A Historical Perspective of Immunology

The discipline of immunology grew out of the observation that individuals who had recovered from certain infectious diseases were thereafter protected from the disease. The Latin term immunis, meaning “exempt,” is the source of the English word immunity, a state of protection from infectious disease. Perhaps the earliest written reference to the phenomenon of immunity can be traced back to Thucydides, the great historian of the Peloponnesian War. In describing a plague in Athens, he wrote in 430 BC that only those who had recovered from the plague could nurse the sick because they would not contract the disease a second time. Thucydides and colleagues must therefore have realized that the human body was able to “learn” from exposure, acquiring some form of protection from future illness of the same kind. (The idea of disease caused by unseen infectious agents, or germ theory, did not arise until much later!) Although early societies recognized the phenomenon of acquired immunity, almost 2000 years passed before the concept was disseminated into the current common medical practice of vaccination.

Early Vaccination Studies Led the Way to Immunology

The first recorded attempts to deliberately induce immunity were performed by the Chinese and Turks in the fifteenth century. They were attempting to prevent smallpox, a disease that is fatal in about 30% of cases and that leaves survivors disfigured for life (Figure 1-1). Reports suggest that the dried crusts derived from smallpox pustules were either inhaled or inserted into small cuts in the skin (a technique called variolation) in order to prevent this dreaded disease. In 1718, Lady Mary Wortley Montagu, the wife of the British ambassador in Constantinople, observed the positive effects of variolation on the native Turkish population and had the technique performed on her own children.

FIGURE 1-1 African child with rash typical of smallpox on face, chest, and arms. Smallpox, caused by the virus Variola major, has a 30% mortality rate. Survivors are often left with disfiguring scars.

The English physician Edward Jenner later made a giant advance in the deliberate development of immunity, again targeting smallpox. In 1798, intrigued by the fact that milkmaids who had contracted the mild disease cowpox were subsequently immune to the much more severe smallpox, Jenner reasoned that introducing fluid from a cowpox pustule into people (i.e., inoculating them) might protect them from smallpox. To test this idea, he inoculated an 8-year-old boy with fluid from a cowpox pustule and later intentionally infected the child with smallpox. As predicted, the child did not develop smallpox. Although this represented a major breakthrough, as one might imagine, these sorts of human studies could not be conducted under current standards of medical ethics.

Jenner’s technique of inoculating with cowpox to protect against smallpox spread quickly through Europe. However, it was nearly 100 years before this technique was applied to other diseases. As so often happens in science serendipity combined with astute observation led to the next major advance in immunology: the induction of immunity to cholera. Louis Pasteur had succeeded in growing the bacterium that causes fowl cholera in culture, and confirmed this by injecting it into chickens that then developed fatal cholera. After returning from a summer vacation, he and colleagues resumed their experiments, injecting some chickens with an old bacterial culture. The chickens became ill, but to Pasteur’s surprise, they recovered. Interested, Pasteur then grew a fresh culture of the bacterium with the intention of trying this experiment again. But as the story is told, his supply of chickens was limited, and therefore he tested this fresh bacterial culture on a mixture of chickens; some previously exposed to the “old” bacteria and some new, unexposed birds. Unexpectedly, the chickens with past exposure to the older bacterial culture were completely protected from the disease and only the previously unexposed chickens died. Pasteur hypothesized and later showed that aging had weakened the virulence of the bacterial pathogen and that such a weakened or attenuated strain could be administered to provide immunity against the disease. He called this attenuated strain a vaccine (from the Latin vacca, meaning “cow”), in honor of Jenner’s work with cowpox inoculation.

Pasteur extended his discovery to other diseases, demonstrating that it was possible to attenuate a pathogen and administer the attenuated strain as a vaccine. In a now classic experiment performed in the small village of Pouilly-le-Fort in 1881, Pasteur first vaccinated one group of sheep with anthrax bacteria (Bacillus anthracis) that were attenuated by heat treatment. He then challenged the vaccinated sheep, along with some unvaccinated sheep, with a virulent culture of the anthrax bacillus. All the vaccinated sheep lived and all the unvaccinated animals died.

In 1885, Pasteur administered his first vaccine to a human, a young boy who had been bitten repeatedly by a rabid dog (Figure 1-2). The boy, Joseph Meister, was inoculated with a series of attenuated rabies virus preparations. The rabies vaccine is one of very few that can be successful when administered shortly after exposure, as long as the virus has not yet reached the central nervous system and begun to induce neurologic symptoms. Joseph lived, and later became a caretaker at the Pasteur Institute, which was opened in 1887 to treat the many rabies victims that began to flood in when word of Pasteur’s success spread; it remains to this day an institute dedicated to the prevention and treatment of infectious disease.

FIGURE 1-2 Wood engraving of Louis Pasteur watching Joseph Meister receive the rabies vaccine.

Key Concepts:

• Long before we understood much about the immune system, key principles of this system were already being studied and applied to solve public health issues associated with infectious disease.
• The principle behind vaccination is that exposure to safe forms of an infectious agent can result in future acquired protection, or immunity, to the real and more dangerous infectious agent.

Vaccination Is an Ongoing, Worldwide Enterprise

The emergence of the study of immunology and the discovery of vaccines are tightly linked. The goal of vaccination is to expose the individual to a pathogen (or a fragment of pathogen) in a safe way, allowing the immune cells to respond, developing and honing a strategy to fight this pathogen or others that are similar. When it works, this experiential learning process can produce extremely specific and long-lived memory cells, capable of protecting the host from the pathogen for many decades. However, the development of effective vaccines for some pathogens is still a major challenge, as discussed in Chapter 17. Yet, despite many biological and social hurdles, vaccination has yielded some of the most profound success stories in terms of improving mortality rates worldwide, especially in very young children.

In 1977, the last known case of naturally acquired smallpox was seen in Somalia. This dreaded disease was eradicated by universal application of a vaccine similar to that used by Jenner in the 1790s. One consequence of eradication is that universal vaccination becomes unnecessary. This is a tremendous benefit, as most vaccines carry at least a slight risk to those vaccinated. In many cases every individual does not need to be immune in order to protect most of the population. As a critical mass of people acquires protective immunity, either through vaccination or recovery from infection, they can serve as a buffer for the rest. This principle, called herd immunity, works by decreasing the number of individuals who can harbor and spread an infectious agent, significantly reducing the chances that susceptible individuals will become infected. This presents an important altruistic consideration: although many of us could survive infectious diseases for which we receive a vaccine (such as the flu), this is not true for everyone. Some individuals cannot receive the vaccine (e.g., the very young or immune compromised), and vaccination is never 100% effective. In other words, the susceptible, nonimmune individuals among us can benefit from the pervasive immunity of their neighbors. For good reason, the balance of personal choice and public good is an area of heated debate (see Clinical Focus Box 1-1).

CLINICAL FOCUS BOX 1-1

Vaccine Controversy: Weighing Evidence against Myth and Personal Freedom against Public Good

Despite the record of worldwide success of vaccines in improving public health, some opponents claim that vaccines do more harm than good, pressing for elimination or curtailment of childhood vaccination programs. There is no dispute that vaccines represent unique safety issues, since they are administered to people who are healthy. Furthermore, there is general agreement that vaccines must be rigorously tested and regulated, and that the public must have access to clear and complete information. Although the claims of vaccine critics must be evaluated, many can be addressed by careful and objective examination of records.

One example is the claim that vaccines given to infants and very young children contribute to the rising incidence of autism. This began with the suggestion that thimerosal, a mercury-based additive used to inhibit bacterial growth in some vaccine preparations since the 1930s, was causing autism in children. In 1999 the U.S. Public Health Service (USPHS) and the American Academy of Pediatrics (AAP) recommended that vaccine manufacturers begin to gradually phase out thimerosal with the goal of keeping children at or below Environmental Protection Agency (EPA)–recommended maximums in mercury exposure. With the release of this recommendation, parent-led public advocacy groups began a media-fueled campaign to build a case demonstrating a link between vaccines and an epidemic of autism, leading to declines in vaccination rates. However, cases of autism in children have continued to rise since thimerosal was removed from all childhood vaccines in 2001, dispelling this claim.

A 1998 study appearing in the Lancet, a reputable British medical journal, further fueled antivaccine organizations. The article, published by Andrew Wakefield, claimed the measles-mumps-rubella (MMR) vaccine caused pervasive developmental disorders in children, including disorders on the autism spectrum. Almost two decades of subsequent research has been unable to substantiate these claims, and 10 of the original 13 authors on the paper later withdrew their support for the conclusions of the study. In 2010, the Lancet retracted the original article when it was shown that the data in the study had been falsified to reach desired conclusions. Nonetheless, in the years between the original publication of the Lancet article and its retraction, this case is credited with decreasing rates of MMR vaccination from a high of 92% to a low of almost 60% in certain areas of the United Kingdom. The resulting expansion in the population of susceptible individuals led to rising rates of measles and mumps infection and is credited with thousands of extended hospitalizations and several deaths of infected children.

Why has there been such a strong urge to cling to the belief that vaccines are linked autism in children despite much scientific evidence to the contrary? One possibility lies in the timing of the two events. Based on current AAP recommendations, most children receive 14 different vaccines and a total of up to 26 shots by the age of 2. In 1983, children received less than half this number. Couple this with the onset of the first signs of autism and other developmental disorders in children, which can appear quite suddenly and peak around 2 years of age. Furthermore, basic scientific literacy among the general public has decreased, while the number of ways to gather medical information (accurate or not) has increased. As concerned parents search for answers, one can begin to see how even scientifically unsupported links could begin to take hold.

Importantly, vaccination is not just a personal health choice; it’s a public health issue. All states require childhood vaccinations before matriculation into the public school system, although medical exemptions are allowed for children who are immunocompromised, or who have known allergic reactions to vaccines. Approximately 20 states also allow a range of personal, philosophical, or moral exemptions, which vary widely in their specifications and required documentation. In June 2015, California joined two other states (Mississippi and West Virginia) by enacting a controversial law (SB277) aimed at removing the religious exemptions clause, which allows families to opt out of vaccinating their children based on their religious beliefs. Research has shown that states with the most lenient exemptions have the lowest vaccination rates and that there is a significant correlation between ease of opting out and the rates of vaccine-preventable illness in that state.

This brings us to an important ethical question: how to draw the line between what is an allowable exemption and what is not? In a classic example of “tragedy of the commons”, how do we weigh public good against personal freedom? Families who choose to opt out of vaccination for social or religious reasons tend to cluster with other such families. This clustering of unprotected individuals can escalate the spread of disease and lead to erosion of herd immunity, placing the entire community at risk. How do we weigh the rights of community members who are not eligible for vaccination, such as the very young, seriously ill, or immune compromised, against personal freedom?

The history of science and medicine is not without stories of bias and harm, vaccines included. However, while answers to these questions may be hard to find, opting for an exemption from rational scientific debate should not be one of them.

REFERENCES

• Larson, H. J., L. Z. Cooper, J. Eskola, S. L. Katz, and S. Ratzan. 2011. Addressing the vaccine confidence gap. Lancet 378:526.
• Gostin, L. O. 2015. Law, ethics, and public health in the vaccination debates: politics of the measles outbreak. JAMA 313:1099.

However, there is a darker side to eradication and the end of universal vaccination. Over time, the number of people with no immunity to the disease will begin to rise, ending herd immunity. Vaccination for smallpox largely ended by the early to mid-1970s, leaving well over half of the current world population susceptible to the disease. This means that smallpox, or a weaponized version, is now considered a potential bioterrorism threat. In response, new and safer vaccines against smallpox are still being developed today, most of which go toward vaccinating U.S. military personnel thought to be at greatest risk of possible exposure.

In the United States and other industrialized nations, vaccines have eliminated a host of childhood diseases that were the cause of death for many young children just 50 years ago. Measles, mumps, chickenpox, whooping cough (pertussis), tetanus, diphtheria, and polio, once thought of as an inevitable part of childhood, are now extremely rare or nonexistent in the United States because of current vaccination practices (Table 1-1). One can hardly estimate the savings to society resulting from the prevention of these diseases. Aside from suffering and mortality, the cost to treat these illnesses and their aftereffects or sequelae (such as paralysis, deafness, blindness, and developmental delays) is immense and dwarfs the costs of immunization.

TABLE 1-1 Cases of selected infectious disease in the United States before and after the introduction of effective vaccines

	ANNUAL CASES/YR	CASES IN 2016
Disease	Prevaccine	Postvaccine	Reduction (%)
Smallpox	48,164	0	100
Diphtheria	175,885	0	100
Measles	503,282	79^	99.98
Mumps	152,209	145*	98.90
Pertussis (“whooping cough”)	147,271	964*	99.35
Paralytic polio	16,316	0	100
Rubella (German measles)	47,745	0*	100
Tetanus (“lockjaw”)	1,314 (deaths)	1* (case)	99.92
Invasive Haemophilus influenzae	20,000	356*	98.22
Data from CDC Statistics of Notifiable Diseases (as of January, 2017). The number of annual cases per year in 2016 increased^ or decreased* since 2010.

Although these diseases have been largely eradicated in the United States, worldwide vaccination efforts continue. In 2000 the Global Alliance for Vaccines and Immunization (Gavi) was born. The goal of this international public-private partnership is to increase immunization coverage for children in poor countries and to accelerate access to new vaccines. In their first 15 years Gavi claims to have reached 500 million additional children, avoiding an estimated 7 million deaths. In addition to raising billions of dollars by the end of 2015, it may also be their unique approach that helps yield the greatest long-term success. The organization allows eligible developing countries to set their own agenda and monitor progress, while also requiring a financial commitment. This is sustained by both monetary and nonfinancial support through such entities as the World Bank, World Health Organization, donor countries, and the Bill & Melinda Gates Foundation. GAVI’s goal is to create equal access to both established and new vaccines so that someday all nations will be able to pay the price for these vaccines in dollars rather than lives.

Despite the many successes of vaccine programs, such as the eradication of smallpox, many vaccine challenges still remain. Perhaps the greatest current challenge is the design of effective vaccines for major killers such as malaria and human immunodeficiency virus (HIV). As the tools of molecular and cellular biology, genomics, and proteomics improve, so will our understanding of the immune system, leaving us better positioned to make progress toward preventing these and other emerging infectious diseases. A further issue is the fact that millions of children in developing countries die from diseases that are fully preventable by available, safe vaccines. High manufacturing costs, instability of the products, and cumbersome delivery problems keep these vaccines from reaching those who might benefit the most. This problem could be alleviated in many cases by development of future-generation vaccines that are inexpensive, heat stable, and administered without a needle. Finally, misinformation and myth surrounding vaccine efficacy and side effects continue to hamper many potentially life saving vaccination programs (see Clinical Focus Box 1-1).

Key Concepts:

• Worldwide vaccination programs have effectively eradicated or protected us from many previously deadly infectious diseases, especially in young children.
• If many individuals in a group are protected from an infectious agent, either naturally or through vaccination, it is less likely to spread and unvaccinated individuals in the group are inadvertently protected as well.

Immunology Is about More than Just Vaccines and Infectious Disease

For some diseases, immunization programs may be the best or even the only effective defense. At the top of this list are infectious diseases that can cause serious illness or even death in unvaccinated individuals. Those transmitted by microbes that spread rapidly between hosts are especially good candidates for vaccination. However, vaccination, a costly process, is not the only way to prevent or treat infectious disease. Many infections are prevented, first and foremost, by other means. For instance, access to clean water, good hygiene practices, and nutrient-rich diets go a long way toward inhibiting transmission of infectious agents. In addition, some infectious diseases are self-limiting, easily treatable, and nonlethal for most individuals; these diseases are unlikely targets for expensive vaccination programs. They include the common cold, caused by rhinovirus infection, and cold sores that result from herpes simplex virus infection. Finally, some infectious agents are just not amenable to vaccination. This could be due to a range of factors, such as the number of different molecular variants of the organism, the complexity of the regimen required to generate protective immunity, or an inability to establish the needed immunologic memory responses (more on this later).

One major breakthrough in the treatment of infectious disease came when the first antibiotics were introduced in the 1920s. Antibiotics are chemical agents designed to destroy certain types of bacteria. They are ineffective against other types of infectious agents, as well as some bacterial species. At present there are more than 100 different antibiotics on the market, although most fall into just six or seven categories based on their mode of action. One particularly worrying trend is the steady rise in antibiotic resistance among bacterial strains traditionally amenable to these drugs, making the design of next-generation antibiotics and new classes of drugs increasingly important.

Although antiviral drugs are also available, most are not effective against many of the more common viruses, including influenza virus. This makes preventive vaccination the only real recourse against many debilitating infectious agents, even those that rarely cause mortality in healthy adults. For instance, because of the high mutation rate of the influenza virus, each year a new flu vaccine must be prepared based on a prediction of the prominent genotypes likely to be encountered in the next season. Some years this vaccine is more effective than others. If and when a more lethal and unexpected pandemic strain arises, there will be a race between its spread and the manufacture and administration of a new vaccine. With the current ease of worldwide travel, emergence of a pandemic strain of influenza today could dwarf the devastation wrought by the 1918 flu pandemic, which left up to 50 million dead.

However, the eradication of infectious disease is not the only worthy goal of immunology research. As we will see later, exposure to infectious agents is part of our evolutionary history. Wiping out all microbes from the bodies of their hosts could potentially cause more harm than good, both for the hosts and for the environment. Thanks to many technical advances allowing scientific discoveries to move efficiently from the bench to the bedside, clinicians can now manipulate the immune response in ways never before possible. For example, treatments to boost, inhibit, or redirect the specific efforts of immune cells are being applied to treat autoimmune disease, cancer, transplant rejection, and allergy, as well as other chronic disorders. These efforts are already extending and saving lives. Likewise, a clearer understanding of immunity has highlighted the interconnected nature of body systems, providing unique insights into areas such as cell biology, human genetics, and metabolism. For example, while a cure for acquired immune deficiency syndrome (AIDS) and a vaccine to prevent HIV infection are still the primary targets for many scientists who study this disease, a great deal of basic science knowledge came from the study of just this one virus and its interaction with the human immune system.

Key Concept:

• Beyond vaccination, it has become increasingly clear that elements of the immune system impact or regulate many other body systems and that these elements can be manipulated for the treatment of a range of human diseases

Immunity Involves Both Humoral and Cellular Components

Pasteur showed that vaccination worked, but he did not understand how. Some scientists believed that immune protection in vaccinated individuals was mediated by cells, while others postulated that a soluble agent delivered protection. The experimental work of Emil von Behring and Shibasaburo Kitasato in 1890 gave the first insights into the mechanism of immunity, earning von Behring the Nobel Prize in Physiology or Medicine in 1901 (Table 1-2). Von Behring and Kitasato demonstrated that serum—the liquid, noncellular component recovered from coagulated blood—from animals previously immunized with diphtheria could transfer the immune state to unimmunized animals.

TABLE 1-2 Nobel Prizes for immunologic research

Year	Recipient	Country	Research
1901	Emil von Behring	Germany	Serum antitoxins
1905	Robert Koch	Germany	Cellular immunity to tuberculosis
1908	Elie Metchnikoff Paul Ehrlich	Russia Germany	Role of phagocytosis (Metchnikoff) and antitoxins (Ehrlich) in immunity
1913	Charles Richet	France	Anaphylaxis
1919	Jules Bordet	Belgium	Complement-mediated bacteriolysis
1930	Karl Landsteiner	United States	Discovery of human blood groups
1951	Max Theiler	South Africa	Development of yellow fever vaccine
1957	Daniel Bovet	Switzerland	Antihistamines
1960	F. Macfarlane Burnet Peter Medawar	Australia Great Britain	Discovery of acquired immunological tolerance
1972	Rodney R. Porter Gerald M. Edelman	Great Britain United States	Chemical structure of antibodies
1977	Rosalyn R. Yalow	United States	Development of radioimmunoassay
1980	George Snell Jean Dausset Baruj Benacerraf	United States France United States	Major histocompatibility complex
1984	Niels K. Jerne César Milstein Georges J. F. Köhler	Denmark Great Britain Germany	Immune-regulatory theories (Jerne) and technological advances in the development of monoclonal antibodies (Milstein and Köhler)
1987	Susumu Tonegawa	Japan	Gene rearrangement in antibody production
1990	E. Donnall Thomas Joseph Murray	United States United States	Transplantation immunology
1996	Peter C. Doherty Rolf M. Zinkernagel	Australia Switzerland	Role of major histocompatibility complex in antigen recognition by T cells
2002	Sydney Brenner H. Robert Horvitz John E. Sulston	South Africa United States Great Britain	Genetic regulation of organ development and cell death (apoptosis)
2008	Harald zur Hausen Françoise Barré-Sinoussi Luc Montagnier	Germany France France	Role of HPV in causing cervical cancer (zur Hausen) and the discovery of HIV(Barré-Sinoussi and Montagnier)
2011	Jules Hoffmann Bruce A. Beutler Ralph M. Steinman	France United States United States	Discovery of activating principles of innate immunity (Hoffmann and Beutler) and role of dendritic cells in adaptive immunity (Steinman)
2015	William C. Campbell Satoshi Ōmura Youyou Tu	United States Japan China	Discoveries concerning novel therapies against parasitic diseases caused by roundworms (Campbell and Ōmura) and malaria (Tu)
2016	Yoshinori Ohsumi	Japan	Elucidation of the mechanisms underlying autophagy, involved in degradation of intracellular proteins during homeostasis and infection

In 1883, even before the discovery that a serum component could transfer immunity, Elie Metchnikoff, another Nobel Prize winner, demonstrated that cells also contribute to the immune state of an animal. He observed that certain white blood cells, which he termed phagocytes, ingested (phagocytosed) microorganisms and other foreign material (Figure 1-3, left). Noting that these phagocytic cells were more active in animals that had been immunized, Metchnikoff hypothesized that cells, rather than serum components, were the major effectors of immunity. The active phagocytic cells identified by Metchnikoff were likely blood monocytes and neutrophils (see Chapter 2), which can now be imaged using very sophisticated microscopic techniques (Figure 1-3, right).

FIGURE 1-3 Left: Drawing by Elie Metchnikoff of phagocytic cells surrounding a foreign particle. Right: Modern image of a phagocyte engulfing bacteria that cause tuberculosis. Metchnikoff first described and named the process of phagocytosis, or ingestion of foreign matter by white blood cells. Today, phagocytic cells can be imaged in great detail using advanced microscopy techniques.

The first drawing shows a phagocytic cell with the nucleus densely colored. The cell is surrounded by numerous irregular shaped particles on all sides. The second micrograph shows a microscopic view of a phagocyte engulfing bacteria.

Humoral Immunity

The debate over cells versus soluble mediators of immunity raged for decades. In search of the protective agent of immunity, various researchers in the early 1900s helped characterize the active immune component in blood serum. This soluble component could neutralize or precipitate toxins and could agglutinate (clump) bacteria. In each case, the component was named for the activity it exhibited: antitoxin, precipitin, and agglutinin, respectively. Initially, different serum components were thought to be responsible for each activity, but during the 1930s, mainly through the efforts of Elvin Kabat, a fraction of serum first called gamma globulin (now immunoglobulin) was shown to be responsible for all these activities. The soluble active molecules in the immunoglobulin fraction of serum are now commonly referred to as antibodies. Because these antibodies were contained in body fluids (known at that time as the body humors), the immunologic events they participated in was called humoral immunity.

The observations made by von Behring and Kitasato were quickly applied to clinical practice. Antiserum, the antibody-containing serum fraction from a pathogen-exposed individual, derived in this case from horses, was given to patients suffering from diphtheria and tetanus. A dramatic vignette of this application is described in Clinical Focus Box 1-2. Today there are still therapies that rely on transfer of immunoglobulins to protect susceptible individuals. For example, emergency use of immune serum containing antibodies against snake or scorpion venom, for treating the victims of certain poisonous bites or stings. This form of immune protection that is transferred between individuals is called passive immunity because the individual receiving it did not make his or her own immune response against the pathogen. Newborn infants benefit from passive immunity provided by the presence of maternal antibodies in their circulation. Passive immunity may also be used as a preventive (prophylaxis) to boost the immune potential of those with compromised immunity or who anticipate future exposure to a particular microbe.

CLINICAL FOCUS BOX 1-2

Passive Antibodies and the Iditarod

In 1890, immunologists Emil Behring and Shibasaburo Kitasato, working together in Berlin, reported an extraordinary experiment. After immunizing rabbits with an attenuated form of tetanus and then collecting blood serum (immune serum) from these animals, they injected a small amount of the immune serum (a cell-free fluid) into the abdominal cavity of six mice. Twenty-four hours later, they infected the treated mice and untreated controls with live, virulent tetanus bacteria. All of the control mice died within 48 hours of infection, whereas the treated mice not only survived but showed no effects of infection. This landmark experiment demonstrated two important points. First, it showed that substances that could protect an animal against pathogens appeared in serum following immunization. Second, this work demonstrated that immunity could be passively acquired, or transferred from one animal to another by taking serum from an immune animal and injecting it into a nonimmune one. These and subsequent experiments did not go unnoticed. Both men eventually received titles (Behring became von Behring and Kitasato became Baron Kitasato). A few years later, in 1901, von Behring was awarded the first Nobel Prize in Physiology or Medicine (see Table 1-2).

These early observations, and others, paved the way for the introduction of passive immunization into clinical practice. During the 1930s and 1940s, passive immunotherapy, the endowment of resistance to pathogens by transfer of antibodies from an immunized donor to an unimmunized recipient, was used to prevent or modify the course of measles and hepatitis A. Subsequently, clinical experience and advances in the technology of immunoglobulin preparation have made this approach a standard medical practice. Passive immunization based on the transfer of antibodies is widely used in the treatment of immunodeficiency and some autoimmune diseases. It is also used to protect individuals against anticipated exposure to infectious and toxic agents against which they have no immunity. Finally, passive immunization can be lifesaving during episodes of certain types of acute infection, such as following exposure to rabies virus.

Immunoglobulin for passive immunization is prepared from the pooled plasma of thousands of donors. In effect, recipients of these antibody preparations are receiving a sample of the antibodies produced by many people to a broad diversity of pathogens—a gram of intravenous immune globulin (IVIG) contains about 10¹⁸ molecules of antibody that recognize more than 10⁷ different antigens. However, a product derived from the blood of such a large number of donors carries a risk of harboring pathogenic agents, particularly viruses. This risk is minimized by modern-day production techniques. The manufacture of IVIG involves treatment with solvents, such as ethanol, and the use of detergents that are highly effective in inactivating viruses such as HIV and hepatitis. In addition to treatment against infectious disease, or in acute situations, IVIG is also used today to treat some chronic diseases, including several forms of immune deficiency. In all cases, the transfer of passive immunity supplies only temporary protection.

One of the most famous instances of passive antibody therapy occurred in 1925, when an outbreak of diphtheria was diagnosed in what was then the remote outpost of Nome, Alaska. Lifesaving diphtheria-specific antibodies were available in Anchorage, but no roads were open and the weather was too dangerous for flight. History tells us that 20 mushers set up a dogsled relay to cover the almost 700 miles between Nenana, the end of the railroad run, and remote Nome. In this relay, two Norwegians and their dogs covered particularly critical territory and withstood blizzard conditions: Leonhard Seppala (Figure 1, left), who covered the most treacherous territory, and Gunnar Kaasen, who drove the final two legs in whiteout conditions, behind his lead dog Balto. Kaasen and Balto arrived in time to save many of the children in the town. To commemorate this heroic event, later that same year a statue of Balto was placed in Central Park, New York City, where it still stands today. This journey is memorialized every year in the running of the Iditarod Trail Sled Dog Race. A map showing the current route of this more than 1000-mile trek is shown in Figure 1, right.

FIGURE 1 Left: Leonhard Seppala, the Norwegian who led a team of sled dogs in the 1925 diphtheria antibody run from Nenana to Nome, Alaska. Right: Map of the current route of the Iditarod Trail Sled Dog Race, which commemorates this historic delivery of lifesaving antibody.

A photo shows Leonhard Seppala kneeling on his right leg. He is hugging a Husky dog on each side. The map shows the route of the Iditarod Trail Sled Dog Race. The route starts at Nome and passes through Safety, White Mountain, Golovin, Elim, Koyuk, Shaktoolik, Unalakleet, Kaltag, Nulato, Galena, Ruby, Cripple, Ophir, Takotna, McGrath, Nikolai, Rohn, Rainy Pass, Finger Lake, Skwenta, Yentna, Willow, Campell Airstrip, and ends at Anchorage.

While passive immunity can supply a quick solution, it is short-lived and limited, as the cells that produce these antibodies are not being transferred. On the other hand, natural infection, or the administration of a vaccine, is said to engender active immunity in the host: the production of one’s own immunity. The induction of active immunity can supply the individual with renewable, long-lived protection from the specific infectious organism. As we discuss further below, this long-lived protection comes from memory cells, which provide protection for years or even decades after the initial exposure.

Cell-Mediated Immunity

As described above, a controversy developed between those who held to the concept of humoral immunity and those who agreed with Metchnikoff’s concept of immunity imparted by specific cells, or cell-mediated immunity. The relative contributions of the two were widely debated at the time. It is now obvious that both are correct—the full immune response requires the action of both cells (cell-mediated) and soluble antibody components (humoral), the latter derived from white blood cells. Early studies of immune cells were hindered by the lack of genetically defined animal models and modern tissue culture techniques, whereas early studies with serum took advantage of the ready availability of blood and established biochemical techniques to purify proteins. Information about cellular immunity therefore lagged behind the characterization of humoral immunity.

In a key experiment in the 1940s, Merrill Chase, working at the Rockefeller Institute, succeeded in conferring immunity against tuberculosis by transferring white blood cells between guinea pigs. Until that point, attempts to develop an effective vaccine or antibody therapy against tuberculosis had met with failure. Thus, Chase’s demonstration helped to rekindle interest in cellular immunity. With the emergence of improved cell culture and transfer techniques in the 1950s, the lymphocyte, a type of white blood cell, was identified as the cell type responsible for both cellular and humoral immunity. Soon thereafter, experiments with chickens pioneered by Bruce Glick at Ohio State University indicated the existence of two types of lymphocytes: T lymphocytes (T cells), derived from the thymus, and B lymphocytes (B cells), derived from the bursa of Fabricius in birds (an outgrowth of the cloaca). In a convenient twist of nomenclature that makes B- and T-cell origins easier to remember, the mammalian equivalent of the bursa of Fabricius is bone marrow, the home of developing B cells in mammals. We now know that cellular immunity is imparted by T cells and that the antibodies produced by B cells confer humoral immunity. The real controversy about the roles of humoral versus cellular immunity was resolved when the two systems were shown to be intertwined and it became clear that both are necessary for a complete immune response against most pathogens.

Key Concepts:

• Humoral immunity involves combating pathogens via antibodies, which are produced by B cells and can be found in bodily fluids. Antibodies can be transferred between individuals to provide passive immune protection.
• Cell-mediated immunity involves the work of pathogen-specific T lymphocytes, which can act directly to eradicate the infectious agent as well as aiding other cells in their work.

How Are Foreign Substances Recognized by the Immune System?

One of the great enigmas confronting early immunologists concerned how the specificity of the immune response was determined for a particular pathogen or foreign material. Around 1900, Jules Bordet at the Pasteur Institute expanded the concept of immunity beyond infectious diseases, demonstrating that nonpathogenic substances, such as red blood cells from other species, could also elicit an immune response. Serum from an animal that had been inoculated with noninfectious but otherwise foreign (nonself) material would nevertheless react with the injected material in a specific manner. The work of Karl Landsteiner and those who followed him showed that injecting an animal with almost any nonself organic chemical could induce production of antibodies that would bind specifically to the chemical. These studies demonstrated that antibodies have an almost unlimited range of reactivity, including being able to respond to compounds that had only recently been synthesized in the laboratory and were otherwise not found in nature! In addition, it was shown that molecules differing in the smallest detail, such as by a single amino acid, could be distinguished by their reactivity with different antibodies. To explain this high degree of specificity the selective theory was proposed.

The earliest conception of the selective theory dates to Paul Ehrlich in 1900. In an attempt to explain the origin of serum antibody, Ehrlich proposed that cells in the blood expressed a variety of receptors, which he called side-chain receptors, that could bind to infectious agents and inactivate them. Borrowing a concept used by Emil Fischer in 1894 to explain the interaction between an enzyme and its substrate, Ehrlich proposed that binding of the receptor to an infectious agent was like the fit between a lock and key. Ehrlich suggested that interaction between an infectious agent and a cell-bound receptor would induce the cell to produce and release more receptors with the same specificity or conformation (Figure 1-4). He thus coined the term antigen, any substance that elicits a specific response by B or T lymphocytes. In Ehrlich’s mind, the cells were pluripotent, expressing a number of different receptors, each of which could be individually “selected” by the antigen. According to Ehrlich’s theory, the specificity of the receptor was determined in the host before its exposure to the foreign antigen, and therefore the antigen selected the appropriate receptor. Ultimately, most aspects of Ehrlich’s theory would be proven correct, with the following minor refinement: instead of one cell making many receptors, each cell makes many copies of just one membrane-bound receptor (one specificity). An army of cells, each with a different antigen specificity, is therefore required. The selected B cell can be triggered to proliferate and to secrete many copies of these receptors in soluble form (now called antibodies) once it has been selected by antigen binding.

FIGURE 1-4 Representation of Paul Ehrlich’s side-chain theory to explain antibody formation. In Ehrlich’s initial theory, the cell is pluripotent in that it expresses a number of different receptors or side chains, all with different specificities. If an antigen encounters this cell and has a good fit with one of its side chains, synthesis of that receptor is triggered and the receptor will be released.

The first illustration shows an oval shaped cell with side chains. Antigens are shown moving toward the side chains. In the second illustration, the number of side chains are higher on the cell body. An antigen is shown attached to a side chain. The third illustration shows the many antigens attaching to the side chains on the cell. The fourth illustration shows the cell covered with side chains and numerous antigens attached to them. Some side chains without antigens are shown detaching from the cell body.

Through the insights of F. Macfarlane Burnet, Niels Jerne, and David Talmadge, this hypothesis was restructured into a model that came to be known as the clonal selection theory. This model has been further refined over the years and is now accepted as an underlying paradigm of modern immunology. According to this theory, an individual B or T lymphocyte expresses many copies of a membrane receptor that is specific for a single, distinct antigen. This unique receptor specificity is determined in the lymphocyte before it is exposed to the antigen. Binding of antigen to its specific receptor activates the cell, causing it to proliferate into a clone of daughter cells that have the same receptor specificity as the parent cell.

Overview Figure 1-5 presents a very basic scheme of clonal selection in the humoral (B-cell) and cellular (T-cell) branches of immunity. We now know that B cells produce antibodies, a soluble version of their receptor protein, that bind to foreign proteins, flagging them for destruction. T cells, which come in several different forms, also use their surface-bound T-cell receptors to sense antigen. These cells can perform a range of different functions once selected by antigen encounter, including the secretion of soluble compounds to aid other white blood cells (such as B lymphocytes) and the destruction of infected host cells.

OVERVIEW FIGURE 1-5

An Outline for the Humoral and Cell-Mediated (Cellular) Branches of the Immune System

The humoral response involves interaction of B cells with foreign proteins, called antigens, and their differentiation into antibody-secreting cells. The secreted antibody binds to foreign proteins or infectious agents, helping to clear them from the body. The cell-mediated response involves various subpopulations of T lymphocytes, which can perform many functions, including the secretion of soluble messengers that help direct other cells of the immune system and direct killing of infected cells.

Foreign proteins or infectious agents are injected into a vertebrate body (mouse). The two different types of responses - Humoral response (B lymphocytes) and Cell-mediated response (T lymphocytes) are depicted. The process of Humoral response shows B cell with B-cell receptors and antigens forming Antigen-selected antibody secreting B cell. This process also requires Cytokine secreted by T cells. This cell produces antibodies that eliminate the antigens.

In cell-mediated response, two kinds of responses are seen. In the first response process, T cell with receptors and antigen form Antigen selected T cells that secrete Cytokine. In the other response process, T cells with receptors, antigens, and cytokine secreted by T cells form Antigen selected T cells that kill the infected cells.

Key Concepts:

• Antigen-specific immunity relies on surface molecules, called B- and T-cell receptors, unique to each individual lymphocyte. These receptors bind to a specific pathogenic structure called an antigen.
• Clonal selection is the process by which individual T and B lymphocytes are engaged by antigen and cloned to create a population of antigen-reactive cells with identical antigen specificity.