Targeting autoreactive B cells in rheumatoid arthritis through MHC class I-presented BCR-derived neo-epitopes

Area of Science:

• Immunology
• Autoimmunity
• Molecular Biology

Background:

• Current B cell therapies for autoimmune diseases lack specificity and durable remission.
• Autoreactive B cells in rheumatoid arthritis produce anti-citrullinated protein antibodies (ACPAs) and undergo somatic hypermutation (SHM).
• The presentation and immunogenicity of mutated B cell receptor (BCR)-derived neoepitopes are poorly understood.

Purpose of the Study:

• To investigate the immunological targetability of autoreactive B cells in rheumatoid arthritis.
• To explore the potential of using mutated BCR-derived neoantigens for selective B cell targeting.
• To identify and validate neoepitopes presented by autoreactive B cells.

Main Methods:

• In silico analysis of MHC class I binding.
• Peptide-elution mass spectrometry.
• CD8+ T cell activation assays using patient-derived BCRs and HLA class I alleles.

Main Results:

• All investigated autoreactive BCRs harbor sequences presentable by multiple HLA class I alleles.
• 85% of these sequences contain somatic hypermutations (SHMs) creating potential neoepitopes.
• Mass spectrometry confirmed predicted neoepitopes, and CD8+ T cells recognized these neoepitopes, but not their unmutated counterparts.

Conclusions:

• An integrated strategy of MHC isolation, peptide identification, and BCR sequencing can uncover neoantigens on autoreactive B cells.
• Mutated BCR-derived neoantigens represent a novel target for specific B cell elimination.
• This approach offers a pathway for personalized immunotherapies in rheumatoid arthritis and other B cell-driven autoimmune diseases.