Abstract

Mycobacterium abscessus (MABS), a rapidly growing non-tuberculous mycobacterium, causes disseminated infections in patients with adult-onset immunodeficiency due to anti-IFN-γ autoantibodies. We investigated whether cytokines produced by MABS-infected cells contribute to plasmablast survival and antibody production. To address this, we first analyzed the cytokine response in monocyte-derived macrophages infected with MABS and found that IL-6 was secreted at high levels. Since IL-6 is known to be produced by fibroblasts, we next characterized the intracellular survival of MABS and its ability to induce cytokine production in fibroblasts. We demonstrated that MABS invaded fibroblasts, replicated intracellularly, and induced high levels of IL-6 secretion. Given the established role of IL-6 in promoting plasmablast survival, we next developed an in vitro culture of B cell-derived plasmablasts to test the effect of IL-6. To do this, B cells from healthy donors were differentiated into early plasmablasts using Toll-like receptor (TLR) 7/8 agonist. After 4 days, plasmablasts were then cultured for an additional 3 days with either recombinant IL-6 or supernatants from infected macrophages. Our results demonstrated that both recombinant IL-6 and supernatants from infected macrophages promoted plasmablast survival and expansion. Blocking the IL-6 receptor with tocilizumab, but not inhibiting JAK1⁄2 with baricitinib, reduced plasmablast survival and IgG secretion in cultures treated with infected macrophage supernatants. Collectively, these findings suggest that infection-induced IL-6 promotes plasmablast survival and antibody production. Targeting IL-6 signaling could, therefore, represent a potential therapeutic strategy to modulate antibody responses.IMPORTANCEThe difficult-to-treat MABS infection is a major clinical problem in Asian patients with adult-onset primary immunodeficiency associated with anti-IFN-γ autoantibodies. Understanding the cytokine responses induced by MABS may support the development of cytokine-targeted therapies that control autoantibody production. In this study, we found that IL-6 was produced at high levels by both macrophages and fibroblasts following infection. Moreover, we demonstrated that IL-6 is a key cytokine promoting plasmablast survival, as IL-6 receptor blockade with tocilizumab significantly reduced plasmablast viability in cultures stimulated with infected macrophage supernatants. Together, these findings provide a rationale for future clinical investigation of cytokine-targeted therapeutic approaches.