Dysregulated autoantibody production is responsible for the severe organ damage that occurs in systemic autoimmune diseases. Immune complexes play important roles in the pathogenesis of these diseases as they initiate and maintain the inflammatory cascade, which leads to tissue destruction. Conventional therapy for autoimmune diseases suppresses immunological accelerator in the absence of knowledge of the immunological brake. Application of a physiological regulatory system could be a rational strategy to treat autoimmune diseases. Accumulating evidence has suggested that specialised subsets of B cells and T cells could control autoantibody production. A significant decrease and impaired function of regulatory B cells (Breg) was recently reported in patients with systemic lupus erythematosus and a mice model of lupus. In T cells, follicular regulatory T cells and Qa-1 restricted CD8 regulatory T cells (Treg) were identified as the populations that control follicular T helper cell-mediated antibody production. Moreover, other Treg populations might also be involved in the control of autoantibody production. Elucidating the roles of Breg and Treg in the control of antibody production might lead to the development of a new therapeutic approach to antibody-mediated autoimmune disease.