B Lineage Cells in ANCA-Associated Vasculitis

Abstract

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease that affects small sized blood vessels and can lead to serious complications in the lungs and kidneys. The prominent presence of ANCA autoantibodies in this disease implicates B cells in its pathogenesis, as these are the precursors of the ANCA-producing plasma cells (PCs). Further evidence supporting the potential role of B lineage cells in vasculitis are the increased B cell cytokine levels and the dysregulated B cell populations in patients. Confirmation of the contribution of B cells to pathology arose from the beneficial effect of anti-CD20 therapy (i.e., rituximab) in AAV patients. These anti-CD20 antibodies deplete circulating B cells, which results in amelioration of disease. However, not all patients respond completely, and this treatment does not target PCs, which can maintain ANCA production. Hence, it is important to develop more specific therapies for AAV patients. Intracellular signalling pathways may be potential therapeutic targets as they can show (disease-specific) alterations in certain B lineage cells, including pathogenic B cells, and contribute to differentiation and survival of PCs. Preliminary data on the inhibition of certain signalling molecules downstream of receptors specific for B lineage cells show promising therapeutic effects. In this narrative review, B cell specific receptors and their downstream signalling molecules that may contribute to pathology in AAV are discussed, including the potential to therapeutically target these pathways.

Keywords: ANCA; ANCA-associated vasculitis; B cells; autoimmunity; plasma cells; signalling.

Figure 1

B cell lineage development and altered B cell populations in ANCA-associated vasculitis (AAV). Schematic representation of human B lineage cell differentiation. Beige boxes highlight the effects of AAV on the indicated cell populations. The extra-follicular pathway of B cell differentiation is not shown for simplicity. Transitional B cells migrate into secondary lymphoid organs, where they differentiate into innate-like B1, marginal zone B (MZB) cells, or naive B cells. Naive B cells enter lymph nodes and become follicular B cells, and it is within the follicle that a T-cell dependent response triggers the formation of germinal centers (GCs). During the GC reaction, the GC B cell may generate memory B cells (Bmem), plasmablasts, or plasma cells (PCs), which reduce the pathogenic anti-neutrophil cytoplasmic antibodies (ANCAs). PCs may be short- or long-lived and home to the bone marrow, whereas Bmem egress into the periphery. B regulatory cells (Breg) may arise from almost all B cell lineage populations. All the aforementioned B cell populations have been found to be dysregulated in AAV, being increased or decreased, as shown by the arrows in the beige boxes. Abbreviations: PR3 (proteinase 3), BCR (B cell receptor).

Figure 2

Selection of key receptors, ligands, signalling molecules, and transcriptional regulators of B lineage cells in AAV. B cells present many different receptors on their surface, each triggering specific signalling pathways that eventually lead to transcription of genes necessary for B cell specific and essential functions. Blue: ligands; brown: receptors; cream: effector molecules/signalling pathways. The circle represents the endosome, and the yellow semicircle the nucleus. Abbreviations: BAFF (B cell activating factor), APRIL (a proliferation-inducing ligand), BAFF-R (B cell activating factor receptor), BCMA (B cell maturation antigen), TACI (transmembrane activator and cyclophilin ligand interactor), BCR (B cell receptor), TLR (toll-like receptor), BTK (Bruton’s tyrosine kinase), SYK (spleen tyrosine kinase), NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells), JAK (Janus family tyrosine kinases), STAT (signal transducer and activator of transcription), PI3K (phpsphatidylinositol-3-kinase), LYN (Lck/Yes related novel protein tyrosine kinase).