Antibody-Mediated Protection through Cross-Reactivity Introduces a Fungal Heresy into Immunological Dogma

Abstract

It is hard to believe that only a decade or so ago the question of whether specific antibodies protected against fungal pathogens was considered controversial (for a review, see reference 5). Since the landmark paper by Dromer et al. in 1987 showing that a monoclonal antibody (MAb) to Cryptococcus neoformans polysaccharide was protective against experimental cryptococcal infection in mice (10), dozens of studies have established conclusively that certain antibodies are protective against fungi. Protective MAbs have now been described for Candida albicans (13, 16, 24, 42), C. neoformans (10, 11, 21, 26, 38), Aspergillus fumigatus (7), Pneumocystis spp. (12), and Histoplasma capsulatum (28). In recent years two antibodies have entered clinical evaluation for fungal diseases (20, 29). A consensus has now emerged that the inability of immune sera to mediate protection against fungi reflects inadequate amounts of protective antibody and/or the simultaneous presence of protective and nonprotective antibodies, rather than a fundamental inability of antibody to protect against fungal pathogens. In support of this concept, in addition to protective MAbs, nonprotective MAbs to C. albicans, C. neoformans, and H. capsulatum have been described (13, 25, 28). Nonetheless, much remains to be learned about the nature of protective antibodies and the relationship between the natural antibody response and resistance and susceptibility to fungal pathogens, since hypogammaglobulinemia is not generally associated with the development of fungal disease and antibody responses to certain fungi and fungal targets can be a marker of disease rather than immunity (19, 30). Perhaps the central event in this odyssey was the application of hybridoma technology to studies of antibody immunity to fungi. This approach made it possible to characterize the functional efficacy of individual immunoglobulin molecules. Hence, medical mycology studies revealed a new immunological paradigm in which the protective potential of immune sera is a function of the aggregate activities of immunoglobulin molecules instead of a singular property. This view challenged the traditionally held dichotomy in which cellular immunity is responsible for resistance to intracellular pathogens and antibody immunity is responsible for resistance to extracellular pathogens. In addition, in recent years studies with fungi have also threatened to tear down another pillar of immunological dogma, namely, that protective immune responses must be pathogen specific.