Unfavourable H-CDR3 Loops in preB Cells Lead to Highly Expanded Plasma Cell Clones.

Area of Science:

• Immunology
• Molecular Biology
• Autoimmunity

Background:

• The immune system distinguishes self from non-self via B-cell antigen receptors (BCRs).
• Autoimmunity arises when this fails, leading to self-attack.
• Immunoglobulin (Ig) V(D)J gene recombination generates BCR diversity, with H-CDR3 sequences critical for antigen binding.

Purpose of the Study:

• To investigate the impact of impaired pre-BCR selection on plasma cell (PC) development in an autoimmune model.
• To understand how unfavorable H-CDR3s contribute to autoimmunity.

Main Methods:

• Utilized a mouse model of autoimmunity with elevated autoantibodies.
• Analyzed B cell development and plasma cell populations.
• Examined H-CDR3 sequences and their translated amino acid properties.

Main Results:

• Absence of pre-BCR selection increased H-CDR3s in unfavorable reading frames, yielding hydrophobic/basic residues.
• These H-CDR3 features persisted in mature B cells despite Ig light chain expression.
• Massive clonal expansion of PCs with extremely short, hydrophobic/basic H-CDR3s was observed.

Conclusions:

• Impaired pre-BCR selection drives the expansion of autoreactive plasma cells.
• Unfavorable H-CDR3 features in pre-B cells are propagated to autoreactive plasma cells, promoting autoimmunity.