GAMMA-3 GENE-DISRUPTED MICE SELECTIVELY DEFICIENT IN THE DOMINANT IGGSUBCLASS MADE TO BACTERIAL POLYSACCHARIDES UNDERGO NORMAL ISOTYPE SWITCHING AFTER IMMUNIZATION WITH POLYSACCHARIDE-PROTEIN CONJUGATE VACCINES

Bacterial polysaccharides (PS) are T-independent type 2 Ags that elici t restricted Ab responses of IgM and IgG3 in mice and IgM and predomin antly IgG2 in humans, Immunodeficiency in the dominant IgG subclass ma de to PS is associated with chronic sinus and pulmonary infections wit h PS-encapsulated bacteria, To elucidate the biologic role of the domi nant IgG subclass in the immune response to PS and to make an animal m odel of human IgG subclass deficiency, we generated mice with a target ed disruption of the exon encoding the CH1 domain of the gamma 3 heavy -chain constant region gene. Homozygotes had no detectable serum IgG3, and their splenocytes did not produce IgG3 after LPS stimulation. IgG 3(-/-) mice immunized with PS from Pseudomonas aeruginosa LPS O-side c hain or Streptococcus pneumoniae type 19F capsule did not produce any IgG3 anti-PS Abs, in contrast to wild-type mice in which IgG3 was the major IgG subclass, Immunizing both wild-type and IgG3(-/-) mice with 19F PS-protein conjugate elicited IgG1 Abs, We conclude that IgG3(-/-) mice have a selective deficiency in the dominant murine IgG subclass made to T-independent type 2 Ags and may be a useful animal model of I gG subclass deficiency. In addition, we show that the anti-PS Ab class switching to IgG1 that occurs when mice are immunized with a PS-prote in conjugate vaccine does not require sequential Ig expression or an i ntact, upstream gamma 3 heavy-chain gene.