A Precision B Cell-Targeted Therapeutic Approach to Autoimmunity Caused by Phosphatidylinositol 3-Kinase Pathway Dysregulation.

A Precision B Cell-Targeted Therapeutic Approach to Autoimmunity Caused by Phosphatidylinositol 3-Kinase Pathway Dysregulation.

Publication date: May 10, 2019

The inositol lipid phosphatases PTEN and SHIP-1 play a crucial role in maintaining B cell anergy and are reduced in expression in B cells from systemic lupus erythematosus and type 1 diabetes patients, consequent to aberrant regulation by miRNA-7 and 155. With an eye toward eventual use in precision medicine therapeutic approaches in autoimmunity, we explored the ability of p110δ inhibition to compensate for PI3K pathway dysregulation in mouse models of autoimmunity. Low dosages of the p110δ inhibitor idelalisib, which spare the ability to mount an immune response to exogenous immunogens, are able to block the development of autoimmunity driven by compromised PI3K pathway regulation resultant from acutely induced B cell-targeted haploinsufficiency of PTEN and SHIP-1. These conditions do not block autoimmunity driven by B cell loss of the regulatory tyrosine phosphatase SHP-1. Finally, we show that B cells in NOD mice express reduced PTEN, and low-dosage p110δ inhibitor therapy blocks disease progression in this model of type 1 diabetes. These studies may aid in the development of precision treatments that act by enforcing PI3K pathway regulation in patients carrying specific risk alleles.

Franks, S.E., Getahun, A., and Cambier, J.C. A Precision B Cell-Targeted Therapeutic Approach to Autoimmunity Caused by Phosphatidylinositol 3-Kinase Pathway Dysregulation. 04586. 2019 J Immunol.

Concepts Keywords
Alleles MTOR
Anergy Phosphoinositide 3-kinase inhibitor
Autoimmunity Autoimmunity
Diabetes PTEN
Exogenous Phosphoinositide 3-kinase
Haploinsufficiency Oncology
Inhibitor Medicine
Inositol Signal transduction
Lipid Branches of biology
MiRNA Progression diabetes
Mount
Phosphatase
Phosphatases
Phosphatidylinositol
PI3K
PTEN
Systemic Lupus Erythematosus
Tyrosine

Semantics

Type Source Name
gene UNIPROT AICDA
disease MESH disease progression
gene UNIPROT ATN1
gene UNIPROT PTPN6
drug DRUGBANK L-Tyrosine
disease MESH haploinsufficiency
disease MESH development
drug DRUGBANK Idelalisib
gene UNIPROT PIK3CG
gene UNIPROT PIK3CB
gene UNIPROT PIK3CD
gene UNIPROT PIK3CA
gene UNIPROT CUX1
gene UNIPROT SART3
disease MESH type 1 diabetes
pathway BSID Systemic lupus erythematosus
disease DOID systemic lupus erythematosus
disease MESH systemic lupus erythematosus
gene UNIPROT INPP5D
gene UNIPROT PTEN
drug DRUGBANK Inositol
disease MESH Autoimmunity

Original Article

Leave a Comment

Your email address will not be published. Required fields are marked *