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We have previously determined that complement receptors on human mononuclear phagocytes and complement component C3 in nonimmune serum mediate phagocytosis of the intracellular bacterial pathogen Mycobacterium leprae, the agent of leprosy. We have also determined that C3 fixes selectively to the major surface glycolipid of M. leprae, phenolic glycolipid 1 (PGL-1). In this study, we have explored the role of natural antibody in nonimmune serum in C3 fixation and C1q binding to M. leprae and PGL-1. At serum concentrations within the range at which phagocytosis of M. leprae is maximal, C3 fixation was mediated by both the classical and the alternative complement pathways. At the low end of this serum concentration range (2.5%), C3 fixation was mediated predominantly by the classical pathway. Consistent with a role for both pathways, C3 fixation to M. leprae was enhanced by the addition of either pure C1q to C1q-depleted serum or pure factor B to factor B-depleted serum. C3 fixation to M. leprae was strictly antibody dependent regardless of the serum concentration used. C3 fixation to M. leprae occurred in nonimmune serum but not in agammaglobulinemic serum unless heat-inactivated nonimmune serum or small amounts of pure immunoglobulin G (IgG) or IgM were added. C3 fixation by both the alternative and the classical complement pathways was mediated by antibody, and the antigen-binding portion of the antibody molecule was required. C3, IgG, IgM, and C1q were readily detected on the surface of M. leprae. Consistent with the previously demonstrated exclusive role of the classical complement pathway in C3 fixation to PGL-1, C1q bound to PGL-1 in a dose-dependent fashion; C1q binding was evident in &gt; 1.25% nonimmune serum. C1q binding to PGL-1 was strictly antibody dependent. When PGL-1 was incubated with pure C1q, little or no C1q bound to PGL-1 unless heat-inactivated nonimmune serum or pure IgG or IgM was added. When PGL-1 was incubated in nonimmune serum, C3 bound directly to PGL-1 and not to anti-PGL-1 antibody, since the amount of C3 bound to PGL-1 was not reduced by acid elution of the antibody. However, the amount of C3 bound to PGL-1 was markedly reduced by hydroxylamine treatment, providing evidence for C3 fixation via a covalent ester bond. Nonimmune serum contained antibody to all four major M. leprae surface carbohydrates. Relative to PGL-1, nonimmune serum contained more antibody to the other surface carbohydrates.(ABSTRACT TRUNCATED AT 400 WORDS)

infection and immunity

A role for natural antibody in the pathogenesis of leprosy: antibody in nonimmune serum mediates C3 fixation to the Mycobacterium leprae surface and hence phagocytosis by human mononuclear phagocytes