Could abatacept directly target expanded plasmablasts in IgG4-related disease?

Yamamoto et al recently reported the case of a patient with long-standing and relapsing IgG4-related disease (IgG4-RD), who developed secondary resistance to rituximab treatment but subsequently improved under abatacept infusions. This interesting observation drives important questions, regarding both IgG4-RD pathophysiology and abatacept mechanisms of action. IgG4-RD is a systemic disease of unknown cause, affecting primarily middle-aged men, characterised by swelling of one or several organs (mainly pancreas, salivary and lachrymal glands, lymphadenopathy, retroperitoneal organs) with infiltration of IgG4-positive plasma cells and fibrosis of involved organs, and high serum IgG4 levels in half of the patients. 3 Several diagnostic or classification systems have been proposed. 5 Its pathophysiology is still ill-defined. IgG4-secreting plasmablasts are central players in the disease: they are the main infiltrating cells in affected organs, they are expanded in the circulation, are oligoclonal and may serve as a biomarker to guide therapy. The efficacy of rituximab in IgG4-RD further suggests the major role of B cells as precursors of these expanded plasmablasts. 10 It has been suggested that a shift towards Th2 immune response promotes the initiation of the disease, and that overexpression of IL-21 by Tfh cells leads to the formation of ectopic germinal centres in the target organs and increased IgG4 production. B-cell/plasmablast and T-cell relative contributions in the pathophysiology of IgG4-RD are