Function, occurrence and inhibition of different forms of BAFF

Area of Science:

• Immunology
• Molecular Biology
• Biochemistry

Background:

• B cell activating factor (BAFF), also known as BLyS, is a crucial cytokine for B cell survival and humoral immunity.
• BAFF is a therapeutic target for systemic lupus erythematosus.

Purpose of the Study:

• To review the structure, function, and inhibition profiles of different BAFF forms: membrane-bound, soluble 3-mer, and soluble 60-mer.
• To elucidate the role of a specific loop region in BAFF receptor activation and multimerization.
• To investigate the implications of BAFF multimerization on drug efficacy and its potential role in neonatal immunity.

Main Methods:

• Literature review focusing on structural and functional aspects of BAFF.
• Analysis of BAFF-to-BAFF interactions mediated by a specific loop region.
• Discussion of BAFF inhibitor (belimumab) epitope accessibility within different BAFF oligomers.

Main Results:

• BAFF possesses a loop region essential for receptor activation through BAFF-to-BAFF contacts.
• This loop facilitates the formation of a BAFF 60-mer, rendering belimumab epitopes inaccessible.
• Adult serum contains activity that dissociates BAFF 60-mers, suggesting limited systemic activity.
• Elevated BAFF levels in cord blood, with some exhibiting 60-mer characteristics, indicate a potential role in fetal/neonatal B cell development.

Conclusions:

• The BAFF 60-mer, if formed in humans, is likely transient and locally acting due to serum dissociation activity.
• The structural properties of BAFF, particularly the 60-mer, may influence therapeutic strategies targeting BAFF.
• BAFF's distinct forms, including the 60-mer, may be critical for B cell development in neonates.