A Concise History of Immunology
Steven Greenberg
The role of smallpox in the development of vaccination
The concept of immunity from disease dates back at least to Greece in the 5th century BC.
Thucydides wrote of individuals who recovered from the plague, which was raging in Athens at
the time. These individuals, who had already contracted the disease, recovered and became“immune” or “exempt.” However, the earliest recognized attempt to intentionally induce
immunity to an infectious disease was in the 10th century in China, where smallpox was
endemic. The process of “variolation” involved exposing healthy people to material from thelesions caused by the disease, either by putting it under the skin, or, more often, inserting
powdered scabs from smallpox pustules into the nose. Variolation was known and practiced
frequently in the Ottoman Empire, where it had been introduced by Circassian traders around
1670. Unfortunately, because there was no standardization of the inoculum, the variolationoccasionally resulted in death or disfigurement from smallpox, thus limiting its acceptance.
Variolation later became popular in England, mainly due to the efforts of Lady Mary WortleyMontague who survived smallpox but who lost a brother to it. Lady Montague was married to
Lord Edward Wortley Montague, the ambassador to the Sublime Porte of the Ottomans in
Istanbul. While in Istanbul, Lady Montague observed the practice of variolation. Determined not
to have her family suffer as she had, she directed the surgeon of the Embassy to learn thetechnique and, in March 1718, to variolate her five year-old son. After her return to England, shepromoted the technique, and had her surgeon variolate her four-year old daughter in the presenceof the king’s physician. The surgeon, Charles Maitland, was given leave to perform what came tobe known as the Royal Experiment, in which he variolated six condemned prisoners who later
survived. By these and other experiments, the safety of the procedure was established, and two of
the king’s grandchildren were variolated on April 17, 1722. After this, the practice of variolation
spread rapidly throughout England in the 1740s and then to the American colonies.
Edward Jenner and the development of the first safe vaccine for smallpox
Although Jenner is rightly celebrated for his development of cowpox as a safe vaccine forsmallpox, he was not the first to make use of a relatively non-pathogenic virus to induce
immunity. In 1774, Benjamin Jesty, a farmer, inoculated his wife with the vaccinia virus
obtained from “farmer Elford of Chittenhall, near Yetminster.” In 1796, Jenner inoculated James
Phipps with material obtained from a cowpox lesion that appeared on the hand of a dairymaid(Fig. 1). Six weeks later, he inoculated the experimental subject with smallpox without
producing disease. Although this experiment justifiably lacked an appropriate control, further
studies by Jenner established the efficacy of his vaccination procedure. For this feat, Jennerreceived a cash prize of 30,000 pounds and election to nearly all of the learned societies
throughout Europe.

1Fig. 1. Jenner’s drawing ofcowpox lesion from which hecreated his vaccine.

Koch, Pasteur, and the germ theory of diseaseIn 1875, Robert Koch, a country physician with no formal scientific training, inoculated the earof a rabbit with the blood of an animal that had died of anthrax. The rabbit died the next day. He
isolated infected lymph nodes from the rabbit and was able to show that the bacteria contained
within them could transfer disease to other animals. He developed and refined techniques
necessary for the cultivation of bacteria, including the development of agar growth medium. He
was appointed to the Institute of Hygiene in Berlin, where his ultimate goal was to identify theorganism responsible for the “White Death”--tuberculosis.
Quite independently, Louis Pasteur began his studies of the “chicken cholera bacillus.” In a
serendipitous discovery, Pasteur inadvertently left a flask of the bacillus on the bench over thesummer and inoculated 8 chickens with this “old but viable” stock of chicken cholera bacillus.
He found that not only did the chickens not die, but they did not even appear ill! Pasteur said thatthe virulent chicken cholera bacillus had become attenuated by sitting on the bench over thesummer months. The similarity between these results and those of and Jenner using vaccinia
virus was immediately apparent to him. In honor of Jenner, Pasteur called his treatment
vaccination. Pasteur later worked on anthrax and rabies and developed the first viable vaccine foranthrax and rabies.
Although Koch and Pasteur were contemporaries, they were intensely competitive and actually
bitter enemies--of course, the outbreak of the Franco-Prussian war (1870) did nothing to cement
their relationship. In a trenchant example of how not to behave toward a colleague at a scientificmeeting, Koch made his way to the podium following Pasteur’s lecture and said: “When I saw inthe program that Monsieur Pasteur was to speak today...I attended the meeting eagerly, hoping tolearn something new...I must confess that I have been disappointed, as there is nothing new inthe speech which Monsieur Pasteur has just made...”Although many consider Pasteur the “father of immunology” (?parent of immunology) it is due
to both his and Koch’s efforts that firmly established the germ theory of disease. Prior to thistime, although the practical benefits of variolation were apparent, there was no known biologicalbasis for either the cause of diseases or the efficacy of vaccination.
2

The emerging distinction between cellular and humoral immunity
Metchnikoff was the first to recognize the contribution of phagocytosis to the generation of
immunity. In Italy, while studying the origin of digestive organs in starfish larvae, he observedthat certain cells unconnected with digestion surrounded and engulfed carmine dye particles andsplinters that he had introduced into the bodies of the larvae. He called these cells phagocytes(from Greek words meaning “devouring cells”). Working first at the Bacteriological Institute in
Odessa (1886-87), and later at the Pasteur Institute in Paris, Metchnikoff established that thephagocyte is the first line of defense against infection. He became a leading proponent of the“Cellularists” who believed that phagocytes, rather than antibodies, played the leading role inimmunity.
Supporters of the alternative theory, the “Humoralists,” believed that a soluble substance in the
body was mainly responsible for mediating immunity. Building upon the demonstration by Von
Behring and Kitasato of the transfer of immunity against Diphtheria by a soluble “anti-toxin” inthe blood, Paul Ehrlich predicted the existence of immune bodies (antibodies) and side-chainsfrom which they arise (receptors). Ehrlich suggested that antigens interact with receptors borneby cells, resulting in the secretion of excess receptors (antibodies). Ehrlich surmised thaterythrocytes would not have this capacity and speculated that this immune function might be a
specialized characteristic or “haemopoietic tissue” (Fig. 2).

Fig. 2. Ehrlich’s drawing of a “haemopoietic” cell bearing“side chains” (receptors) and releasing “immune bodies”(antibodies).

Ehrlich was probably the first scientist to introduce the concept of immunological self/not-self
discrimination, a mechanism “...which prevents the production within the organism ofamboceptors (antibodies) directed against its own tissues. In this horror autoxicus, we are
dealing with a well-adapted regulatory contrivance.”
Summary of the state of immunology at the end of the 19th century
By the turn of the century, several paradigms had been established that laid the groundwork for
future studies in immunology. The first was based on the “germ theory” of disease (Koch andPasteur) which held that disease was caused by bacteria. The second paradigm was that3

immunity to infection could be transferred by a soluble substance in the serum (Von Behring andKitasato) elaborated by specialized cells of the immune system (Ehrlich) and that the regulationof this process (generation of antibodies) was important to minimize the possibility ofdeveloping an immune response against self (Ehrlich). Finally, the immune system responds tobacterial pathogens by the recruitment of “phagocytes,” which recognize, engulf, and destroy the
microbes via “phagocytosis” (Metchnikoff). The first Nobel prize in Physiology or Medicine wasawarded to von Behring “for his work on serum therapy, especially its application against
diphtheria, by which he has opened a new road in the domain of medical science and thereby
placed in the hands of the physician a victorious weapon against illness and deaths.” Metchnikoff
and Ehrlich shared the Nobel prize in 1908 “in recognition of their work on immunity.”
The early dominance of humoral theories of immunity and later emergence of theories ofcellular immunity
Between the years 1900 and 1942 the “Humoralists” played a dominant role in immunology.
There were several reasons for this, not the least of which was the demonstration that transfer of
immunity could be accomplished by soluble factors later shown to be antibodies (Von Behring,Roux) and complement (Bordet). Furthermore, much of the phenomenology of
immunopathology (e.g., the Arthus reaction, anaphylaxis, serum sickness, hemolytic anemia)
could be associated with the activity of specific circulating antibodies. Indeed, no other basis for
immunological specificity was recognized. The case for antibodies as the fundamental unit of
immunity was strengthened by the ascendancy of immunochemistry, a term coined by Arrhenius.
The chemistry of antigen-antibody reactions was uncovered largely by the development of thequantitative precipitin reactions by Michael Heidelberger and Elvin Kabat (a former Professor at
The College of Physicians & Surgeons). These studies paved the way for a more fundamental
understanding of the immunoglobulin molecule, which culminated in the elucidation of antibody
structure by Rodney Porter and Gerard Edelman in the late 1950s.
However, several experimental observations challenged the prevailing view that antibodies alone
served to confer specific immunity. Delayed type hypersensitivity (e.g., tuberculin reactivity),
first recognized by Koch in 1883, and allograft rejection (Medawar, 1944) appeared to beunrelated to the presence of circulating antibodies. The definitive proof that cells played a role inimmunity came from the classic experiments of Landsteiner and Chase, in 1942. Cells fromguinea pigs, which had been immunized with Mycobacterium tuberculosis or hapten, weretransferred into naive guinea pigs. Later, when antigen or hapten was injected into these guinea
pigs, they elicited an immune recall response that was not present in the naive controls. This did
not happen when the serum fraction was transferred. Similar results were obtained using acontact dermatitis model. Thus, the dichotomy of immediate (antibody-mediated) and delayedtype (cell-mediated) hypersensitivity had become firmly established by the 1940s, although thethe identity of the cell that conferred the latter response was unknown. It was not until thepioneering experiments of Gowans that lymphocytes were recognized as being essential toimmunity (Gowans et al., Initiation of immune responses by small lymphocytes. Nature
196:651-55, 1962). In the meantime, the genetic basis for the immune response, and its
ontogeny, were gradually uncovered during the 1950s and 1960s.
A major paradigm shift: the clonal selection theory as an explanation for the diversity of4the antibody repertoire
Prior to the 1950s, it was not known how antibody diversity was generated. Because thevariability of antibodies was so great, early theories assumed that antibodies could not be
preformed; rather, they would be synthesized on demand following exposure. It was therefore
suggested that antigen instructs the cell about the specificity of the antibody. Indeed, in 1956,
Burnet himself published a book maintaining the position that an antigen directs, rather thanselects, the formation of specific antibody. In the late 1950s, three scientists (Jerne, Talmage,
Burnet), working independently, developed what is widely referred to as the clonal selection
theory. In 1955, Jerne published a paper (The natural-selection theory of antibody formation.
Proc. Nat. Acad. Sci. 41: 849-857, 1955) that described a “selective” hypothesis, which held thatevery animal had a large set of natural globulins that had become diversified in some unknown
fashion According to Jerne, the function of an antigen was to combine with those globulins withwhich it made a chance fit. The antigen would serve to transport the selected globulins to
antibody-producing cells, which would then make many identical copies of the globulin
presented to them. This was a seminal paper in the history of immunology, which presaged thekey 1957 publications of Talmage (Allergy and immunology. Annu. Rev. Med. 8, 239-256, 1957)
and Burnet (A modification of Jerne’s theory of antibody production using the concept of clonal
selection. Aust. J. Sci. 20, 67-69, 1957).
In 1957, Talmage wrote:“...it is tempting to consider that one of the multiplying units in the antibody response is the cell
itself. According to this hypothesis, only those cells are selected for multiplication whose
synthesized product has affinity for the antigen injected. This would have the disadvantage ofrequiring a different species of cell for each species of protein produced, but would not increase
the total amount of configurational information required on the hereditary process.”
The evidence he cited to support his theory included the kinetics of the antibody response, theexistence of “immunological memory” and the ability of myeloma tumors to secrete massive
amounts of “one globulin randomly selected from the family of normal globulins.”
According to Burnet, the clonal selection theory states:
1. Animals contain numerous cells called lymphocytes.
2. Each lymphocyte is responsive to a particular antigen by virtue of specific surface receptor
molecules.
3. Upon contacting its appropriate antigen, the lymphocyte is stimulated to proliferate (clonal
expansion) and differentiate.
4. The expanded clone is responsible for the secondary response (more cells to respond) while
the differentiated (“effector”) cells secrete antibody.
On the basis of many experiments in the ensuing years, the clonal selection theory was proven to
be correct (Fig. 3). In 1960, along with Peter Medawar, Burnet was awarded the Nobel prize,“for discovery of acquired immunological tolerance” rather than the clonal selection theory.
Jerne would later win the Nobel prize in 1984 “for theories concerning the specificity indevelopment and control of the immune system.” Although Talmage received numerous awards,
he did not receive the Nobel prize.

5

Fig. 3. The Clonal selection theory of lymphocytes. Schematic of clonal selection hypothesis
illustrating the idea that each naïve lymphocyte has a different receptor specificity, each of which
can bind a different antigenic determinant. When a pathogen is recognized by the cells, in this caseby two different antigenic determinants, then the cells that bind to these determinants are selected
to proliferate or undergo clonal expansion, and then differentiate into effector cells that either
secrete antibody or mediate various effector mechanisms of cell-mediated immunity. From Abbas
and Janeway Cell 100:129, 2000.

How lymphocytes function: the discovery of the Major Histocompatibility Complex and theemerging science of transplantation
The clonal selection theory represented a conceptual breakthrough in the history of immunology,
but it did not explain how lymphocytes actually recognize antigen. These insights would
eventually come principally from two sources: studies of the genetics of graft rejection in inbred
strains of mice by Snell in the 1930s and studies of the agglutination of white blood cells by serafrom transfused patients by Dausset in the 1950s. Snell was interested in tumor genetics andobserved that tumor grafts were accepted between inbred mice, but not between mice of different
strains. The same was true for normal tissues. Snell termed the underlying genes
histocompatibility genes. In collaboration with Peter Gorer, Snell established that the major locus
was identical to a locus encoding antigen II, renamed locus histocompatibility 2, or H-2.
Analogously, Dausset observed that patients, who had received many blood transfusions,produced antibodies that could agglutinate white blood cells from donors, but not the patient’s
own cells. Subsequent family studies indicated a genetically determined system, termed HLA,
was found to the ortholog of H-2 in the mouse. Research in mice and humans became mutuallycomplementary and the Nobel Prize was awarded to Dausset in 1980, together with Snell andBenaceraff.
The discovery of the MHC had widespread implications, paricularly in the field of organtransplantation. The impetus for the study of transplantation biology came from the war, which
led to a marked increase in the number of burn victims. In many of these individuals, a skinautograft was not feasible. The application of skin grafts from other individuals (allografts) was
known for its high failure rate, due to rejection. The British Medical Council assigned a young
Oxford-trained zoologist named Peter Medawar to investigate the problem of graft rejection. In
1943, Medawar and Gibson published “The Fate of Skin Homografts in Man” based on a single
burn victim who received multiple “pinch grafts” of skin. The authors concluded that autografts
succeed, while allografts fail after an initial take, and that the destruction of the foreign

6epidermis is brought about by a mechanism of active immunization. Medawar returned to Oxford
University to study the homograft rejection in laboratory animals and proved that this was an
immunologic phenomenon.
Medawar concluded that the mechanism by which foreign skin is eliminated belongs to thecategory of “actively acquired immune reactions.” His early insight into the mechanism oftransplant rejection is reflected by statements such as “The accelerated regression of second-set
homografts argues for the existence of a systemic immune state.”
The concept of immunological tolerance and the “self-nonself” model of immune
development
The discovery of neonatal transplant tolerance has been credited to Ray Owen, a geneticist at the
University of Wisconsin who studied the inheritance of red blood cell antigens in cattle. He
reported in 1945 that dizygotic twins had mixtures of their own cells and their twin partner cells.
Owen recognized that the common intrauterine circulation of cattle leads to an exchange ofhematopoietic stem cells during embryonic life and the establishment of a chimeric state of red
cells. These calves did not develop antibodies to their twin partners. A few years later, Burnet
and Fenner acknowledged in their influential book “The Production of Antibodies” theimportance of Owen’s findings, which led to the “self-nonself” hypothesis for immune
development. They postulated that, during embryonic development, “a process of selfrecognition takes place” and “no antibody response should develop against the foreign cell
antigen when the animal takes on independent existence.” Owen’s red cell chimeric model indizygotic cattle and Burnet’s own studies of foreign embryonic cells in the chick embryo led
Burnet to hypothesize that the existence of “tolerance acquired by fetal exposure to ‘nonself’constituents.”
Medawar predicted that an exchange of skin grafts between dizygotic calves would verify
Burnet’s hypothesis. Together with his post-doctoral fellow Rupert Billingham, he performed aseries of grafting experiments that provided direct support for the concept of neonatally-acquired
transplantation tolerance. At the same time, Milan Hasek in Prague demonstrated that parabiosis
of different strain chick embryos induced a immune hyporesponsive state to each other’s red
cells.
The discovery of MHC restriction as the genetic basis for “self-nonself” recognition
In 1974, Peter Doherty and Rolf Zinkernagel sought to learn the role of T lymphocytes (T-cells)in the immune response to viral meningitis. They theorized that it was the strength of theimmune response that caused the fatal destruction of brain cells infected with this virus. To test
this theory, they mixed virus-infected mouse cells with T lymphocytes from other infected mice.
The T lymphocytes did destroy the virus-infected cells, but only if the infected cells and thelymphocytes came from a genetically identical strain of mice. T lymphocytes would ignore
virus-infected cells that had been taken from another strain of mice (Zinkernagel RM, Doherty
PC Restriction of in vitro T cell-mediated cytotoxicity in lymphocytic choriomeningitis within asyngeneic or semiallogeneic system. Nature 248:701-2, 1974); (Fig. 3).

7

Fig. 3. Zinkernagel-Doherty
experiment demonstrating thatMHC restriction is required for
activation of a cytotoxic T-cell
response.

The implications of the Zinkernagel-Doherty experiment were profound. First, it established theprinciple of MHC restriction: T cells recognize antigen only in the context of MHC molecules. It
would take another 13 years to prove that the antigen in question was a peptide actually bound to
the MHC molecule. Second, the experiment established that cells must recognize two separate
signals on an infected cell before they can destroy it. One signal is a fragment of the invadingvirus that the cell displays on its surface; the other is a self-identifying tag from the cell’s major
histocompatibility complex (MHC) antigens. Thus, the experiment pointed to the identity of themolecular structure that constituted immunological “self”--it is the MHC molecule; a virusinfected cell bearing MHC molecules constitutes “altered-self.” Finally, the fact that MHC ishighly polymorphic (i.e., multiple alleles expressed in different individuals) implies that any one
allele may respond differently to a given stimulus; thus, the specific identity of the MHC
molecule itself determines the strength of the immune response.
The generation of immunological diversity
Because the immune system has the capacity to respond to a multitude of environmental insults,
it must have an efficient way of insuring the diversity of its responses; this is sometimes referredto the T- or B-cell “repertoire.” The mechanism by which this was accomplished remained
elusive until 1978, when Susumu Tonegawa provided direct evidence for somatic rearrangementof immunoglobulin genes. This represented a radical departure from one of the fundamental
dogmas of molecular genetics, which held that the genetic makeup of an organism remained8unchanged throughout ontogeny (unless altered by pathological states, such as cancer). Indeed,
the immunoglobulin genes and the genes that make up the T-cell antigen receptor are the only
genes that have been shown to undergo somatic rearrangements. The various combinations ofgenetic elements within these loci accounts for much of the diversity of the T- and B-cell
repertoire, although other mechanisms, such as somatic hypermutation, would later be
discovered to generate further diversity.
The complementary roles played by cellular and molecular immunology
Since 1974, much progress has been made in uncovering precisely how antigens are recognizedby the immune system. These insights have come from two complementary approaches: amolecular one, involving the cloning of the genes for the T-cell antigen receptor (1984-87) andsolving the crystal structure of peptide bound to the MHC molecule (1987), and a cellular one,delineating the cellular mechanisms of antigen presentation, leukocyte trafficking, and signaltransduction. In 1978, Ralph Steinman identified the dendritic cell, a phagocytic cell, as theprincipal antigen-presenting cell of the immune system. This constituted a major revision to therole of the phagocyte assigned by Metchnikoff in the 19th century! Other advances included theidentification of adhesion molecules (Butcher, 1979) and chemokines (Leonard, Yoshimura, andBaggiolini,1989) together which provide the cellular basis for leukocyte trafficking.
Since 1986, a major effort has been directed towards identifying markers of individual T-cell
subsets (“phenotyping”) and characterizing their function. In 1986, Tim Mossmann and Bob
Coffman discovered a major dichotomy in T helper subsets: TH1 cells, which are responsible forthe production of interferon-γ and the activation of macrophages (as well as the principal
lymphocyte effector of delayed-type hypersensitivity), and TH2 cells, which are required for the
production of certain types of immunoglobulins and are implicated in the pathogenesis ofallergic diseases and immediate hypersensitivity. These specific T cell subsets elaborate a
distinct array of soluble substances that influence the behavior of other cells (“cytokines”). The
search for cytokines began in 1957 with the discovery of interferon (Issacs and Lindemann), but
the characterization of the properties of various cytokines is an ongoing enterprise.
Progress in cellular immunology leads to insights into T-cell effector functions: “two signal
models” for lymphocyte activation
The origins of cellular immunology date back to Metchnikoff, who discovered the important rolethat phagocytes play in immunity. Although he mistakenly identified the phagocyte, itself, as thecell type responsible for antibody production, it would take another 58 years before any further
understanding of the cellular basis of immunity would exist. In 1942, Landsteiner and Chasedemonstrated that cells, rather than antibodies, were recognized to contribute to specific immune
phenomena. As there was no technology available to separate different types of circulating
leukocytes, the nature of the immune-conferring cell remained elusive. It was not until theexperiments of Gowans in 1959 that lymphocytes were shown to confer specific immunity. In
many ways, Gowans’ discovery of the central role of lymphocytes in immunity was analogous tothe molecular genetic experiments of Avery, McLeod, and Lederberg, who demonstrated that
DNA was the substance that conferred heredity.
The focus on the lymphocyte led to the discovery of the involvement of the thymus in cellular9immunity and the distinction between T-cells, which provided “help” or cytotoxicity, and Bcells, which produced antibody (Jacques Miller and Graham Mitchell, 1961-1968). These
workers also discovered the importance of T- and B-cell collaboration in the immune response.
In 1968, Bretscher and Cohn proposed the first two-signal model of lymphocyte activation.
Although the original model proved to be incorrect, the model has been refined over the years totake into account new experimental findings.
The two signal hypothesis basically states that, in addition to the delivery of antigen/MHCmediated signals to the lymphocyte, there must be another signal provided by the MHC-bearing
antigen-presenting cell (Fig. 4 ). The nature of this “second stimulus” was unknown until theFig. 4. The Two-signal theory of T-cell activation. When a T-cell encounters an antigen
presenting cell (APC) that expresses costimulatory molecules but no foreign antigens, there is noapparent signal (left panel); when a T cell encounters a tissue cell or an APC that expresses
antigens recognized by the TCR in the absence of costimulatory signals, the result is either no
response or inactivation of the cell (anergy). However, when a T cell encounters an activateddendritic cell or other APC expressing both antigen and costimulatory molecules, then the T cell is
activated to proliferate and undergo differentiation to an effector cell. Thus, T cells only become
activated by their ligands when they are presented by a cell that expresses costimulatory
molecules. From Abbas and Janeway Cell 100:129, 2000.

the interaction of CD28 on the T-cell and B7 (CD80/CD86) on the antigen-presenting cell wasnecessary for optimal production of antibody. Later studies (1992) identified CD40 ligand(CD154) on activated T-cell as a critically important molecule that provides co-stimulation to Bcells; in humans. In the following year, it was demonstrated that mutations in the gene for CD40
ligand was responsible for a human disease, X-linked hyper-IgM immunodeficiency.
However, even before the precise identity of co-stimulatory molecules was known, a theoreticalframework for T-cell function was proposed by Burnet (1959) and later refined over the ensuing
years. These models for T-cell function incorporated the “two signal” concept of lymphocyte

10activation, originally proposed by Bretscher and Cohn, into a model of immune recognition
based on “self vs non-self.” (Table I).
Table I. Evolution of “Two Signal” Model of Lymphocyte Activation
Basis of Immune
Recognition
Self vs. Non-self
Self vs. Non-self
Self vs. Non-self
Non-infected self vs.
Infected non-selfDangerCellular
Determinants

Authors

B-cell/Ag
Signal one (B cell/Ag)
Signal two (T helper)
Signal one (T cell-Ag)
Signal two (APC)
Signal one (T cell-Ag)
Signal two (APCs activated by PRR*)
Signal one (T cell-Ag)
Signal two (APCs activated by distressed cell)

Burnet, 1959
Bretscher and Cohn,
1970
Lafferty andCunningman, 1975
Janeway, 1989
Matzinger, 1994

*Pattern recognition receptor

How valid are these models? There is no doubt that the activation of T-cells requires multiple
signals from antigen-presenting cells. Where the models diverge, and where the mostcontroversy exists, is the very basis of immune recognition. What constitutes “non-self”?
Because the immune response in any individual depends upon the selection of a small subset oflymphocytes out of a total of 105 to 106 possible clones, the very existence of these clones
implies that they were positively selected by the immune system. But this occurs through an
ongoing low-level presentation of self antigens, thus constituting a paradox: recognition of “nonself” depends on prior recognition of “self.” How can this be resolved?
The role of innate immunity in the acquired immune response
The components of acquired immunity (i.e., lymphocytes, immunoglobulins, MHC molecules,
antigen receptors) are absent in primitive species. Genes for these proteins appeared abruptly inevolution with the advent of lower vertebrates. Recognizing the presence of components ofprimitive or “innate” immunity in higher organisms, Janeway proposed in 1989 an alternative to“self/nonself” recognition by the immune system. He suggested that the immune system
recognizes “infectious non-self.” Early in an immune response, when components of innate
immunity are called into play, lymphocytes and/or antigen presenting cells are stimulated torespond in a stereotypic fashion that serves to initiate the acquired immune response. Janeway
predicted the existence of “pattern recognition receptors” that recognize products of microbial
pathogens that differed from “self” in that they bore repetitive structures (e.g., components ofbacterial cell walls) that were not present in the host. Although there was as yet no formal proof
for this highly original concept, in 1997, Janeway and Medzhitov identified a human homolog ofa transmembrane protein in Drosophila, Toll, that conferred responsiveness tolipopolysaccharide, a component derived from the cell wall of gram-negative bacteria.

11Furthermore, ectopic expression of this receptor resulted in the secretion of a pro-inflammatory
cytokine and resulted in the up-regulation of co-stimulatory molecules known to be important intriggering an acquired immune response in T-cells.
The discovery of the components of the innate immune system, and their likely role in triggering
acquired immunity, represents a paradigm shift in immunology perhaps as profound as the clonal
selection theory. Since Janeway proposed this in 1989, Matzinger suggested that, rather thansensing pathogen-derived signals directly, the immune system senses “danger” that results as aconsequence of infection. This danger can be in the form of injured or dying cells; indeed,
several proteins released from necrotic cells, including heat-shock proteins, have been
demonstrated to stimulate antigen-presenting cells, such as macrophages. Interestingly, the same
receptors on macrophages that respond to bacterial products (Toll-like receptors) are also
required for the response to heat shock proteins!
The future of immunology?
"Predictions are hard to make, especially ones about the future"-Peter Medawar

It is pure speculation (but fun) to guage the direction that immunology is headed in the next 2030 years. Further advances in the cell biology of the immune system will no doubt occur, which
will lead to novel vaccines for infectious and non-infectious diseases, such as cancer anddiseases of aging. New receptor- or cytokine-modifying therapeutics will be developed, based on
insights obtained from experimental immunology. The application of the human genome projectto diseased populations will identify new drug targets, and high-throughput screens andcombinatorial chemistry will accelerate the pace of drug discovery. Gene and protein microarray
techniques and proteomics will reveal new components of immunity that will expand ourknowledge of how the immune system works. Perhaps more importantly, we will begin toappreciate the fundamental role that the immune system plays in nearly all human diseases, andexploit this knowledge to alter the natural history of these diseases.

12History of Immunology Time Line

1879
1890

Smallpox vaccination
Validation of germ theory of disease by discoveringbacterial basis of anthrax
Chicken cholera vaccine development
Discovery of Diphtheria“anti-toxin” in blood

1882
1883
1884
1891
1891
1894
1900
1901
1903

Isolation of the tubercule bacillus
Delayed type hypersensitivity
Phagocytosis; Cellular theory of immunity
Proposal that antibodies are responsible for immunity
Passive immunity
Complement and antibody activity in bacteriolysis
A, B, and O blood groupings
Cutaneous allergic reaction
Opsonization by antibody

1907
1910
1917
1921

Discipline of immunochemistry founded
Viral immunology theory
Haptens dicovered
Cutaneous reactions

1924
1939
1942

Reticuloendothelial system
Discovery that antibodies are gamma globulins
Adjuvants

1942

1953

Cellular transfer of sensitivity in guinea pigs
(anaphylaxis)
Immunological hypothesis of allograft rejection
Demonstration of antibody production in plasma B cells
Distinguishing self vs. non-self and its role in maintaining
immunological unresponsiveness (tolerance)to self
Discovery of agammaglobulinemia (antibody
immunodeficiency)
Immunological tolerance hypothesis

1955-59

Clonal selection theory

1957

Discovery of Interferon

1958

Identification of first autoantibody and first recognition of
autoimmune diseases

1798
1876

1944
1948
1949
1952

13

Edward Jenner
Robert KochLouis Pasteur
Emil Von Behring,
Shibasaburo Kitasato
Robert Koch
Robert Koch
Elie Metchnikoff
Paul Ehrlich
Emil Roux
Jules Bordet
Karl Landsteiner
Maurice Arthus
Almroth Wright & Stewart
DouglasSvante Arrhenius
Peyton Rous
Karl Landsteiner
Carl Prausnitz & Heinz
Kustner
Ludwig Aschoff
Elvin Kabat
Jules Freund & Katherine
McDermottKarl Landsteiner & Merill
ChasePeter Medawar
Astrid Fagraeus
Macfarlane Burnet & FrankFennerOgden Bruton
Rupert Billingham, Leslie
Brent, Peter Medawar &Milan Hasek
Niels Jerne, David
Talmage, & Macfarlane
BurnetAlick Isaacs & Jean
Lindemann
Henry Kunkel

1959-62

Elucidation of antibody structure

1959

1965
1968-70
1970

Lymphocytes as the cellular units of clonal selection;
Discovery of lymphoid circulation
Discovery of thymus involvement in cellular immunity
Recognition of B- and T-cells in immunodeficiencies
Distinction of bone marrow- and thymus-derived
lymphocyte populations; Discovery or T- and B-cellcollaboration
Proof that B-cells demonstrate allelic exclusion
Elaboration of two-signal model of lymphocyte activation
Discovery of membrane immunoglobulins

1971
1972

Recognition of hypervariable regions in Ig chains
Elucidation of the Major Histocompatibility Complex

1974

Discovery of MHC restriction

1974
1975

HLA-B27 predisposes to an autoimmune disease
Monoclonal antibodies used in genetic analysis

1976
1978

1984-87First demonstration of cross-priming
Direct evidence for somatic rearrangement in
immunoglobulin genes
Recognition that dendritic cells are distinctive and highly
potent antigen-presenting cells
Discovery of leukocyte adhesion molecules and their rolein lymphocyte trafficking
Identification of genes for the T cell antigen receptor

1987

Crystal structure of MHC-peptide solved

1989
1994
1986

Emerging field of innate immunity. Infectious non-selfmodel of immune recognition (“stranger hypothesis”)
Danger hypothesis of immune responsivenessDiscovery of T helper subsets

1989

Discovery of first chemokines

1991

Discovery of the first co-stimulatory pathway (CD28/B7)
for T-cell activation
Cloning of CD40 ligand and recognition of its role in Tcell -dependent B-cell activation

1961
1968
1968

1978
1979

1992

14

Rodney Porter & Gerard
EdelmanJames Gowans
Jaques Miller
Robert Good
Jacques Miller & Graham
MitchellBenvenuto PernisPeter Bretscher & M. Cohn
Benvenuto Pernis & Martin
Raff
Elvin Kabat
Baruj Benacerraf, Jean
Dausset, & George Snell
Rolf Zinkernagel & Peter
Doherty
Derek Brewerton
Georges Kohler & Cesar
MilsteinMichael Bevan
Susumu Tonegawa
Ralph Steinman
Eugene Butcher
Mark Davis, Leroy Hood,
Stephen Hedrick, & Gerry
Siu
Pam Bjorkman, Jack
Strominger, & Don Wiley
Charlie Janeway
Polly Matzinger
Tim Mossmann & Bob
Coffman
Edward Leonard, Teizo
Yoshimura, & Marco
Baggiolini
Kevin Urdahl & Mark
Jenkins
Armitage, Spriggs,
Lederman, Chess, Noelle,
Aruffo, et al.

1996-97

Discovery of the role of Toll and Toll-like receptors inimmunity

15

Ruslan Medzhitov, Charlie
Janeway, & Jules Hoffmann