iral and bacterial infections may enter the organism in various ways and the immunological effector mechanisms necessary for the efficient control of an infectious agent are dependent upon these distinct routes (Table 1). One important route used by a large number of pathogens is local infection via mucosal surfaces in the respiratory, digestive or urinary tract 1 . Most bacterial and viral infections at mucosal surfaces induce an immune response that is initially limited to the mucosal surface itself and then to local lymph nodes. The main initial effector mechanisms include secretory IgA antibodies and granulocytes 1 . Viral infections of peripheral solid organs including the skin are largely controlled by activated cytotoxic T lymphocytes with the capacity to extravasate and enter the infected peripheral solid tissues; antibodies play virtually no role in this process 2 . Occasionally, infectious agents enter the blood circulation directly, either via lowdose infection (e.g. arthropod-borne viruses) or via high-dose infections with contaminated blood transfusions. A hematogenically spreading infectious pathogen is best controlled by neutralizing antibodies 3 .
The handling by the immune system of a low dose of arthropodborne, or other directly intravenous transmitted infections, is interesting because these are normally low-dose infections by a cytopathic virus (Table 1). This situation is distinct from that where viruses or bacteria spread hematogenically after initial local infection of mucosa or skin, where they may be locally controlled on the mucosal surface before systemic distribution, as illustrated by infections with Streptococcus pneumoniae, Haemophilus influenzae, enteroviridae, measles, influenza and pox virus 4,5 . In such cases, during the generalized hematogenic spread, natural antibodies (NAs), complement and early T-cellindependent (TI) and/or -dependent (TD) (depending upon the dose of infection) IgM antibodies are crucial for enhancing immunogenicity and for the efficient control of infectious pathogens to avoid infection of vital organs 5 . This review discusses how these early protective antibody responses are enhanced by components of innate immunity. These components include antigen structure (versus antigen dose), NAs and complement-enhancing antigen trapping to marginal zone macrophages. In addition, other links from innate to acquired immunity, including lowering the threshold for B-cell activation and enhancing germinal center (GC) formation, are reviewed.
Natural antibodies
Natural or spontaneous antibodies to toxins, bacteria and erythrocytes are present in the sera of normal, non-immunized humans and mice 6,7 . This observation dates back to the beginning of immunological research and includes Landsteiner's observations of anti-A and anti-B agglutinins in the sera of non-immunized humans of the respective alternative blood group 8 .
Peritoneal CD5 Ο© B1 cells are a major source of natural IgM antibodies 5,7,9 but other observations (including our own unpublished results) indicate that some NAs are synthesized by splenic CD5 Οͺ B2 cells 6 . Antigen-and germ-free mice have similar patterns of NAs when analyzed in a quantitative immunoblot assay 10 . They also have comparable titers of antibodies specific for bacterial or viral antigens 11,12 . Therefore, NA production seems to be largely independent of internal or external