Kallikrein Cleaves C3 and Activates Complement.

The human plasma contact system is an immune surveillance system activated by the negatively charged surfaces of bacteria and fungi and includes the kallikrein-kinin, the coagulation, and the fibrinolytic systems. Previous work shows that the contact system also activates complement, and that plasma enzymes like kallikrein, plasmin, thrombin, and FXII are involved in the activation process. Here, we show for the first time that kallikrein cleaves the central complement component C3 directly to yield active components C3b and C3a. The cleavage site within C3 is identical to that recognized by the C3 convertase. Also, kallikrein-generated C3b forms C3 convertases, which trigger the C3 amplification loop. Since kallikrein also cleaves factor B to yield Bb and Ba, kallikrein alone can trigger complement activation. Kallikrein-generated C3 convertases are inhibited by factor H; thus, the kallikrein activation pathway merges with the amplification loop of the alternative pathway. Taken together, these data suggest that activation of the contact system locally enhances complement activation on cell surfaces. The human pathogenic microbe Candida albicans activates the contact system in normal human serum. However, C. albicans immediately recruits factor H to the surface, thereby evading the alternative and likely kallikrein-mediated complement pathways.

Immune defence strategies of generalist and specialist insect herbivores.

Ecological immunology examines the adaptive responses of animals to pathogens in relation to other environmental factors and explores the consequences of trade-offs between investment in immune function and other life-history traits. Among species of herbivorous insects, diet breadth may vary greatly, with generalists consuming a wide variety of plant families and specialists restricted to a few species. Generalists may thus be exposed to a wider range of pathogens exerting stronger selection on the innate immune system. To examine whether this produces an increase in the robustness of the immune response, we compared larvae of the generalist herbivore Heliothis virescens and the specialist Heliothis subflexa challenged by entomopathogenic and non-pathogenic bacteria. Heliothis virescens larvae showed lower mortality, a lower number of recoverable bacteria, lower proliferation of haemocytes and higher phagocytic activity. These results indicate a higher tolerance to entomopathogenic bacteria by the generalist, which is associated with a more efficient cell-mediated immune response by mechanisms that differ between these closely related species. Our findings provide novel insights into the consequences of diet breadth and related environmental factors, which may be significant in further studies to understand the ecological forces and investment trade-offs that shape the evolution of innate immunity.

ß2-glycoprotein I, the major target in antiphospholipid syndrome, is a special human complement regulator.

The human plasma protein ß(2)-glycoprotein I (ß(2)-GPI) is the major target of autoantibodies associated with antiphospholipid syndrome. However, the biologic function of this abundant protein is still unclear. Here we identify ß(2)-GPI as a complement regulator. ß(2)-GPI circulates in the plasma in an inactive circular form. On surface binding, such as to apoptotic cells, ß(2)-GPI changes conformation to an elongated form that acquires C3/C3b binding activities. ß(2)-GPI apparently changes conformation of C3, so that the regulator factor H attaches and induces subsequent degradation by the protease factor I. ß(2)-GPI also mediates further cleavage of C3/C3b compared with factor H alone. Our data provide important insights into innate immune regulation by plasma protein ß(2)-GPI, which may be exploited in the prevention and therapy of autoimmune disease antiphospholipid syndrome.