se to Infectious Diseases cHAPTEr 17 399 The ability of some bacteria to survive intracellularly with- little tissue damage, and only a mild inflammatory reaction in infected cells can result in chronic antigenic activation of develops. The virulence of the organism is due completely to CD4* Tcells, leading to tissue destruction by a cell-mediated its potent exotoxin. The toxin causes destruction of the response with the characteristics of a delayed-type hypersen- underlying tissue, resulting in the formation of a tough fibri- sitivity reaction(see Chapter 14). Cytokines secreted by these nous membrane(pseudomembrane") composed of fibrin, activated CD4 T cells can lead to extensive accumulation white blood cells, and dead respiratory epithelial cells. The and activation of macrophages, resulting in formation of a membrane itself can cause suffocation. The exotoxin also is granuloma. The localized concentrations of lysosomal en- responsible for widespread systemic manifestations. Pro- zymes in these granulomas can cause extensive tissue necro- nounced myocardial damage (often leading to conge sis. Much of the tissue damage seen with M. tuberculosis is heart failure)and neurologic damage(ranging from mild due to a cell-mediated immune response weakness to complete paralysis)are common The exotoxin that causes diphtheria symptoms is encoded Diphtheria( Corynebacterium diphtheriae by the tox gene carried by phage B. Within some strains of May Be Controlled by Immunization with C. diphtheriae, phage B can exist in a state of lysogeny, in which the B-prophage DNa persists within the bacterial cell Inactivated toxoid Only strains that carry lysogenic phage B are able to produce Diphtheria is the classic example of a bacterial dis ease caus the exotoxin. The diphtheria exotoxin contains two disulfide- by a secreted exotoxin to which immunity can be induced by linked chains, a binding chain and toxin chain. The binding immunization with an inactivated toxoid. The causative chain interacts with ganglioside receptors on susceptible agent, a gram-positive, rodlike organism called Corynebac- ells, facilitating internalization of the exotoxin. Toxicity re- terium diphtheriae, was first described by Klebs in 1883 and sults from the inhibitory effect of the toxin chain on protein was shown a year later by Loeffler to cause diphtheria in synthesis. The diphtheria exotoxin is extremely potent; a sin- guinea pigs and rabbits. Autopsies on the infected animals gle molecule has been shown to kill a cell Removal of the revealed that, while bacterial growth was limited to the site of binding chain prevents the exotoxin from entering the cell, inoculation, there was widespread damage to a variety of thus rendering the exotoxin nontoxic. As described in Chap- organs, including the heart, liver, and kidneys. This finding ter 4, an immunotoxin can be prepared by replacing the led Loeffler to speculate that the neurologic and cardiologic binding chain with a monoclonal antibody specific for a manifestations of the disease were caused by a toxic sub- tumor-cell surface antigen; in this way the toxin chain can be stance elaborated by the organ targeted to tumor cells(see Figure 4-23) Loeffler's hypothesis was validated in 1888, when Roux Today, diphtheria toxoid is prepared by treating diphthe- and Yersin produced the disease in animals by injecting them ria toxin with formaldehyde. The reaction with formalde- with a sterile filtrate from a culture of C. diphtheriae. Two hyde cross-links the toxin, resulting in an irreversible loss in years later, von Behring showed that an antiserum to the its toxicity while enhancing its antigenicity. The toxoid is toxin was able to prevent death in infected animals. He pre administered together with tetanus toxoid and inactivated pared a toxoid by treating the toxin with iodine trichloride Bordetella pertussis in a combined vaccine that is given to and demonstrated that it could induce protective antibodies children beginning at 6-8 weeks of age. Immunization with in animals. Howeve the toxoid was still quite toxic an he toxoid induces the production of antibodies(antitoxin) therefore unsuitable for use in humans. In 1923. Ramon which can bind to the toxin and neutralize its activity Be- found that exposing the toxin to heat and formalin rendered cause antitoxin levels decline slowly over time, booster doses showed that formaldehyde-treated toxoid conferred a high levels within the protective range Interestingly, antibodies level of protection against diphtheria. As immunizations with the toxoid increased, the number exotoxin are critical for toxin neutralization because these of cases of diphtheria decreased rapidly. In the 1920s, there ntibodies block internalization of the active toxin chain were approximately 200 cases of diphtheria per 100,000 pop ulation in the United States. In 1989, the Centers for Disease Tuberculosis(Mycobacterium tuberculosis)Is Control reported only three cases of diphtheria in the entire Primarily Controlled by CD4+T Cells been an alarming epidemic of diphtheria due to a reduction Tuberculosis is the leading cause of death in the world from a in vaccinations single infectious agent, killing about 3 million individuals Natural infection with C. diphtheriae occurs only in hu- every year and accounting for 18.5% of all deaths in adults mans. The disease is spread from one individual to another between the ages of 15 and 59. About 1.79 billion people, by airborne respiratory droplets. The organism colonizes the roughly one-third of the world s population, are infected with nasopharyngeal tract, remaining in the superficial layers of the causative agent M. tuberculosis and are at risk of develop- the respiratory mucosa. Growth of the organism itself causes ing the disease. Long thought to have been eliminated as aThe ability of some bacteria to survive intracellularly with￾in infected cells can result in chronic antigenic activation of CD4+ T cells, leading to tissue destruction by a cell-mediated response with the characteristics of a delayed-type hypersen￾sitivity reaction (see Chapter 14). Cytokines secreted by these activated CD4+ T cells can lead to extensive accumulation and activation of macrophages, resulting in formation of a granuloma. The localized concentrations of lysosomal en￾zymes in these granulomas can cause extensive tissue necro￾sis. Much of the tissue damage seen with M. tuberculosis is due to a cell-mediated immune response. Diphtheria (Corynebacterium diphtheriae) May Be Controlled by Immunization with Inactivated Toxoid Diphtheria is the classic example of a bacterial disease caused by a secreted exotoxin to which immunity can be induced by immunization with an inactivated toxoid. The causative agent, a gram-positive, rodlike organism called Corynebac￾terium diphtheriae, was first described by Klebs in 1883 and was shown a year later by Loeffler to cause diphtheria in guinea pigs and rabbits. Autopsies on the infected animals revealed that, while bacterial growth was limited to the site of inoculation, there was widespread damage to a variety of organs, including the heart, liver, and kidneys. This finding led Loeffler to speculate that the neurologic and cardiologic manifestations of the disease were caused by a toxic sub￾stance elaborated by the organism. Loeffler’s hypothesis was validated in 1888, when Roux and Yersin produced the disease in animals by injecting them with a sterile filtrate from a culture of C. diphtheriae. Two years later, von Behring showed that an antiserum to the toxin was able to prevent death in infected animals. He pre￾pared a toxoid by treating the toxin with iodine trichloride and demonstrated that it could induce protective antibodies in animals. However, the toxoid was still quite toxic and therefore unsuitable for use in humans. In 1923, Ramon found that exposing the toxin to heat and formalin rendered it nontoxic but did not destroy its antigenicity. Clinical trials showed that formaldehyde-treated toxoid conferred a high level of protection against diphtheria. As immunizations with the toxoid increased, the number of cases of diphtheria decreased rapidly. In the 1920s, there were approximately 200 cases of diphtheria per 100,000 pop￾ulation in the United States. In 1989, the Centers for Disease Control reported only three cases of diphtheria in the entire United States. Recently in the former Soviet Union, there has been an alarming epidemic of diphtheria due to a reduction in vaccinations. Natural infection with C. diphtheriae occurs only in hu￾mans. The disease is spread from one individual to another by airborne respiratory droplets. The organism colonizes the nasopharyngeal tract, remaining in the superficial layers of the respiratory mucosa. Growth of the organism itself causes little tissue damage, and only a mild inflammatory reaction develops. The virulence of the organism is due completely to its potent exotoxin. The toxin causes destruction of the underlying tissue, resulting in the formation of a tough fibri￾nous membrane (“pseudomembrane”) composed of fibrin, white blood cells, and dead respiratory epithelial cells. The membrane itself can cause suffocation. The exotoxin also is responsible for widespread systemic manifestations. Pro￾nounced myocardial damage (often leading to congestive heart failure) and neurologic damage (ranging from mild weakness to complete paralysis) are common. The exotoxin that causes diphtheria symptoms is encoded by the tox gene carried by phage . Within some strains of C. diphtheriae, phage can exist in a state of lysogeny, in which the -prophage DNA persists within the bacterial cell. Only strains that carry lysogenic phage are able to produce the exotoxin. The diphtheria exotoxin contains two disulfide￾linked chains, a binding chain and toxin chain. The binding chain interacts with ganglioside receptors on susceptible cells, facilitating internalization of the exotoxin. Toxicity re￾sults from the inhibitory effect of the toxin chain on protein synthesis. The diphtheria exotoxin is extremely potent; a sin￾gle molecule has been shown to kill a cell. Removal of the binding chain prevents the exotoxin from entering the cell, thus rendering the exotoxin nontoxic. As described in Chap￾ter 4, an immunotoxin can be prepared by replacing the binding chain with a monoclonal antibody specific for a tumor-cell surface antigen; in this way the toxin chain can be targeted to tumor cells (see Figure 4-23). Today, diphtheria toxoid is prepared by treating diphthe￾ria toxin with formaldehyde. The reaction with formalde￾hyde cross-links the toxin, resulting in an irreversible loss in its toxicity while enhancing its antigenicity. The toxoid is administered together with tetanus toxoid and inactivated Bordetella pertussis in a combined vaccine that is given to children beginning at 6–8 weeks of age. Immunization with the toxoid induces the production of antibodies (antitoxin), which can bind to the toxin and neutralize its activity. Be￾cause antitoxin levels decline slowly over time, booster doses are recommended at 10-year intervals to maintain antitoxin levels within the protective range. Interestingly, antibodies specific for epitopes on the binding chain of the diphtheria exotoxin are critical for toxin neutralization because these antibodies block internalization of the active toxin chain. Tuberculosis (Mycobacterium tuberculosis) Is Primarily Controlled by CD4+ T Cells Tuberculosis is the leading cause of death in the world from a single infectious agent, killing about 3 million individuals every year and accounting for 18.5% of all deaths in adults between the ages of 15 and 59. About 1.79 billion people, roughly one-third of the world’s population, are infected with the causative agent M. tuberculosis and are at risk of develop￾ing the disease. Long thought to have been eliminated as a Immune Response to Infectious Diseases CHAPTER 17 399