New players in an old game: Role of immunoglobulins in the pathogenesis of multiple myeloma

Abstract

Multiple myeloma is a haematological malignancy characterized by uncontrolled proliferation of malignant plasma cells. The myeloma cells secrete immunoglobulins, which leads to the presence of high levels of monoclonal immunoglobulins (M-component) in the circulation. Frequent infections and bone loss are common complications of the disease and are associated with increased morbidity and mortality. The main aim of this work was to investigate if myeloma cell-derived immunoglobulins play a role in myeloma disease progression. More specifically, we examined if these immunoglobulins play a role in the development of the bone disease (Paper I), and if they interfere with macrophage activation during infection (Paper II). In short, we found that immunoglobulins isolated from myeloma patients with bone disease promote osteoclast differentiation in vitro, whereas immunoglobulins from patients without bone disease do not. This effect was primarily mediated by immune complexes or aggregates. We also found that immunoglobulins from patients with bone disease were less sialylated and galactosylated on their Ig-Fc part compared with immunoglobulins from patients without bone disease. Modifying immunoglobulin glycosylation in vitro and in vivo, had a beneficial effect on osteoclastogenesis and osteolytic lesions, respectively. Taken together, our data support that immunoglobulins promote bone loss in multiple myeloma. We also found that immunoglobulins obtained from myeloma patients modified LPS-induced cytokine secretion from human primary macrophages. The effect was dependent on the relative expression of FcRIIa and FcRIIb on the macrophages. A similar effect was observed for IgA, where macrophages from some donors enhanced LPS-induced cytokine response in response to IgA while in other IgA inhibited cytokine production. In general, IgG and IgA from myeloma patients modify LPS-induced macrophage activation which may interfere with a normal immune response during infection. Overall, our work uncovered a new role for immunoglobulins in the pathogenesis of multiple myeloma.