The case of an APDS patient: Defects in maturation and function and decreased in vitro anti-mycobacterial activity in the myeloid compartment

Chiriaco, Maria; Brigida, Immacolata; Ariganello, Paola; Cesare, Silvia Di; Matteo, Gigliola Di; Taus, Francesco; Cittaro, Davide; Lazarevic, Dejan; Scarselli, Alessia; Santilli, Veronica; Attardi, Enrico; Stupka, Elia; Giannelli, Stefania; Fraziano, Maurizio; Finocchi, Andrea; Rossi, Paolo; Aiuti, Alessandro; Cancrini, Caterina

doi:10.1016/j.clim.2015.12.008

Cited by 33 publications

(32 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, analysis of APDS patient neutrophils did not reveal an obvious increase in ROS production, or indeed in PIP 3 production, in response to stimulation with microbial peptides1. However, the increased susceptibility of patients with APDS to staphylococcal skin infections and abscess formation1, 65, as well as defective killing of mycobacteria by macrophages from an APDS patient64, suggest that abnormalities may indeed exist in the innate immune system which remain to be more completely investigated. Increased PI3K activity has been shown to compromise the migratory accuracy of neutrophils, and hence prolong their tissue-transit time, leading to increased opportunities for bystander tissue injury mediated by surface-associated neutrophil proteases79.…”

Section: Alterations In Pi3kδ Signalling Leads To Pids In Humansmentioning

confidence: 95%

“…Subsequently, a number of additional studies have identified APDS patients with mutations in PIK3CD 5, 7, 64–69 or PIK3R1 6, 70–73. Patients with GOF mutations in either of these genes appear to largely phenocopy each other, despite the fact that p85α is ubiquitously expressed and can pair with p110α and p110β in addition to p110δ.…”

Section: Alterations In Pi3kδ Signalling Leads To Pids In Humansmentioning

confidence: 99%

“…Frequent isolates of some respiratory viruses such as adenovirus and echovirus have also been described 1.Opportunistic infections are rare, although a few patients have experienced recurrent viral warts or molluscum contagiosum infections49.An increased incidence of abscess formation, lymphadenitis and cellulitis with gram-positive bacteria (mainly Staphylococcus aureus ), and defective killing of mycobacteria by macrophages isolated from a patient with APDS suggest a mild deficit in innate immunity1, 64.Benign lymphoproliferation (lymphadenopathy, hepatosplenomegaly and focal nodular lymphoid hyperplasia) is a common feature of all patients with APDS that have been studied to date.Histopathological analysis of lymphoid tissue from affected patients demonstrates atypical follicular hyperplasia with attenuation of mantle zones in APDS1, and small B cell follicles in APDS2. Germinal centres were disrupted by infiltrating T cells (often PD1-positive) in both APDS1 and APDS2 6, 7.…”

Section: Clinical Features Of Apdsmentioning

confidence: 99%

“…An increased incidence of abscess formation, lymphadenitis and cellulitis with gram-positive bacteria (mainly Staphylococcus aureus ), and defective killing of mycobacteria by macrophages isolated from a patient with APDS suggest a mild deficit in innate immunity1, 64.…”

Section: Clinical Features Of Apdsmentioning

confidence: 99%

See 3 more Smart Citations

PI3Kδ and primary immunodeficiencies

et al. 2016

View full text Add to dashboard Cite

Primary immunodeficiencies are inherited disorders of the immune system, often caused by the mutation of genes required for lymphocyte development and activation. Recently, several studies have identified gain-of-function mutations in the phosphoinositide 3-kinase (PI3K) genes PIK3CD (which encodes p110δ) and PIK3R1 (which encodes p85α) that cause a combined immunodeficiency syndrome, referred to as activated PI3Kδ syndrome (APDS) or p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency (PASLI). Paradoxically, both loss-of-function and gain-of-function mutations that affect these genes lead to immunosuppression, albeit via different mechanisms. Here, we review the roles of PI3Kδ in adaptive immunity, describe the clinical manifestations and mechanisms of disease in APDS and highlight new insights into PI3Kδ gleaned from these patients, as well as implications of these findings for clinical therapy.

show abstract

Section: Alterations In Pi3kδ Signalling Leads To Pids In Humansmentioning

confidence: 95%

Section: Alterations In Pi3kδ Signalling Leads To Pids In Humansmentioning

confidence: 99%

Section: Clinical Features Of Apdsmentioning

confidence: 99%

Section: Clinical Features Of Apdsmentioning

confidence: 99%

See 2 more Smart Citations

PI3Kδ and primary immunodeficiencies

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Gain‐of‐function mutation in PI3K ‐δ leads to increased activity in the p110δ catalytic protein (a product of PIK3CD gene), the subunit of PI3K ‐δ . Germline, autosomal dominant mutations lead to the clinical entity called APDS (also called PASLI [P110δ activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency]), wherein patients may suffer from recurrent respiratory infections and progressive airway damage, autoimmune cytopenias, lymphopenia, increased numbers of circulating transitional B cells, increased serum IgM levels, lymphoid hyperplasia, increased risk for malignancy, and impaired vaccine responses . Splice site mutations in PIK3R1 also appear to cause a phenotype similar to APDS …”

Section: Common Variable Immunodeficiencymentioning

confidence: 99%

Diagnosis and management of chronic and refractory immune cytopenias in children, adolescents, and young adults

Rotz

Ware

Kumar

2018

Pediatric Blood & Cancer

View full text Add to dashboard Cite

Children, adolescents, and young adults with chronic refractory autoimmune cytopenias represent a rare but challenging group of patients, who are managed frequently by pediatric hematologists. Novel diagnostic tests and genomic discoveries are refining historical diagnoses of Evans syndrome and common variable immunodeficiency, while also elucidating the cellular and molecular basis for these disorders. Genetic characterization of chronic and refractory autoimmune cytopenias has led to targeted therapies with improved clinical outcomes and fewer off-target toxicities. In this review, we focus on the appropriate diagnostic workup, expanded genetic testing, and novel treatment opportunities that are available for these challenging patients.

show abstract

Systematic review of mortality and survival rates for APDS

Hanson,

Bonnen

2024

Clin Exp Med

View full text Add to dashboard Cite

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a rare genetic disorder that presents clinically as a primary immunodeficiency. Clinical presentation of APDS includes severe, recurrent infections, lymphoproliferation, lymphoma, and other cancers, autoimmunity and enteropathy. Autosomal dominant variants in two independent genes have been demonstrated to cause APDS. Pathogenic variants in PIK3CD and PIK3R1, both of which encode components of the PI3-kinase, have been identified in subjects with APDS. APDS1 is caused by gain of function variants in the PIK3CD gene, while loss of function variants in PIK3R1 have been reported to cause APDS2. We conducted a review of the medical literature and identified 256 individuals who had a molecular diagnosis for APDS as well as age at last report; 193 individuals with APDS1 and 63 with APDS2. Despite available treatments, survival for individuals with APDS appears to be shortened from the average lifespan. A Kaplan–Meier survival analysis for APDS showed the conditional survival rate at the age of 20 years was 87%, age of 30 years was 74%, and ages of 40 and 50 years were 68%. Review of causes of death showed that the most common cause of death was lymphoma, followed by complications from HSCT. The overall mortality rate for HSCT in APDS1 and APDS2 cases was 15.6%, while the mortality rate for lymphoma was 47.6%. This survival and mortality data illustrate that new treatments are needed to mitigate the risk of death from lymphoma and other cancers as well as infection. These analyses based on real-world evidence gathered from the medical literature comprise the largest study of survival and mortality for APDS to date.

show abstract

The case of an APDS patient: Defects in maturation and function and decreased in vitro anti-mycobacterial activity in the myeloid compartment

Cited by 33 publications

References 27 publications

PI3Kδ and primary immunodeficiencies

PI3Kδ and primary immunodeficiencies

Diagnosis and management of chronic and refractory immune cytopenias in children, adolescents, and young adults

Systematic review of mortality and survival rates for APDS

Contact Info

Product

Resources

About