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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 IgG11
Departments of
*
Pediatrics,
Biochemistry, and
Pathology, Case Western Reserve University School of Medicine, and Division of Infectious Diseases, Allergy, Immunology, and Rheumatology, Rainbow Babies and Children’s Hospital, Cleveland, OH 44106
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 
3 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
CRM197-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.
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