Gene usage for naturally occurring antibodies

NTIBODIES that bind to both foreign and selfantigens are present in the serum of normal individuals as well as in patients with autoimmune diseases. Such natural antibodies are most prominently of the IgM isotype, bind with low affinity, and are produced spontaneously rather than as a result of specific antigen stimulation. 1 They are already detectable in cord blood. Considerable evidence suggests that natural antibodies can be highly cross-reactive. This was initially established by studying hybridomas produced upon fusion of B cells from normal animals to immortalized lymphoid cell lines that secreted large amounts of Ig that could be tested for binding to a diverse array of foreign and self-antigens. It was seen that crossreactive lymphocytes were present in the repertoire of normal mice by 6 days of age, whereby it is generally accepted that the newborn mouse is immunologically younger than the newborn human. Some researchers concluded that polyreactive antibodies improved the ability of the newborn to neutralize environmental pathogens at a time when their immune system was immature. Others argued that the increased use of cross-reactive B cells conferred no selective advantage to the newborn but instead reflected the more frequent usage of germ-line and proximal Ig VH sequences by young animals. The immune system is the only system so far known to display such high polymorphism and diversity. This relates to the dynamics of the large multigene families (MHC genes, V regions of antibodies) and of the selective forces involved. Furthermore, the combinatorial recombination of antibodies raises the question of potential, actual, or available repertoire at any given time in a particular individual. 2 In fact, cross-reactive antibodies are more commonly encoded by germ line rather than by somatically mutated Ig genes. Finally, it was suggested that cross-reactive B cells were deleterious, but that the immune system of the newborn was too immature to prevent the activation of such cells. So far little is known of the genetic or structural factors that confer cross-reactivity to an Ig molecule. Most or all VH region families are capable of encoding polyreactive antibodies. 3 The variable region repertoire is selected by antigenic structures in the body and remains conserved throughout life. 4 The sequence diversity in antibodies is concentrated in six complementarity-determining regions (CDRs), three from the heavy chain variable domain (CDRH1, CDRH2, and CDRH3) and three from the light chain variable domain (CDRL1, CDRL2, and CDRL3). In the primary repertoire the CDRH1 1 2 regions are encoded by the VH segment, whereas CDRH3 is a product of VH-D-JH recombination. The possibility for variability and thus adaptation of the humoral immune response in germ-line diversity and somatic mutation are located at amino acid positions 30 to 37 and 50 to 65 as well as around 90 for CDRL3 5 (Table 1).