue as a target of autoimmune attack because the gut is also an endocrine organ. The scurfy mouse also has mutations in Foxp3 but does not appear to have colitis; instead, the mouse dies at about 3–4 weeks of age showing lymphohistiocytic infiltration of many tissues and lymphadenopathy. Both of these situations differ markedly from human IBD, where, especially for Crohn's disease, pathologic manifestations in tissues other than the gut are generally thought to be a consequence of the gut lesions. It is also worth noting that prior to the development of the transfer model of colitis in lymphopenic mice, there was an extensive literature in the rat where transfer of naive T cells into athymic animals caused generalized autoimmune disease, including colitis.
Gastroenterology
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
A rare disorder, recognised in European, Arab, North American and Japanese children. There is evidence of a genetic predisposition with both a high incidence of autoimmune disease in first-degree relatives and, in some families, apparent X-linked, recessive inheritance (overall male to female ratio 2:1). IPEX syndrome is one inherited form, characterised by the association of autoimmune enteropathy with polyendocrinopoathy and immunodysregulation (linked to dysfunction of the transcriptional activator FoxP3).
The role of TNF-α and anti-TNF-α agents in the immunopathogenesis and management of immune dysregulation in primary immunodeficiency diseases
Published in Immunopharmacology and Immunotoxicology, 2022
Sharafudeen Dahiru Abubakar, Stella Amarachi Ihim, Amir Farshchi, Shayan Maleknia, Hamisu Abdullahi, Takanori Sasaki, Gholamreza Azizi
Infliximab was reported to control diarrhea and IBD-like complication in monogenic PID including IPEX syndrome, autoimmune infiltration and enteropathy (LATAIE) patients, cytotoxic T lymphocyte antigen 4 haploinsufficiency with autoimmune infiltration (CHAI) and lipopolysaccharide- responsive beige- like anchor deficiency with autoantibodies and regulatory T cell defects patients [86–88]. The application of infliximab was reported for the treatment of 4.8% of CHAI and 7.1% of LATAIE patients [86]. Infliximab therapy induces clinical resolution of gastrointestinal manifestations and sacroiliitis that concurs with increased circulating FOXP3+ T cells in patient with IPEX syndrome. Infliximab therapy has been showed to rapidly control back pain as well as digestive improvement and also reduced serum inflammatory markers in patients with IPEX syndrome. Corresponding to this observation, flow cytometry analysis revealed an increase in the frequency of circulating CD4+FOXP3+ Treg cells. Put together, these findings show that anti-TNF-α may represent a capable therapeutic option in patients with IPEX syndrome [89]. However, it has been reported that infliximab is not effective in all patients with STAT3 GOF mutation with manifestations of autoimmune cytopenia, enteropathy and lymphoproliferation [52].
CD4+CD25-FoxP3+ T cells: a distinct subset or a heterogeneous population?
Published in International Reviews of Immunology, 2021
Mahshid Zohouri, Fereshteh Mehdipour, Mahboobeh Razmkhah, Zahra Faghih, Abbas Ghaderi
In 1997, another type of immune dysregulation, i.e., polyendocrinopathy, enteropathy, x-linked (IPEX) syndrome, was reported to be associated with normal FoxP3 expression but deficient CD25 expression.81 Therefore, the disease was subdivided further to “classic IPEX” and “IPEX-like” phenotype.82 About nine cases have been published to date.81,83–88 These patients have near-normal lymphocyte counts; however, because IL-2–CD25 interaction is necessary for both effector and regulatory T cell function, they present with features of both immunodeficiency and autoimmunity.89 Although they exhibit features similar to FoxP3-deficient IPEX, they are unique in their profound susceptibility to viral, fungal and bacterial infections.90 Furthermore, in proliferation assays their CD25-deficient cells demonstrate lower proliferative capacity than Tregs in response to TCR stimulation and IL-2 83,88 but express high levels of Ki-67.86 These cells show features of memory T cells,85,86 and produce IL-1088 and IFN-γ, but not significant amounts of IL-4 or IL-17.83 Because all CD4+FoxP3+ cells in these patients are negative for CD25 and at the same time have features of immune dysregulation, it is conceivable that CD4+CD25‒FoxP3+ T cells are not a subtype of either regulatory or effector T cells.
Association study of FOXP3 gene and the risk of 0020 pre-eclampsia
Published in Clinical and Experimental Hypertension, 2018
Milad Gholami, Reza Mirfakhraie, Reihaneh Pirjani, Robabeh Taheripanah, Sahar Bayat, Seyyedeh Anita Daryabari, Matina Noori, Sayyed Mohamad Hossein Ghaderian
Normal pregnancy requires maternal immunological tolerance to the semi allogeneic fetus (18). Tregs are thought to play an important role in immune suppression, and are involved in the pathogenesis of a variety of autoimmune disorders, including multiple sclerosis, lupus, type I diabetes, and rheumatoid arthritis (19). Tregs also participate in mediating human maternal tolerance to the fetus (20). In a recent study, Treg CD4+CD25+FoxP3+ cells were diminished both in number and functional activity in PE patients compared with normal pregnancies (21). FOXP3 mutations has been identified in patients with immune dysregulation polyendocrinopathy and enteropathy X-linked (IPEX) syndrome disorder (11). FOXP3 expression now serves as the most specific marker of Tregs and it has been used to determine the proportion of Tregs in humans with a variety of disease states (22). Down-regulation of FOXP3 in PE has been reported in previous studies and thus results in the decreased number of FOXP3 regulatory T cells in preeclampsia, however, the mechanism involved in is still unclear (23,24). Therefore, we assumed that FOXP3 variants might be involved in development of PE via quantitative and functional influences on T-regsCD4+CD25+.