TY - JOUR
T1 - Biallelic PI4KA Mutations Disrupt B-Cell Metabolism and Cause B-Cell Lymphopenia and Hypogammaglobulinemia
AU - Saettini, Francesco
AU - Guerra, Fabiola
AU - Mauri, Mario
AU - Salter, Claire G.
AU - Adam, Margaret P.
AU - Adams, David
AU - Baple, Emma L.
AU - Barredo, Estibaliz
AU - Bhatia, Sanil
AU - Borkhardt, Arndt
AU - Brusco, Alfredo
AU - Bugarin, Cristina
AU - Chinello, Clizia
AU - Crosby, Andrew H.
AU - D’Souza, Precilla
AU - Denti, Vanna
AU - Fazio, Grazia
AU - Giuliani, Silvia
AU - Kuehn, Hye Sun
AU - Amel, Hassan
AU - Elmi, Asha
AU - Lo, Bernice
AU - Malighetti, Federica
AU - Mandrile, Giorgia
AU - Martín-Nalda, Andrea
AU - Mefford, Heather C.
AU - Moratto, Daniele
AU - Emam Mousavi, Fatemeh
AU - Nelson, Zoe
AU - Gutiérrez-Solana, Luis González
AU - Macnamara, Ellen
AU - Michaud, Vincent
AU - O’Leary, Melanie
AU - Pagani, Lisa
AU - Pavinato, Lisa
AU - Santamaria, Patricia VVelez
AU - Planas-Serra, Laura
AU - Quadri, Manuel
AU - Raspall-Chaure, Miquel
AU - Rebellato, Stefano
AU - Rosenzweig, Sergio D.
AU - Roubertie, Agathe
AU - Holzinger, Dirk
AU - Deal, Christin
AU - Vockley, Catherine Walsh
AU - Savino, Angela Maria
AU - L.Stoddard, Jennifer
AU - Uhlig, Holm H.
AU - Pujol, Aurora
AU - Magni, Fulvio
AU - Paglia, Giuseppe
AU - Cazzaniga, Gianni
AU - Piazza, Rocco
AU - Barberis, Matteo
AU - Biondi, Andrea
N1 - Publisher Copyright:
© The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature 2024.
PY - 2024/9/23
Y1 - 2024/9/23
N2 - Purpose PI4KA-related disorder is a highly clinically variable condition characterized by neurological (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus) and gastrointestinal (inflammatory bowel disease and multiple intestinal atresia) manifestations. Although features consistent with immunodeficiency (autoimmunity/autoinflammation and recurrent infections) have been reported in a subset of patients, the burden of B-cell deficiency and hypogammaglobulinemia has not been extensively investigated. We sought to describe the clinical presentation and manifestations of patients with PI4KA-related disorder and to investigate the metabolic consequences of biallelic PI4KA variants in B cells. Methods Clinical data from patients with PI4KA variants were obtained. Multi-omics analyses combining transcriptome, proteome, lipidome and metabolome analyses in conjunction with functional assays were performed in EBV-transformed B cells. Results Clinical and laboratory data of 13 patients were collected. Recurrent infections (7/13), autoimmune/autoinflammatory manifestations (5/13), B-cell deficiency (8/13) and hypogammaglobulinemia (8/13) were frequently observed. Patients' B cells frequently showed increased transitional and decreased switched memory B-cell subsets. Pathway analyses based on differentially expressed transcripts and proteins confirmed the central role of PI4KA in B cell differentiation with altered B-cell receptor (BCR) complex and signalling. By altering lipids production and tricarboxylic acid cycle regulation, and causing increased endoplasmic reticulum stress, biallelic PI4KA mutations disrupt B cell metabolism inducing mitochondrial dysfunction. As a result, B cells show hyperactive PI3K/mTOR pathway, increased autophagy and deranged cytoskeleton organization. Conclusion By altering lipid metabolism and TCA cycle, impairing mitochondrial activity, hyperactivating mTOR pathway and increasing autophagy, PI4KA-related disorder causes a syndromic inborn error of immunity presenting with B-cell deficiency and hypogammaglobulinemia.
AB - Purpose PI4KA-related disorder is a highly clinically variable condition characterized by neurological (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus) and gastrointestinal (inflammatory bowel disease and multiple intestinal atresia) manifestations. Although features consistent with immunodeficiency (autoimmunity/autoinflammation and recurrent infections) have been reported in a subset of patients, the burden of B-cell deficiency and hypogammaglobulinemia has not been extensively investigated. We sought to describe the clinical presentation and manifestations of patients with PI4KA-related disorder and to investigate the metabolic consequences of biallelic PI4KA variants in B cells. Methods Clinical data from patients with PI4KA variants were obtained. Multi-omics analyses combining transcriptome, proteome, lipidome and metabolome analyses in conjunction with functional assays were performed in EBV-transformed B cells. Results Clinical and laboratory data of 13 patients were collected. Recurrent infections (7/13), autoimmune/autoinflammatory manifestations (5/13), B-cell deficiency (8/13) and hypogammaglobulinemia (8/13) were frequently observed. Patients' B cells frequently showed increased transitional and decreased switched memory B-cell subsets. Pathway analyses based on differentially expressed transcripts and proteins confirmed the central role of PI4KA in B cell differentiation with altered B-cell receptor (BCR) complex and signalling. By altering lipids production and tricarboxylic acid cycle regulation, and causing increased endoplasmic reticulum stress, biallelic PI4KA mutations disrupt B cell metabolism inducing mitochondrial dysfunction. As a result, B cells show hyperactive PI3K/mTOR pathway, increased autophagy and deranged cytoskeleton organization. Conclusion By altering lipid metabolism and TCA cycle, impairing mitochondrial activity, hyperactivating mTOR pathway and increasing autophagy, PI4KA-related disorder causes a syndromic inborn error of immunity presenting with B-cell deficiency and hypogammaglobulinemia.
KW - Hypogammaglobulinemia
KW - Inborn error of immunity
KW - Pi4ka
KW - Syndromic immunodeficiency
UR - https://www.scopus.com/pages/publications/85204758920
U2 - 10.1007/s10875-024-01793-8
DO - 10.1007/s10875-024-01793-8
M3 - Article
C2 - 39312004
AN - SCOPUS:85204758920
SN - 0271-9142
VL - 45
JO - Journal of Clinical Immunology
JF - Journal of Clinical Immunology
IS - 1
M1 - 15
ER -