B cells and their signaling pathways The guiding lights to decipher and target autoimmunity

Autoimmunity arises when the immune system misrecognizes self as non-self, leading to chronic inflammation and tissue damage. B cells are central to this process by producing autoantibodies, presenting self-antigens, and secreting pro-inflammatory mediators. This thesis focuses on B cell biology in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), idiopathic inflammatory myopathies (IIM), and rheumatoid arthritis (RA), with the aim of (i) characterizing B cell subsets across immune compartments and inflamed tissues, and (ii) exploring disease-relevant intracellular signaling pathways as therapeutic targets.
In AAV, kidney biopsies revealed diverse B and T cell populations, including atypical memory B cells, plasma cells, and pro-inflammatory T helper cells, within a microenvironment shaped by NF-κB and interferon signaling. Furthermore, enhanced canonical and non-canonical NF-κB signatures were identified in peripheral B cells in active AAV, which were effectively inhibited by IKKβ and NIK blockade, resulting in reduced B cell proliferation, differentiation, and autoantibody production. In IIM, characterized by an interferon signature and JAK/STAT activation, B cell profiling uncovered skewed transitional/naïve and memory subsets. Additionally, JAK inhibition preferentially suppressed B cell differentiation and reduced autoantibody production, supporting its therapeutic potential in IIM. In RA, autoreactive ACPA⁺ B cells displayed enhanced proliferation as well as (auto)antibody and cytokine production, which were abrogated by NF-κB inhibition, while JAK inhibition broadly suppressed B cell activity.
This thesis demonstrates that targeting NF-κB and JAK/STAT signaling in AAV, IIM and RA modulates autoreactive B cell responses. Targeting these pathways in B cells offers opportunities for more precise therapies, moving beyond broad B cell depletion toward durable, pathway-specific modulation.