Endotoxin Shock in Antibody-Deficient Mice: Unraveling the Role of Natural Antibody and Complement in the Clearance of Lipopolysaccharide

Russell R. Reid, Andrey P. Prodeus, Wasif Khan, Tom Hsu, Fred S. Rosen, Michael C. Carroll

Research output: Contribution to journalArticle

139 Scopus citations

Abstract

While the significance of natural Ab is not entirely clear, one proposed role is clearance of bacterial Ags. To determine whether natural Ab was involved in clearance of endotoxin, we have examined novel strains of mice with either a total or selective deficiency in Ig. Recombinase-activating gene-2 (RAG-2-/-)-deficient mice, which have no serum Ig due to arrested development of B cells at the pro-B stage, demonstrate increased sensitivity to endotoxin that correlates with an impaired clearance. When RAG-2-/- mice are reconstituted with pooled sera from normal mice, both survival and clearance of circulating endotoxin are enhanced. To further define the nature of the protective Ab, Bruton's tyrosine kinase (Btk)-deficient mice were characterized in the high dose LPS model. Like RAG-2-/- mice, they are highly sensitive to endotoxin and have an impaired clearance of LPS. Reconstitution of Btk-/- mice, which have reduced levels of IgG3 and IgM, with purified normal mouse IgM dramatically enhances their ability to clear endotoxin compared with mock (saline)-reconstituted littermates. The cellular source of natural anti-LPS IgM was identified as the peritoneal-residing B-1 cell by enzyme-linked immunospot (ELISPOT) assay. Taken together, these studies demonstrate the important role of natural Ab and complement in the clearance of pathogenic substances from the circulation.

Original languageEnglish (US)
Pages (from-to)970-975
Number of pages6
JournalJournal of Immunology
Volume159
Issue number2
StatePublished - Jul 15 1997

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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