Immunobiology of Diphtheria

Between 1821 and 1826 Pierre Fidele Bretonneau (1826) established the clinical entity diphtheria. Its hallmark was the pseudomembrane or diphtheritic membrane. By 1869 Trendelenberg had shown that pseudomembranes could be produced in rabbits and in pigeons following the injection of pseudomembranous material from human cases of diphtheria. Bretonneau conceived of diphtheria as a disease of singular etiology comparable in its uniqueness to the causes of measles and of variola. This Unitarian view was soon lost to some students of the disease. In methyleneblue-stained smears of material taken from pseudomembranes, more than one shape of bacterium could be observed. In fact, Klebs (1875) found diphtheria from one locality to be caused by a fungus, Microsporon diphthericum, and later he described a bacillary type of diphtheria from another locality (Klebs, 1883). When Friedrich Loeffler tackled the problem of the etiology of diphtheria, he accepted the concept of a single etiology as promulgated by Bretonneau. Working in Koch’s laboratory, he designed a program for direct microscopic examination of methylene-bluestained material from pseudomembranes, cultivation of such materials on solid media, and inoculation of animals with bacterial cultures (Loeffler, 1884). This remarkable investigator was the first to distinguish the probable role of streptococci in diphtheria associated with scarlatinal infections from that of occasional chains of streptococci (normal flora) found associated with frank cases of diphtheria.* He was able to demonstrate diphtheria bacilli in smears of only 13 out of 22 cases of clinical diphtheria. From six of these he isolated Corynebacterium diphtheriae. He isolated diphtheria bacilli from one normal child. Because of the lack of a one-to-one correlation in these findings, he was not adamant in claiming to have established the etiology of the disease. But he had in fact clearly established its etiology. From the time of Loeffler, it has been evident that harboring diphtheria bacilli is not synonymous with diphtheria and that Koch’s postulates cannot be fulfilled in every case of diphtheria. Loeffler’s experimental infections in animals led to the discovery that diphtheria bacilli tended to remain at the site of injection, although autopsy revealed damage to organs far from that site. Roux and Yersin (1888) demonstrated that the connection between diphtheria bacilli at one site and damage to distant internal organs was a soluble poison, diphtherial toxin. These observations have given rise to the concept that diphtheria bacilli always remain at the superficial site of colonization, the pseudomembrane or the cutaneous lesion.* Further, since Roux and Yersin pointed out that toxin itself could be responsible for many of the signs of the disease, in the legend of diphtheria there has been a tendency to confuse intoxication with infection. The discovery of antibodies capable of neutralizing the toxicity of diphtherial toxin (Behring and Kitasato, 1890) and their apparent effects in reducing case fatality rates in epidemics of diphtheria obscured for many the need for investigating antibacterial immunity toward C. diphtheriae. As a result, textbook presentations of the immunology of diphtheria are often confused. In fact, it has been implied that immunization with toxoid has got rid of diphtheria bacilli in some societies. Bonventre (1975) has called this sort of assertion a manifestation of arrogance and has suggested that there are still many questions about diphtheria which remain unanswered. The discussion of the immunology of diphtheria that follows indicates a number of aspects of the interaction of diphtheria bacilli and human beings which merit further study.