ENDOTOXIN-SHOCK IN ANTIBODY-DEFICIENT MICE - UNRAVELING THE ROLE OF NATURAL ANTIBODY AND COMPLEMENT IN THE CLEARANCE OF LIPOPOLYSACCHARIDE

While the significance of natural Ab is not entirely clear, one propos ed role is clearance of bacterial Ags, To determine whether natural Ab was involved in clearance of endotoxin, we have examined novel strain s of mice with either a total or selective deficiency in Ig, Recombina se-activating gene-2 (RAC-2(-/-))-deficient mice, which have no serum Ig due to arrested development of B cells at the pro-B stage, demonstr ate increased sensitivity to endotoxin that correlates with an impaire d clearance, When RAC-2(-/-) mice are reconstituted with pooled sera f rom normal mice, both survival and clearance of circulating endotoxin are enhanced, To further define the nature of the protective Ab, Bruto n's tyrosine kinase (Btk) deficient mice were characterized in the hig h dose LPS model. Like RAG-2(-/-) mice, they are highly sensitive to e ndotoxin and have an impaired clearance of LPS, Reconstitution of Btk( -/-) mice, which have reduced levels of IgG3 and IgM, with purified no rmal mouse IgM dramatically enhances their ability to clear endotoxin compared with mock (saline)-reconstituted littermates. The cellular so urce 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 comple ment in the clearance of pathogenic substances from the circulation.