title: Gamma 3 gene-disrupted mice selectively deficient in the dominant IgG subclass made to bacterial polysaccharides. II. Increased susceptibility to fatal pneumococcal sepsis due to absence of anti-polysaccharide IgG3 is corrected by induction of anti-polysaccharide IgG1.
abstract: Bacterial polysaccharides (PS) are type 2 T-independent Ags that elicit Abs restricted in isotype to IgM and predominantly IgG2 in humans and IgM, and IgG3 in mice. Humans with IgG2 subclass deficiency are susceptible to sinus and pulmonary infections with PS-encapsulated bacteria. We previously developed an IgG3-deficient mouse by disrupting the gamma3 H chain constant region gene via targeted mutagenesis. Mutant mice lacking IgG3 were backcrossed for 10 generations to wild-type (WT) BALB/c mice to generate BALB/c mice that have complete absence of IgG3. WT mice immunized with type 3 Streptococcus pneumoniae capsular PS made anti-PS IgM, IgG3, and small quantities of IgG1, which opsonized S. pneumoniae for killing by polymorphonuclear leukocytes. These mice were protected against death from lethal doses of type 3 S. pneumoniae. In contrast, IgG3(-/-) mice made similar titers of anti-PS IgM and IgG1 as WT mice but no IgG3, and had poorly opsonic sera with significantly increased mortality after S. pneumoniae challenge. Immunization of IgG3(-/-) mice with type 3 S. pneumoniae PS conjugated to carrier protein CRM(197)-elicited IgM and high-titer IgG1 Abs, restored serum opsonization, and gave protection from mortality after S. pneumoniae, challenge comparable to WT mice. We conclude that mice lacking the dominant IgG3 subclass made to bacterial PS are more susceptible to fatal S. pneumoniae sepsis than WT mice, but that IgG1 induced by a S. pneumoniae glycoconjugate can adequately protect against S. pneumoniae sepsis. This model suggests that IgG subclass of anti-PS Ab is an important component of immunity to encapsulated bacteria.
authors.affiliation: Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: John
authors.initials: J
authors.lastname: McLay
authors.forename: Ethan
authors.initials: E
authors.lastname: Leonard
authors.forename: Sheryl
authors.initials: S
authors.lastname: Petersen
authors.forename: David
authors.initials: D
authors.lastname: Shapiro
authors.forename: Neil S
authors.initials: NS
authors.lastname: Greenspan
authors.forename: John R
authors.initials: JR
authors.lastname: Schreiber
mesh_terms: D000483:Alleles; D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis / Q000235:genetics; D016667:Bacterial Capsules; D001426:Bacterial Proteins / Q000008:administration & dosage / Q000276:immunology; D005260:Female; D005803:Genes, Immunoglobulin; D020022:Genetic Predisposition to Disease; D005838:Genotype; D017098:IgA Deficiency / Q000235:genetics / Q000276:immunology; D017099:IgG Deficiency / Q000235:genetics* / Q000276:immunology; D007106:Immune Sera / Q000008:administration & dosage; D007116:Immunization, Passive; D007074:Immunoglobulin G / Q000096:biosynthesis* / Q000145:classification / Q000235:genetics*; D007274:Injections, Intraperitoneal; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009895:Opsonin Proteins / Q000494:pharmacology; D010641:Phenotype; D011018:Pneumonia, Pneumococcal / Q000235:genetics* / Q000276:immunology* / Q000401:mortality / Q000517:prevention & control; D011135:Polysaccharides, Bacterial / Q000008:administration & dosage / Q000276:immunology*; D018805:Sepsis / Q000235:genetics / Q000276:immunology / Q000401:mortality; D013296:Streptococcus pneumoniae / Q000254:growth & development / Q000276:immunology; D018074:Vaccines, Conjugate / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D001426:Bacterial Proteins; D007106:Immune Sera; D007074:Immunoglobulin G; D009895:Opsonin Proteins; D011135:Polysaccharides, Bacterial; D018074:Vaccines, Conjugate; C413446:type 3 capsular polysaccharide, Streptococcus pneumoniae; C028581:CRM197 (non-toxic variant of diphtheria toxin)