Highly reduced protection againstStreptococcus pneumoniaeafter deletion of a single heavy chain gene in mouse

Abstract

Phosphocholine (PC) is the immunodominant epitope found on the surface of Streptococcus pneumoniae (SPn). T15-idiotype Abs, whose heavy (H) chain variable region is encoded by the V1 gene, are dominant in the anti-PC response in adult mice and protect mice from lethal pneumococcal infection. The ability of anti-PC Abs using H chains other than the V1 H chain to protect against pneumococcal infection remains controversial. We generated V1 ؊/؊ knockout mice to determine whether protective anti-PC Abs could be produced in the absence of the V1 gene. No anti-PC Abs were produced in V1 ؊/؊ mice immunized with avirulent SPn; however, PC-BSA binding Abs were induced after immunization with PC-keyhole limpet hemocyanin but at significantly lower levels than those in wild-type mice. These Abs provided poor protection against virulent SPn; thus, <25% of V1 ؊/؊ mice survived challenge with 10 4 bacteria as compared with 100% survival of V1 ؉/؉ mice. The anti-PC Abs in V1 ؊/؊ mice were heteroclitic, binding to nitrophenyl-PC better than to PC. None of nine hybridomas produced from V1 ؊/؊ mice provided passive protection. However, the V1 ؊/؊ mice produced normal amounts of Ab to SPn proteins that can partially protect mice against SPn. These data indicate that the V1 gene is critical for the production of anti-PC Abs providing optimum protection against infection with SPn, and the V1 ؊/؊ mice could be useful in unmasking epitopes other than the immunodominant PC epitope on SPn capable of providing cross protection.

The role of innate immunity in atherogenesis

“…The T15 clone, which was a spontaneous murine plasmacytoma that secreted an IgA with the T15 idiotype, is considered the classic germline NAb. It was intensively studied because it binds to PC (not as part of a PL) covalently linked to the cell wall polysaccharide of pathogens and confers optimal protection to mice from lethal infection with Streptococcus pneumonia (27). In further studies cited below, we went on to show that such OxPL were greatly increased in apoptotic cells as well (28).…”

Naturally Occurring Human Phosphorylcholine Antibodies Are Predominantly Products of Affinity-Matured B Cells in the Adult

“…Knocking out this particular Ab has deleterious effects on the ability of mice to mount effective immune responses against PC (19).…”

B Cells Producing Pathogenic Autoantibodies

“…T15 antibodies are highly represented in germ-free mice and dominate anti-PC responses in newborn mice [8]. These pre-existing, naturally occurring T15 antibodies provide an innate-like immune response against virulent pneumococcal infection even before adaptive immunity becomes fully mature or activated [9][10][11]. At the same time, T15 antibodies also exhibit autoreactivity specific for the PC head group of oxidized phospholipids present on oxidized lowdensity lipoprotein (OxLDL) and on apoptotic cells [12].…”