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Recent compelling results indicate possible links between neurotransmitters, intestinal mucosal IgA+ B cell responses, and immunoglobulin A nephropathy (IgAN) pathogenesis. Here, we demonstrated that γ-amino butyric acid (GABA) transporter-2 (GAT-2) deficiency induces intestinal germinal center (GC) B cell differentiation and worsens the symptoms of IgAN in a mouse model. Mechanistically, GAT-2 deficiency enhances GC B cell differentiation through activation of GABA-mammalian target of rapamycin complex 1 (mTORC1) signaling. In addition, IgAN patients have lower GAT-2 expression but higher activation of mTORC1 in blood B cells, and both are correlated with kidney function in IgAN patients. Collectively, this study describes GABA signaling-mediated intestinal mucosal immunity as a previously unstudied pathogenesis mechanism of IgAN and challenges the current paradigms of IgAN. [ABSTRACT FROM AUTHOR]

The article presents a study of the effect of γ-aminobutyric acid (GABA) transporter (GAT) on interleukin (IL)-1β production in macrophage-associated diseases. Topics discussed include the use of BCX-1777 inhibitor of purine nucleoside phosphorylase (PNP) to suppress hypoxanthine biosynthesis, failure of the study to clearly define the mechanism that led to the alteration of macrophage polarization, and the effect of GAT2 deficiency on intracellular accumulation of hypoxanthine.