mTOR Activation Underlies Enhanced B Cell Proliferation and Autoimmunity in PrkcdG510S/G510S Mice

Area of Science:

• Immunology
• Molecular Biology
• Genetics

Background:

• Autosomal recessive PRKCD deficiency is linked to systemic lupus erythematosus (SLE) in humans.
• The precise mechanisms driving autoimmunity in PRKCD deficiency are not fully understood.

Purpose of the Study:

• To investigate the role of PRKCD in B cell function and autoimmunity using a mouse model.
• To elucidate the molecular pathways involved in PRKCD-associated SLE.

Main Methods:

• CRISPR-Cas9 gene editing was used to introduce the Prkcd G510S mutation into mouse models.
• B cell activation, PI3K/mTOR pathway signaling, and NK cell populations were analyzed.
• Rapamycin, an mTORC1 inhibitor, was administered to assess its therapeutic effect.

Main Results:

• PrkcdG510S/G510S mice exhibited a lupus-like phenotype and reduced lifespan, recapitulating human disease.
• B cells in these mice showed upregulated PI3K/mTOR pathway signaling upon B cell receptor engagement, leading to lymphoproliferation.
• Rapamycin treatment ameliorated autoimmune symptoms, confirming the role of mTOR pathway activation.
• A decrease in peripheral mature NK cells was observed, potentially explaining susceptibility to viral infections.

Conclusions:

• PRKCD plays a B cell-autonomous role in regulating autoimmunity.
• Aberrant PI3K/mTOR pathway activation downstream of PRKCD contributes to lymphoproliferation and SLE pathogenesis.
• Targeting the mTOR pathway offers a potential therapeutic strategy for PRKCD-associated autoimmune diseases.