B Cells and Generation of Antibodies

The humoral immune response protects an organism from environmental pathogens by producing antibodies (immunoglobulins) that mediate the destruction or inactivation of microbial organisms and their toxins. It also produces antibodies to self to assist in the removal of cellular debris in a noninflammatory fashion. To perform these functions, the immune system generates antibodies to a diverse and changing array of antigens, yet it must do so without generating pathogenic antibodies to self. The production of high-affinity antibodies that bind to self-determinants is a prominent feature of systemic lupus erythematosus (SLE).1 Some autoantibodies in SLE are considered markers for disease (e.g., antinuclear antibody) because they have no established pathogenicity, whereas others also play a role in disease pathogenesis and tissue damage.2-6 There have been extensive investigations of autoantibodies in SLE, which address a number of specific questions: What is the genetic contribution to pathogenic antibody generation? Do B cells producing autoantibodies arise from an antigen-triggered and antigen-selected response? If so, are these triggering and selecting antigens self or foreign? Are particular B-cell lineages or differentiation pathways responsible for autoantibody production? What defects in immune regulation permit the sustained production of pathogenic autoantibodies? What are the characteristics of pathogenic autoantibodies, and how do they mediate pathology? This chapter discusses autoantibody structure, assembly, and regulation as well as the B-cell subsets that produce antibodies. Based on new advances in the knowledge of autoantibody structure and regulation, novel potential therapeutic strategies are also briefly addressed.