Disseminated and Congenital Toxoplasmosis in a Mother and Child With Activated PI3-Kinase δ Syndrome Type 2 (APDS2): Case Report and a Literature Review of Toxoplasma Infections in Primary Immunodeficiencies

Karanovic, Djuro; Michelow, Ian C.; Hayward, Anthony R.; Ravin, Suk See De; Delmonte, Ottavia M.; Grigg, Michael E.; Dobbs, Kerry; Niemela, Julie E.; Stoddard, Jennifer; Alhinai, Zaid; Rybak, Natasha; Hernandez, N C; Pittaluga, Stefania; Rosenzweig, Sergio D.; Uzel, Gülbû; Notarangelo, Luigi D.

doi:10.3389/fimmu.2019.00077

Cited by 19 publications

(7 citation statements)

References 52 publications

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“…He had been vaccinated at birth with BCG with referred good tolerance, although he developed a controversial adenomegaly in the first year of life diagnosed from another Center as toxoplasmosis. A susceptibility for toxoplasma infection is reported in patient with APDS (58). The occurrence of a subsequent atypical mycobacterial infection and the susceptibility already reported by Coulter et al (15) such as persistent granulomatous skin lesions after BCG vaccination, underlie the importance of screening these pathogens.…”

Section: Discussionmentioning

confidence: 75%

Case Report: EBV Chronic Infection and Lymphoproliferation in Four APDS Patients: The Challenge of Proper Characterization, Therapy, and Follow-Up

et al. 2021

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Activated PI3K-kinase Delta Syndrome (APDS) is an autosomal-dominant primary immunodeficiency (PID) caused by the constitutive activation of the PI3Kδ kinase. The consequent hyperactivation of the PI3K-Akt-mTOR pathway leads to an impaired T- and B-cells differentiation and function, causing progressive lymphopenia, hypogammaglobulinemia and hyper IgM. Patients with APDS show recurrent sinopulmonary and chronic herpes virus infections, immune dysregulation manifestations, including cytopenia, arthritis, inflammatory enteropathy, and a predisposition to persistent non-neoplastic splenomegaly/lymphoproliferation and lymphoma. The recurrence of the lymphoproliferative disorder and the difficulties in the proper definition of malignancy on histological examination represents the main challenge in the clinical management of APDS patients, since a prompt and correct diagnosis is needed to avoid major complications. Targeted therapies with PI3Kδ-Akt-mTOR pathway pharmacologic inhibitors (i.e., Rapamycin, Theophylline, PI3K inhibitors) represent a good therapeutic strategy. They can also be used as bridge therapies when HSCT is required in order to control refractory symptoms. Indeed, treated patients showed a good tolerance, improved immunologic phenotype and reduced incidence/severity of immune dysregulation manifestations. Here, we describe our experience in the management of four patients, one male affected with APDS1 (P1) and the other three, a male and two females, with APDS2 (P2, P3, P4) presenting with chronic EBV replication, recurrent episodes of immune dysregulation manifestations and lymphomas. These cases highlighted the importance of a tailored and close follow-up, including serial endoscopic and lymph nodes biopsies control to detect a prompt and correct diagnosis and offer the best therapeutic strategy.

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Section: Discussionmentioning

confidence: 75%

Case Report: EBV Chronic Infection and Lymphoproliferation in Four APDS Patients: The Challenge of Proper Characterization, Therapy, and Follow-Up

et al. 2021

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“…AKT1 and PIK3R1 are important members of the PI3K/Akt signaling pathway, which has been found to play a critical role in many physiological and pathological processes in the central nervous system. 58−60 The PI3K/Akt signaling pathway can also affect lymphocyte function, regulate immune defects and immune disorders, 61,62 and affect the survival of pancreas islet β cells and insulin secretion. 63−65 GSK3B is a serine/threonine protein kinase that can modulate immune diseases such as chronic leukemia and autoimmune diseases, 66,67 affect Alzheimer's disease by suppressing tau protein expression, 68 and regulate thyroid function.…”

Section: Discussionmentioning

confidence: 99%

“…We determined seven potential therapeutic targets for the NIM function of LWDH in this study, and the results are listed in Table . AKT1 and PIK3R1 are important members of the PI3K/Akt signaling pathway, which has been found to play a critical role in many physiological and pathological processes in the central nervous system. − The PI3K/Akt signaling pathway can also affect lymphocyte function, regulate immune defects and immune disorders, , and affect the survival of pancreas islet β cells and insulin secretion. − GSK3B is a serine/threonine protein kinase that can modulate immune diseases such as chronic leukemia and autoimmune diseases, , affect Alzheimer’s disease by suppressing tau protein expression, and regulate thyroid function . MAPK9, an important protein kinase in the MAPK signaling pathway, is involved in regulating neurological diseases like epilepsy and cognitive impairment, immune diseases like leukemia and type 1 diabetes, , and metabolic diseases like nonalcoholic fatty liver disease .…”

Section: Discussionmentioning

confidence: 99%

Insights into the Molecular Mechanisms of Liuwei Dihuang Decoction via Network Pharmacology

Chen

Teng

et al. 2020

Chem. Res. Toxicol.

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The traditional Chinese medicines (TCMs) have been used to treat diseases over a long history, but it is still a great challenge to uncover the underlying mechanisms for their therapeutic effects due to the complexity of their ingredients. Based on a novel network pharmacology-based approach, we explored in this study the potential therapeutic targets of Liuwei Dihuang (LWDH) decoction in its neuroendocrine immunomodulation (NIM) function. We not only collected the known targets of the compounds in LWDH but also predicted the targets for these compounds using the balanced substructure-drug-target networkbased inference (bSDTNBI), which is a target prediction method based on network inferring developed by our laboratory. A "target-(pathway)-target" (TPT) network, in which targets of LWDH were connected by relevant pathways, was constructed and divided into several separate modules with strong internal connections. Then the target module that contributes the most to NIM function was determined through a contribution scoring algorithm. Finally, the targets with the highest contribution score to NIM-related diseases in this target module were recommended as potential therapeutic targets of LWDH.

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“…Systemic viral infection caused by CMV, EBV, and HSV are also observed (67,80). Finally, APDS patients are also prone to gastrointestinal bacterial diseases, such as Clostridium difficile infection (78), and parasitic infections, such as toxoplasmosis (81).…”

Section: Insights From Pi3k Mutationsmentioning

confidence: 99%

A Case for Phosphoinositide 3-Kinase–Targeted Therapy for Infectious Disease

Adefemi

Fruman

Marshall

2020

The Journal of Immunology

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PI3Ks activate critical signaling cascades and have multifaceted regulatory functions in the immune system. Loss-of-function and gain-of-function mutations in the PI3Kδ isoform have revealed that this enzyme can substantially impact immune responses to infectious agents and their products. Moreover, reports garnered from decades of infectious disease studies indicate that pharmacologic inhibition of the PI3K pathway could potentially be effective in limiting the growth of certain microbes via modulation of the immune system. In this review, we briefly highlight the development and applications of PI3K inhibitors and summarize data supporting the concept that PI3Kδ inhibitors initially developed for oncology have immune regulatory potential that could be exploited to improve the control of some infectious diseases. This repurposing of existing kinase inhibitors could lay the foundation for alternative infectious disease therapy using available therapeutic agents.

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Disseminated and Congenital Toxoplasmosis in a Mother and Child With Activated PI3-Kinase δ Syndrome Type 2 (APDS2): Case Report and a Literature Review of Toxoplasma Infections in Primary Immunodeficiencies

Cited by 19 publications

References 52 publications

Case Report: EBV Chronic Infection and Lymphoproliferation in Four APDS Patients: The Challenge of Proper Characterization, Therapy, and Follow-Up

Case Report: EBV Chronic Infection and Lymphoproliferation in Four APDS Patients: The Challenge of Proper Characterization, Therapy, and Follow-Up

Insights into the Molecular Mechanisms of Liuwei Dihuang Decoction via Network Pharmacology

A Case for Phosphoinositide 3-Kinase–Targeted Therapy for Infectious Disease

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