B-cell signaling in persistent polyclonal B lymphocytosis (PPBL).

Area of Science:

• Hematology
• Immunology
• Molecular Biology

Background:

• Persistent polyclonal B lymphocytosis (PPBL) is a benign condition with expanded marginal zone (MZ)-like B cells.
• PPBL B cells exhibit impaired in vitro activation, proliferation, and survival, with the underlying defect being previously unknown.

Purpose of the Study:

• To investigate the molecular mechanisms behind the impaired B cell function in PPBL.
• To identify specific signaling pathway defects in PPBL.

Main Methods:

• Analyzed canonical NF-κB and MAPK/ERK pathway activation following CD40 stimulation in PPBL B cells.
• Assessed B cell receptor (BCR) and Toll-like receptor 9 (TLR9) signaling.
• Examined IκBα, CD40, and Bcl-xL expression.
• Studied a mouse model with targeted gene knockouts in the CD40 pathway.
• Sequenced relevant genes in sorted MZ-like B cells from PPBL patients.

Main Results:

• PPBL B cells showed attenuated activation of the canonical NF-κB and MAPK/ERK pathways upon CD40 stimulation.
• This defect was selective, sparing alternative NF-κB, BCR, and TLR9 signaling.
• Reduced canonical NF-κB activation correlated with decreased IκBα and CD40 expression.
• Bcl-xL expression did not increase upon activation, leading to higher apoptosis rates in PPBL B cells.
• Mouse models mimicked PPBL, but no relevant genetic alterations were found in PPBL patient genes.

Conclusions:

• A selective defect in canonical NF-κB and MAPK/ERK signaling after CD40 stimulation characterizes PPBL.
• This impairment contributes to reduced B cell survival and increased apoptosis in PPBL.
• Findings highlight the relevance of NF-κB pathway signaling in PPBL pathogenesis, potentially linking to MZ lymphomas.