Odile Djossou

Generation and characterization of a human monoclonal autoantibody that acts as a high affinity interleukin-1α specific inhibitor

Interleukin-1 (IL-1) defines two polypeptides, IL-1α and IL-1β, that possess a wide spectrum of biological effects. Two natural antagonists of IL-1 action have been characterized: the IL-1 receptor antagonist (IL-1Ra) and a soluble form of the type II IL-1 receptor. Neutralizing autoantibodies to IL-1α have also been detected in sera of healthy individuals and patients with autoimmune or inflammatory diseases. To characterize such antibodies molecularly, we attempted to generate B cell clones producing anti-IL-1α human monoclonal antibody (HuMAb) by combining Epstein-Barr virus-immortalization and CD40-activation of B lymphocytes from individuals with circulating anti-IL-1α. We describe herein the generation and properties of a natural IgG4κ anti-IL-1α monoclonal autoantibody, HuMAb X3, that bound specifically to human IL-1α, but not to IL-1β and IL-1Ra, with a high affinity (Kd = 1.2 × 10−10 M). HuMAb X3 inhibited IL-1α binding to IL-1 receptors and neutralized biological activities of both recombinant and natural forms of IL-1α. A recombinant form of HuMAb X3 was found to display identical specific IL-1α antagonism. The presence of somatic mutations within X3 variable regions suggests an antigen-driven affinity maturation. This study extends the demonstration of the presence of high affinity neutralizing anti-IL-1α autoantibodies that can function as a third type of IL-1 antagonist.

Increased incidence of neutralizing autoantibodies against interleukin-1α (IL-1α) in nondestructive chronic polyarthritis

Cytokines such as IL-1 and tumor necrosis factor a (TNFa) play a critical role in chronic joint inflammation and destruction. To study their regulation, we looked for circulating antiproinflammatory cytokine autoantibodies in 318 patients with chronic arthritis by immunoprecipitation with protein G. Anti-IL-1α but not anti-IL-1β or anti-TNFα IgG antibodies were detected in 9% of blood donors and 18.9% of chronic arthritis patients. These antibodies were found more commonly and at a higher level in patients with nondestructive arthritis. Negative correlations were observed between the antibody levels and indices of disease activity and joint destruction. There was a negative association between the presence of anti-IL-1α antibodies and that of HLA-DR4. These circulating anti-IL-1α antibodies were not complexed with IL-1α and could block specifically the biological activity of IL-1α and its binding to membrane IL-1 receptors. These results indicate that these antibodies are beneficial, suggesting their contribution in the clinical presentation.