Perspectives from B cell immunology: fact and fancy

In this article, the formation of antibodies during enzyme replacement therapy (ERT) for lysosomal storage diseases (LSDs) is reviewed in the light of present-day immunological concepts of immunogenicity and tolerance. Except in Gaucher disease, anti-enzyme antibodies frequently form (mainly immunoglobulin G) in patients receiving ERT, though they tend to wane as treatment continues. If the therapeutic enzyme is inhibited by antibodies, no significant modification to treatment is normally warranted, in clear contrast to therapy of hemophilia with clotting factors. The main adverse consequences of ERT, observed in only some patients, are sporadic hypersensitivity reactions, which are likely to be humorally mediated. Some infusion-related reactions are probably due to antibodies. In order to minimize immunogenicity, infused enzymes should be deaggregated and administered at low doses. In addition, inadvertent exposure to co-stimuli that might activate antigen-specific T or B lymphocytes should be avoided. The presence of cross-reacting immunological material, such as in patients with low levels or missense mutations of a gene coding for a lysosomal enzyme, tends to correlate with immune tolerance to the administered enzyme. There is a need for reliable biomarkers for therapeutic efficacy: some directions for further exploration are suggested. In animal models of LSDs, gene therapy delivered via viral vectors can rectify the lysosomal defect, and regulatory T cells that suppress antibody formation can be induced. This is a promising strategy that warrants further investigation in patients with LSDs.