The biological activity of soluble antigen-antibody complexes: II. Physical properties of soluble complexes having skin-irritating activity

Previous work by Germuth and McKinnon (1), Trapani et al. (2), and ourselves (3) has established the fact that soluble antigen-antibody complexes formed in excess antigen can, (a) induce symptoms similar to anaphylaxis, (b) cause contraction of isolated smooth muscle from normal guinea pigs, and (c) increase the permeability of skin capillaries in a manner similar to that obtained in passive cutaneous anaphylaxis. These findings immediately raise many questions as to the fundamental mechanisms involved. For example, is the free antigen playing some role; is the toxicity dependent upon some change in the molecular structure of either antigen or antibody upon combination; is the complex itself toxic without any change in the molecular structure of the components; is the antigen-antibody ratio important; and, is complement involved? The work reported here involves a study of the possible role of free antigen and the nature of the complex. Some study was also made of untreated and decomplemented antiserums and, although there was no difference, this cannot rule out the possible participation of the test animal's (guinea pig's) own complement

Identification of IgE

Progress in protein chemistry in the 1950s revealed that the biologic activities of proteins, such as hemoglobin and enzymes, are based on partial structures in the protein molecules. This principle suggested to us the possibility that the human antibodies responsible for induction of reaginic hypersensitivity reactions might have unique structures that are lacking in the antibody molecules involved in immunity and that the differences in the structures of human antibody molecules can be recognized by the immune systems of experimental animals. Our studies were based on the hypothesis that reaginic antibody activity is associated with a unique immunoglobulin isotype, which is now called IgE. As expected, identification of IgE facilitated the analysis of immunologic mechanisms of reaginic hypersensitivity. Subsequent studies revealed that IgE specifically bound to basophilic granulocytes and mast cells through the Fc portion of the molecules and that cross-linking of the cell-bound IgE antibody molecules by allergen induced the release of bioactive mediators, such as histamine and leukotrienes, which initiate allergic reactions

Mast Cells and IgE: From History to Today

Role of mast cells in allergy had remained undetermined until the discovery of IgE in 1966. Then, IgE purified from many Liters of plasma, which had been donated from a patient with fatal myeloma, was distributed to researchers all over the world, and thus accelerated exploring the mechanisms involved in allergic reactions, particularly about the role of mast cells and basophils in the IgE-mediated reactions. Identification of mast cells as a progeny of a bone marrow hematopoietic stem cell in 1977 led us to successful in vitro culture of human mast cells. Along with the development of molecular biological techniques, the structure of the high affinity IgE receptor (FceRI) was determined in 1989. These findings and subsequent investigations brought deeper understanding of IgE-mediated allergic diseases in the past half century, especially where mast cells are involved. We have now even obtained the information about whole genome expression of FceRI-dependently activated mast cells. In sharp contrast to our comprehension of allergic diseases where IgE and mast cells are involved, the mechanisms involved in non-IgE-mediated allergic diseases or non-IgE-mediated phase of IgE-mediated diseases are almost left unsolved and are waiting for devoted investigators to reveal it