BAFF and APRIL signaling in the B-cell lineage: implications for the pathogenesis of ANCA-associated vasculitis.

Among the immune mechanisms underlying the pathogenesis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), B-lineage cells play crucial roles by producing ANCA, presenting antigens to T cells, and secreting proinflammatory cytokines. The upregulated signaling pathways of the B-cell activation factor of tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL), which are broadly produced by several types of myeloid cells, contribute to the activation and survival of autoreactive B cells, leading to disease onset and relapse. Furthermore, elevated levels of soluble BAFF and APRIL persist even in patients who achieve clinical remission following conventional induction therapies such as cyclophosphamide and rituximab (RTX), resulting in the cause of relapse. Active AAV is characterized by expansions of specific phenotypes in circulating B-cell lineages, including plasmablasts and plasma cells. Conversely, reductions in transitional, memory, and regulatory B cells are observed. Significant expressions of affinity receptors binding to secreting BAFF/APRIL, including decreased BAFF receptor expression on memory B cells and transitional B cells or increased transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) expression on transitional B cells and plasmablasts/plasma cells, are also observed during acute and remission AAV. Enhanced BAFF and APRIL signaling through these receptors, especially TACI, activates the intracellular nuclear factor-κB pathway in B cells, promoting their proliferation and ANCA production. B-cell depletion therapy using RTX is effective; however, it requires repeated administration to maintain remission, which can occasionally lead to infection. Belimumab, a BAFF-inhibiting monoclonal antibody, alone has shown limited efficacy in preventing relapse of AAV. Targeting BAFF/APRIL signaling pathways and their binding receptors, along with the downstream molecular pathways in targeted B cells, is essential for developing novel therapeutic strategies aimed at achieving complete and sustained AAV remission.