Hyperactivation of the PI3K pathway in inborn errors of immunity: current understanding and therapeutic perspectives

Abstract

The phosphoinositide-3-kinase (PI3K) pathway function is crucial to the normal development, differentiation, and function of immune cells including B, T, and NK cells. Following the description of two cohorts of patients with an inboirn error of immunity (also known as primary immunodeficiency) with gain-of-function variants in the PIK3CD gene a decade ago, the disease entity activated PI3K delta syndrome (APDS) was named. Since then, many more patients with PIK3CD variants have been described, and loss-of-function variants in PIK3R1 and PTEN have also been linked to APDS. Importantly, the availability of small molecules that inhibit the PI3K pathway has enabled targeted treatment of APDS patients. In this review, we define (i) the PI3K pathway and its role in inborn errors of immunity; (ii) the clinical and immunological presentation of APDS1 (PIK3CD GOF), APDS2 (PIK3R1 LOF), and related disorders; (iii) Diagnostic approaches to identify and functionally validate the genetic causes of disease; (iv) therapeutic interventions to target PI3K hyperactivation; and finally (v) current challenges and future perspectives that require attention for the optimal treatment of patients with APDS and APDS-L diseases.

Keywords: APDS-like; PI3K pathway; activated PI3K delta syndrome; immunodeficiency; immunotherapy.

Graphical Abstract

Figure 1.

Schematic of the PI3K pathway in immune (B cells, T cells) and non-immune cells (neurons of the brain). Class I PI3K signalling pathways in A. B and T cells and C. neurons. The schematics show a simplified class IA PI3K signalling pathways in immune and non-immune cells. In B cells and T cells, are activated downstream of a multitude of cell surface receptors (e.g. BCR, TCR, cytokine receptors, CD27, CD28, and ICOS). In neurons, PI3K is activated upon ligation of cell surface receptors including RTKs, cytokines and GPCRs. Once activated, PI3K phosphorylates PIP2 (PI(4,5)P2) to PIP3 (PI(3,4,5)P3) inducing downstream activation of AKT, a central hub of signalling in these cells. This results in phosphorylation of downstream effector proteins including mTORC1, ribosomal S6 and GSK, as well as transcription factor FOXO leading to nuclear exclusion. Phosphorylation of mTORC1 and S6 regulates cell biology including proliferation, survival, growth and metabolism. While inhibition of FOXO reduces transcription of genes including AICDA, RAG1, and RAG2. Created with BioRender.com ©.

Figure 2.

Schematic of the clinical and laboratory investigations used for the diagnosis of APDS and APDS-L. Diagnosis of disease requires thorough evaluation of patients current and past clinical history to identify characteristics of disease consistent with APDS and APDS-L, alongside quantitation of serum Ig levels, vaccination responses, and immunophenotyping of peripheral blood immune cells. This will firstly confirm that the patient has an inborn error of immunity and provides a means to identify characteristic immunological patterns that can aid in differentiating between different APDS and APDS-L disease. Further to this genomics is employed identify the affected gene underlying disease, with supporting assays to functionally validate and confirm these genetics lesions as causative of disease. Thereby, providing informative that could stratify a patient for treatment with PI3K inhibitors, or other treatments such as HSCT. Created with BioRender.com ©.