Lupus Genetics – BANK1 Isoforms impact lupus pathogenesis differentially

Lead: Aalekhya Biswas

Team Members: Geethangili Madamanchi, Anto-Sam Crosslee

Collaborators: Vidya Ganesh, Julie Trinh, Chen Yanping, Rajalakshmy Ayilam Ramachandran

Project Summary:

Genetic studies have identified the B cell scaffold protein with ankyrin repeat 1 (BANK1) as a susceptibility locus for SLE and other autoimmune diseases. Clinical observations suggest that expression of the full-length BANK1 isoform (BANK1^FL) is associated with lupus pathogenesis, whereas the exon 2–deleted isoform (BANK1^Del) may confer protection. However, the mechanistic contribution of these isoforms to lupus development has not been established in vivo.

To address this knowledge gap, we generated two B cell–specific transgenic mouse models on a C57BL/6 background expressing either human BANK1^FL or BANK1^Del under the control of the CD19 promoter. BANK1^FL transgenic mice displayed significant alterations in B cell differentiation, including expansion of marginal zone (MZ) and B1a B cells and a reduction in follicular (FO) B cells. These changes were accompanied by increased plasma cell differentiation, elevated serum total IgG and anti-dsDNA IgG levels, and modest renal pathology. Transcriptomic analyses revealed enhanced expression of class-switched IgG transcripts and activation-induced cytidine deaminase (AID), a key regulator of class switch recombination. Notably, these autoimmune phenotypes were observed exclusively in female mice. In contrast, BANK1^Del transgenic mice did not exhibit comparable immunological or pathological abnormalities, supporting a protective role for this isoform in lupus pathogenesis.

 What is already known in the field?

• BANK1 is a critical adaptor protein involved in B cell receptor–mediated signaling. Genetic polymorphisms and alternative splicing of BANK1 are associated with increased risk of SLE and other autoimmune diseases.
• Clinical studies suggest opposing roles for BANK1 isoforms, with BANK1^FL linked to disease susceptibility and BANK1^Del associated with protection.

What is new?

• Development of B cell–specific transgenic mouse models expressing human BANK1 isoforms.
• First in vivo mechanistic evidence demonstrating that BANK1^FL drives lupus-like immune dysregulation, while BANK1^Del lacks pathogenic effects.
• Identification of sex-specific autoimmune phenotypes linked to BANK1^FL
• Direct association of BANK1^FL with enhanced class-switch recombination and autoantibody production.

Why is this important?

• B cell–targeted therapies are central to current lupus treatment strategies, yet patient responses remain variable. Understanding how specific BANK1 isoforms regulate B cell fate, autoantibody production, and disease susceptibility provides critical insight into lupus pathogenesis and heterogeneity.
• These findings highlight BANK1 isoform–specific signaling as a potential biomarker and therapeutic target, paving the way for more precise and personalized approaches to SLE treatment.

Ongoing/Future Steps

• Define the molecular signaling pathways downstream of BANK1^FL and BANK1^Del in B cells.
• Investigate the mechanisms underlying female-specific susceptibility in BANK1^FL transgenic mice.
• Evaluate the interaction of BANK1 isoforms with established lupus-prone genetic backgrounds.
• Explore BANK1 isoform modulation as a potential therapeutic strategy in autoimmune disease.