The endurance running hypothesis is the hypothesis that the evolution of certain human characteristics can be explained as adaptations to long-distance running. The hypothesis suggests that endurance running played an important role for early hominins in obtaining food. Researchers have proposed that endurance running began as an adaptation for scavenging and later for persistence hunting.
Anatomical and physiological adaptations
Running vs. walking
Much research has been geared towards the mechanics of how bipedal walking has evolved in the genus Homo.
However, little research has been conducted to examine how the specific
adaptations for running emerged, and how they influenced human
evolution.
The bit of research that has focused on human running provides
much evidence for bodily function and structures that improve running
only, and are not used in walking. This suggests that running was an
adaptation, not that it came about as a byproduct of walking.
Running and walking incorporated different biomechanisms. Walking
requires an "inverted pendulum" where the body's center of mass is
shifted over the extended leg, to exchange potential and kinetic energy
with each step.
Running involves a "mass spring" mechanism to exchange potential and
kinetic energy, with the use of tendons and ligaments. Tendons and
ligaments are elastic tissues that store energy. They are stretched and
then release energy as they recoil. This mass spring mechanism becomes
less energetically costly at faster speeds and is therefore more
efficient than the inverted pendulum of walking mechanics when traveling
at greater speeds. Tendons and ligaments, however, do not provide these benefits in walking.
Although the mass spring mechanism can be more energetically
favorable at higher speeds, it also results in an increase in ground
reaction forces
and is less stable because there is more movement and pitching of the
limbs and core of the body. Ground forces and body pitching movement is
less of an issue in the walking gait, where the position of the body's
center of mass varies less, making walking an inherently more stable
gait. In response to the destabilization of the running gait, the human
body appears to have evolved adaptations to increase stabilization, as
well as for the mass-spring mechanism in general. These adaptations,
described below, are all evidence for selection for endurance running.
Skeletal evidence
Many researchers compare the skeletal structures of early hominins such as Australopithecus to those of Homo in order to identify structural differences that may be significant to endurance running.
Nuchal ligament: Because the head is decoupled from the shoulders, early Homo
needed a way to stabilize the head. The nuchal ligament is an important
evolved feature in head stabilization. It starts at the midline of the occiput and connects to the upper trapezius.
This ligament is also important in terms of archaeological findings,
because it leaves a small indentation and ridge in the skull, allowing
researchers to see if various species had a nuchal ligament. The ability
to see traces of ligaments in archaeological findings is rare because
they degrade quickly and often leave no trace. In the case of the nuchal
ligament, a trace of its existence is left with the presence of the
skull ridge. Because neither Australopithecus nor Pan had the skull ridge, it has been concluded that this feature is unique to Homo.
Because the nuchal ligament is only activated while running, the amount
of running can be inferred from the rugosity of the muscle insertions.
In the case of Homo Erectus
and Neanderthals, very strong nuchal ligament markings are present, but
are less marked in modern humans, indicating a decrease in running
behavior.
Nuchal ligament of Homo sapiens
Shoulder and head stabilization: The human skeleton is different from early hominins as there is less of a connection between the pectoral girdle
parts of the shoulders and upper back and head, which would be
advantageous for climbing but would hinder the movements of the upper
body needed to counter leg movement and therefore stabilize the body and
head when running. This stabilization is unnecessary in walking.
Limb length and mass:Homo has longer legs relative
to body mass, which helps to decrease the energetic costs of running,
as time in contact with the ground increases.
There is also a decrease in mass of distal parts of limbs of humans,
which is known to decrease metabolic costs in endurance running, but has
little effect on walking. Additionally, the mass of the upper body limbs in Homo
has decreased considerably, relative to total body mass, which is
important to reduce the effort of stabilizing the arms in running.
Joint surface: Humans have evolved to absorb great shock
and force on the skeletal structure while running. The impact force on
the body can reach up to 3–4 times body weight in endurance running,
putting the skeletal structure under great stress. To reduce this stress
humans have increased joint surfaces relative to body mass to spread
force over larger surface areas, particularly in the lower body.
This adaptation, which allows humans to absorb great shock and force
applied to the skeleton, is not seen in australopithecine skeletal
structures.
Plantar arch: The plantar arch in the human foot has an elastic spring function that generates energy for running but not walking.
Fossils of the australopithecine foot show only partial arch,
suggesting less of a spring capacity. For the plantar arch spring
mechanism to function fully, there must also be restricted rotation in
the hind and front parts of the foot. This restriction comes from
projected toe bone and compacted mid-foot joint structures in humans,
which does not become present until Homo habilis.
Calcaneal tuber and Achilles tendon: Studies have explored the calcaneal tuber, the posterior half of the calcaneus bone, as a correlate for Achilles tendon
length and have found correlation between calcaneal tuber length and
Achilles tendon length. Because shorter calcaneal tuber length leads to
greater Achilles stretch, more kinetic energy is converted to elastic
energy, translating into better overall running economy.
Comparisons between Neanderthals and modern humans reveal that this
adaptation was absent in Neanderthals, leading researchers to conclude
that endurance running capabilities may have been enhanced in
anatomically modern humans.
Calcaneus
Shorter toes: Human toes are straight and extremely short in
relation to body size compared to other animals. In running, the toes
support 50 to 75% of body mass in humans. Impulse
and mechanical work increase in humans as toe length increases, showing
that it is energetically favorable to have shorter toes. The costs of
shorter toes are decreased gripping capabilities and power output.
However, the efficiency benefits seem to outweigh these costs, as the
toes of A. afarensis remains were shorter than great apes, but
40% longer than modern humans, meaning that there is a trend toward
shorter toes as the primate species moves away from tree-dwelling. This
40% increase in toe length would theoretically induce a flexor impulse
2.5 times that of modern humans, which would require twice as much
mechanical work to stabilize.
Stabilization
Semicircular canal: The semicircular canal,
a series of three interconnected tubes within each ear, is important
for sensing angular rotations of the head and thus plays a crucial role
in maintaining balance and sensing and coordinating movement.
Comparative studies have shown that animals with larger semicircular
canals are able to sense a greater range of head movements and therefore
have greater speed and agility. Evolutionarily, greatly reduced
semicircular canal diameters are evident in Neanderthals but expanded in
modern humans, suggesting that this adaptation was selected for in
response to increased endurance running.
Vestibulo-ocular reflexes (VORs):VORs
are enabled by muscles in the eye, which sense angular accelerations of
the head and adjust eye movements to stabilize these images. This was
an important adaptation for running because it allowed Homo to see more clearly during the rough pitching motion that occurs during running.
Gluteals: The gluteus maximus in Homo erectus is significantly larger than that of Australopithecus.
It is suited to absorb and return force, much like a spring, as the
body oscillates vertically with each step. Gluteals of that size and
strength are not necessary for walking.
Iliac spine:Homo has expanded areas on the sacrum
and posterior iliac spine for greater muscle attachment. These areas are
used to stabilize the trunk and reduce the body's forward pitch caused
by running strides.
Increased efficiency
Thermoregulation
In addition to advances in skeletal structure and stabilization,
adaptations that led to increased efficiency in dissipation of heat were
instrumental in the evolution of endurance running in Homo.
The duration for which an animal can run is determined by its capacity
to release more heat than is produced to avoid lethal temperatures.
The majority of mammals, including humans, rely on evaporative
cooling to maintain body temperature. Most medium-to-large mammals rely
on panting, while humans rely on sweating,
to dissipate heat. Advantages of panting include cooler skin surface,
little salt loss, and heat loss by forced convection instead of reliance
on wind or other means of convection. On the other hand, sweating is
advantageous in that evaporation occurs over a much larger surface area
(the skin), and it is independent of respiration, thus is a much more
flexible mode of cooling during intense activity such as running.
Because human sweat glands are under a higher level of neuronal control
than those of other species, they allow for the excretion of more sweat
per unit surface area than any other species. Heat dissipation of later
hominins was also enhanced by the reduction in body hair. By ridding themselves of an insulating fur coat, running humans are better able to dissipate the heat generated by exercise.
In addition to improved thermoregulation, hominins have evolved
an enhanced method of respiration consistent with the demands of
running. Due to their orientation, respiration in quadrupedal mammals is
affected by skeletal and muscular stresses generated through the motion
of running. The bones and muscles of the chest cavity are not only
responsible for shock absorption, but are also subjected to continuous
compression and expansion during the running cycle. Because of this
movement, quadrupeds are restricted to one breath per locomotor cycle,
and thus must coordinate their running gait and respiration rate.
This tight coordination then translates into another restriction: a
specific running speed that is most energetically favorable. The upright
orientation of bipedal hominins, however, frees them from this
respiration-gait restriction. Because their chest cavities are not
directly compressed or involved in the motion of running, hominins are
able to vary their breathing patterns with gait.
This flexibility in respiration rate and running gait contributes to
hominins having a broader range of energetically favorable running
speeds.
Storage and utilization of energy
During periods of prolonged exercise, animals are dependent on a combination of two sources of fuel: glycogen
stored in the muscles and liver, and fat. Because glycogen is more
easily oxidized than fat, it is depleted first. However, over longer
periods of time, energy demands require that fat stores be utilized as
fuel. This is true for all mammals, but hominins, and later modern
humans, have an advantage of being able to alter their diet to meet
these prolonged energy demands.
In addition to flexibility in the utilization of energy, hominins have evolved larger thyroid and adrenal
glands which enable them to utilize the energy in carbohydrates and
fatty acids more readily and efficiently. These organs are responsible
for releasing hormones including epinephrine, norepinephrine,
adrenocorticotropic hormone (ACTH), glucagon, and thyroxine. Larger
glands allows for greater production of these key hormones and
ultimately, maximized utilization of stored fuel.
Taken together, the flexibility in diet and the enhanced usage of
fuel heightens the previously mentioned finding that, unlike
quadrupeds, hominins do not have a single energetically optimal running
speed. For quadrupeds, increasing running speed means increasing the
demand for oxygen and fuel. Due to skeletal structure and bipedalism,
hominins are free to run energetically over a broader range of speeds
and gaits, while maintaining a constant energy consumption rate of
approximately 4.1 MJ per 15 km. Thus their utilization of energy is
greatly enhanced.
Endurance running and scavenging
All
of the aforementioned adaptations enabled Homo to scavenge for food
more effectively. Endurance running could have been used as a means of
gaining access to distant carcasses or food stores faster than other
scavengers and/or carnivores. Scavenging may have taken one or both of
two forms: opportunistic scavenging and strategic scavenging.
Early Homo almost certainly scavenged opportunistically.
Scavenging is considered opportunistic when one "come[s] across
carcasses in the course of [their] daily foraging activities".
Strategic scavenging involves a planned search for carcasses.
This style of scavenging would have benefitted from endurance running
much more than opportunistic scavenging. Strategic scavenging would have
involved the use of long range cues, such as birds circling overhead.
Endurance running would have been advantageous in this setting because
it allowed hominins to reach the carcass more quickly. Selection
pressures would have been very high for strategic scavenging, because
hominins were diurnal, while their major competitors (hyenas, lions,
etc.) were not. Thus, they would have had to make sure to capitalize on
daytime carcasses. Selection pressure also came from the weakness of
Homo. Because they were very weak, they were unlikely to drive off any
large competition at the carcass. This fact led to an even higher need
for a way to reach the carcass before these competitors.
Endurance running and persistence hunting
Persistence hunting is "a form of pursuit hunting in which [the
hunter uses] endurance running during the midday heat to drive [prey]
into hyperthermia and exhaustion so they can easily be killed". Many question persistence hunting's plausibility when bow and arrow and
other technologies were so much more efficient. However, in the Early
Stone Age (ESA), spears were only sharpened wood, and hominins had not
begun using tools. The lack of spearheads or bows meant they could only
hunt from very close range—between 6 and 10 meters.
Hominins thus must have developed a way to stab prey from close range
without causing serious bodily harm to themselves. Persistence hunting
makes killing an animal easier by first bringing it to exhaustion, so
that it can no longer retaliate violently.
Persistence hunters work by hunting in the middle of the day,
when it is hottest. Hunters choose a single target prey and chase it at a
speed between its trot and gallop, which is extremely inefficient for
the animal. The hunter then continues pursuing over a period of hours,
during which he may lose sight of the animal. In this case, the hunter
must use tracks and an understanding of the animal to continue the
chase. The prey eventually overheats and becomes unable to continue
fleeing. Homo, which does not overheat as quickly because of its
superior thermoregulation capabilities, is then able to stab the prey
while it is incapacitated and cannot attack.
Tracking and running
Due
to the complexity of following a fleeing animal, tracking methods must
have been a prerequisite for the use of endurance running in persistence
hunting. Scientists posit that early tracking methods were developed in
open, sparsely vegetated terrain such as the Kalahari Desert
in southern Africa. This "systemic tracking" involves simply following
the footprints of animals and was most likely used for tracking
grassland species on soft terrain. Skeletal remains suggest that during
the Middle Stone Age, hominins used systemic tracking to scavenge for
medium-sized animals in vegetation cover, but for hunting antelope in
more open grasslands. From the Middle Stone Age into the Later Stone
Age, tracking methods developed into what is termed "speculative
tracking". When tracks could not easily be found and followed, Homo predicted where tracks were most likely to be found and interpreted other signs to locate prey.
This advanced method of tracking allowed for the exploitation of prey
in a variety of terrains, making endurance running for persistence
hunting more plausible.
The process of tracking can last many hours and even days in the
case of very large mammals. Often, the hunter(s) will have to run after
the animal to keep up. The skeletal parameters of the tibia of early
modern humans and Neanderthals have been compared with runners, and it
surprisingly shows that these individuals were running even more than
cross-country runners today. Particularly, European Neanderthals, the Skhul and Qafzeh hominins, and Late Stone AgeKhoisan
score very high compared to runners. This is consistent with modern
observations of Khoisan, who routinely spend hours running after animals
that have been shot with arrows.
Examples of persistence hunters
Although
exact dates and methods of persistence hunting are difficult to study,
several recent accounts of persistence hunting have been recorded.
Tribes in the Kalahari Desert in Botswana have been known to employ
endurance running to scavenge and hunt prey. In the open country, the Xo
and Gwi tribes run down slow-moving animals such as aardvark and
porcupines, while during the hotter part of the day, they target animals
such as eland, kudu, gemsbok, hartebeest, duiker, steenbok, cheetah, caracal, and African wildcats. In addition to these existing African tribes, it has been suggested that the Tarahumara people in Mexico and the Paiute people and Navajo in the American Southwest, used persistence hunting to capture prey including deer and pronghorn. The Aborigines in Australia are known to have hunted kangaroo in similar ways.
Due to the increased availability of weapons, nutrition, tracking
devices, and motor vehicles, one may argue that persistence hunting is
no longer an effective method of hunting animals for food. However,
there are examples of the practice occurring in modern times: the Xo and
Gwi in the central Kalahari, still practice persistence hunting and
have developed advanced methods of doing so. Similarly, the Russian Lykov family that lived in isolation for 40 years also used persistence hunting due to a lack of weapons.
In the first epoch, the world was inhabited by large hairy humanoids called Akakaanebe ("ancestors"), who did not yet possess tools or fire. They simply "stared" at game until it fell dead, referring to either scavenging or early persistence hunting without weapons, or a combination of the two. They did not build houses but slept under trees.
The Tlaatlanebe of the second epoch, however, were large but
without hair and lived in caves. As animals had grown more wary of
humans due to earlier hunting, they now had to be chased and hunted with
dogs.
Criticisms
While
there is evidence supporting selection on human morphology to improve
endurance running ability, there is some dispute over whether the
ecological benefits of scavenging and persistence hunting foraging
behaviors were the driving force behind this development.
The majority of the arguments opposing persistence hunting and
scavenging behaviors are linked to the fact that the paleohabitat and paleoecology of early Homo were not conducive to these behaviors. It is thought that the earliest members of Homo lived in African savanna-woodlands.
This environment consisted of open grassland, as well as parts with
dense vegetation—an intermediate between forest and open savannas. The
presence of such tree covering would reduce visibility and so require
tracking skills. This causes problems for the hypothesis of persistence
hunting and running to aid scavenging.
Against persistence hunting
Ungulates are known from archaeological evidence to have been the main prey of the early Homo,
and given their great speed, they would have easily been able to outrun
early hominins. Ungulate speed, coupled with the variable visibility of
the savanna-woodland, meant that hunting by endurance running required
the ability to track prey. Pickering and Bunn argue that tracking is
part of a sophisticated cognitive skill set that early hominins would
not have had, and that even if they were following a trail of blood left
by an injured ungulate—which may have been in their cognitive
capacity—the ability to craft penetrating projectile technology was
absent in early hominins.
It has been suggested that modern hunters in Africa do not use
persistence hunting as a foraging method, and most often give up a chase
where the trail they were following ends in vegetation.
The rare groups of hunters who do occasionally participate in
persistence hunting are able to do so because of the extremely hot and
open environments. In these groups, a full day of rest and recovery is
required after a hunt, indicating the great toll persistence hunts take
on the body, making them rare undertakings.
Finally, in critique of Liebenberg's research on modern day
persistence hunting, it was revealed that the majority of the hunts
initiated were prompted for filming rather than spontaneous, and that
few of these hunts were successful. The hunts that were successful
involved external factors such as the hunters being able to stop and
refill water bottles.
A response to these criticisms has been formulated by Lieberman et al.,
noting that it is unclear how humans could have grown to occupy a new
niche as a diurnal social carnivore without persistence hunting, as the
weapons preferred in modern hunter-gatherer tribes would not have been
available at the time.
Against scavenging
The
proposed benefit of endurance running in scavenging is the ability of
early hominins to outcompete other scavengers in reaching food sources.
However paleoanthropological studies suggest that the savanna-woodland
habitat caused a very low competition environment. Due to low
visibility, carcasses were not easily located by mammalian carnivores,
resulting in less competition.
In paleoanthropology, the hunting hypothesis is the hypothesis that human evolution was primarily influenced by the activity of hunting for relatively large and fast animals, and that the activity of hunting distinguished human ancestors from other hominins.
While it is undisputed that early humans were hunters, the
importance of this fact for the final steps in the emergence of the
genus Homo out of earlier australopithecines, with its bipedalism and production of stone tools (from about 2.5 million years ago), and eventually also control of fire (from about 1.5 million years ago), is emphasized in the "hunting hypothesis", and de-emphasized in scenarios that stress the omnivore status of humans as their recipe for success, and social interaction, including mating behaviour as essential in the emergence of language and culture.
Advocates of the hunting hypothesis tend to believe that tool use and toolmaking essential to effective hunting were an extremely important part of human evolution, and trace the origin of language and religion to a hunting context.
As societal evidence David Buss cites that modern tribal population deploy hunting as their primary way of acquiring food. The Aka pygmies in the Central African Republic spend 56% of their quest for nourishment hunting, 27% gathering, and 17% processing food. Additionally, the !Kung in Botswana retain 40% of their calories from hunting and this percentage varies from 20% to 90% depending on the season. For physical evidence Buss first looks to the guts of humans and apes. The human gut consists mainly of the small intestines, which are responsible for the rapid breakdown of proteins and absorption of nutrients. The ape's gut is primarily colon,
which indicates a vegetarian diet. This structural difference supports
the hunting hypothesis in being an evolutionary branching point between
modern humans and modern primates. Buss also cites human teeth in that
fossilized human teeth have a thin enamel coating with very little heavy
wear and tear that would result from a plant diet. The absence of thick
enamel also indicates that historically humans have maintained a
meat-heavy diet.
Buss notes that the bones of animals human ancestors killed found at
Olduvai Gorge have cut marks at strategic points on the bones that
indicate tool usage and provide evidence for ancestral butchers.
According
to the hunting hypothesis, women are preoccupied with pregnancy and
dependent children and so do not hunt because it is dangerous and less
profitable. Gijsbert Stoet highlights the fact that men are more
competent in throwing skills, focused attention, and spatial abilities.
(Experiments 1 and 2).
Another possible explanation for women gathering is their inherent
prioritization of rearing offspring, which is difficult to uphold if
women were hunting.
Provisioning hypothesis
Parental investment
Buss
purports that the hunting hypothesis explains the high level of human
male parental investment in offspring as compared to primates. Meat is
an economical and condensed food resource in that it can be brought home
to feed the young, however it is not efficient to carry low-calorie
food across great distances. Thus, the act of hunting and the required
transportation of the kill in order to feed offspring is a reasonable
explanation for human male provisioning.
Male coalitions
Buss
suggests that the Hunting hypothesis also explains the advent of strong
male coalitions. Although chimpanzees form male-male coalitions, they
tend to be temporary and opportunistic. Contrastingly, large game
hunters require consistent and coordinated cooperation to succeed in
large game hunting. Thus male coalitions were the result of working
together to succeed in providing meat for the hunters themselves and
their families.
Kristen Hawkes suggests further that obtaining resources intended for
community consumption increases a male's fitness by appealing to the
male's society and thus being in the good favor of both males and
females. The male relationship would improve hunting success and create
alliances for future conflict and the female relationship would improve
direct reproductive success.
Buss proposes alternate explanations of emergence of the strong male
coalitions. He suggests that male coalitions may have been the result of
group-on-group aggression, defense, and in-group political alliances.
This explanation does not support the relationship between male
coalitions and hunting.
Hawkes proposes that hunters pursue large game and divide the
kill across the group. Hunters compete to divvy up the kill to signal
courage, power, generosity, prosocial intent, and dedication. By
engaging in these activities, hunters receive reproductive benefits and
respect. These reproductive benefits lead to greater reproductive success in more skilled hunters. Evidence of these hunting goals that do not only benefit the families of the hunters are in the Ache and Hadza
men. Hawkes notes that their hunting techniques are less efficient than
alternative methods and are energetically costly, but the men place
more importance on displaying their bravery, power, and prosocial intent
than on hunting efficiency. This method is different as compared to
other societies where hunters retain the control of their kills and
signal their intent of sharing. This alternate method aligns with the
coalition support hypothesis, in efforts to create and preserve
political associations.
Reciprocal altruism
The
meat from successful large game hunts are more than what a single
hunter can consume. Further, hunting success varies by week. One week a
hunter may succeed in hunting large game and the next may return with no
meat. In this situation Buss suggests that there are low costs to
giving away meat that cannot be eaten by the individual hunter on his
own and large benefits from the expectation of the returned favor in a
week where his hunting is not successful.
Hawkes calls this sharing “tolerated theft” and purports that the
benefits of reciprocal altruism stem from the result that families will
experience “lower daily variation and higher daily average” in their
resources.
Provisioning may actually be a form of sexual competition between males for females. Hawkes suggests that male provisioning is a particularly human behavior, which forges the nuclear family.
The structure of familial provisioning determines a form of resource
distribution. However, Hawkes does acknowledge inconsistencies across
societies and contexts such as the fluctuating time courses dedicated to
hunting and gathering, which are not directly correlated with return
rates, the fact that nutrition value is often chosen over caloric count,
and the fact that meat is a more widely spread resource than other
resources.
The show-off hypothesis
The
show-off hypothesis is the concept that more successful men have better
mate options. The idea relates back to the fact that meat, the result
of hunting expeditions, is a distinct resource in that it comes in large
quantities that more often than not the hunter's own family is not able
to consume in a timely manner so that the meat doesn't go sour.
Also the success of hunting is unpredictable whereas berries and
fruits, unless there is a drought or a bad bush, are fairly consistent
in seasonality. Kristen Hawkes argues that women favor neighbors opting
for men who provide the advantageous, yet infrequent meat feasts.
These women may profit from alliance and the resulting feasts,
especially in times of shortage. Hawkes suggests that it would be
beneficial for women to reward men who employ the “show-off strategy” by
supporting them in a dispute, caring for their offspring, or providing
sexual favors.
The benefits women may gain from their alignment lie in favored
treatment of the offspring spawned by the show-off from neighbors.
Buss echoes and cites Hawke's thoughts on the show-off's benefits in
sexual access, increased likelihood of having children, and the
favorable treatment his children would receive from the other members of
the society. Hawkes also suggests that show-offs are more likely to live in large groups and thus be less susceptible to predators.
Show-offs gain more benefits from just sharing with their family
(classical fitness) in the potential favorable treatment from the
community and reciprocal altruism from other members of the community.
Hawkes uses the Ache people of Paraguay as evidence for the
Show-off hypothesis. Food acquired by men was more widely distributed
across the community and inconsistent resources that came in large
quantities when acquired were also more widely shared.
While this is represented in the Ache according to Hawkes, Buss
notes that this trend is contradicted in the Hadza who evenly distribute
the meat across all members of their population and whose hunters have
very little control over the distribution. In the Hadza the show-off
hypothesis does not have to do with the resources that result from
hunting, but from the prestige and risk that is involved in big game
hunting. There are possible circuitous benefits such as protection and
defense.
Autoimmunity means presence of antibodies or T cells that react with self-protein
and is present in all individuals, even in normal health state. It
causes autoimmune diseases if self-reactivity can lead to tissue damage.
History
In the later 19th century it was believed that the immune system was unable to react against the body's own tissues. Paul Ehrlich, at the turn of the 20th century, proposed the concept of horror autotoxicus.
Ehrlich later adjusted his theory to recognize the possibility of
autoimmune tissue attacks, but believed certain innate protection
mechanisms would prevent the autoimmune response from becoming
pathological.
In 1904 this theory was challenged by the discovery of a
substance in the serum of patients with paroxysmal cold hemoglobinuria
that reacted with red blood cells. During the following decades, a
number of conditions could be linked to autoimmune responses. However,
the authoritative status of Ehrlich's postulate hampered the
understanding of these findings. Immunology became a biochemical rather
than a clinical discipline. By the 1950s the modern understanding of autoantibodies and autoimmune diseases started to spread.
More recently it has become accepted that autoimmune responses are an integral part of vertebrate immune systems (sometimes termed "natural autoimmunity"). Autoimmunity should not be confused with alloimmunity.
Low-level autoimmunity
While
a high level of autoimmunity is unhealthy, a low level of autoimmunity
may actually be beneficial. Taking the experience of a beneficial factor
in autoimmunity further, one might hypothesize with intent to prove
that autoimmunity is always a self-defense mechanism of the mammal
system to survive. The system does not randomly lose the ability to
distinguish between self
and non-self; the attack on cells may be the consequence of cycling
metabolic processes necessary to keep the blood chemistry in
homeostasis.
Second, autoimmunity may have a role in allowing a rapid immune
response in the early stages of an infection when the availability of
foreign antigens limits the response (i.e., when there are few pathogens present). In their study, Stefanova et al. (2002) injected an anti-MHC class IIantibody into mice expressing a single type of MHC Class II molecule (H-2b) to temporarily prevent CD4+ T cell-MHC interaction. NaiveCD4+ T cells
(those that have not encountered non-self antigens before) recovered
from these mice 36 hours post-anti-MHC administration showed decreased
responsiveness to the antigen pigeon cytochrome c peptide, as determined by ZAP70phosphorylation, proliferation, and interleukin 2
production. Thus Stefanova et al. (2002) demonstrated that self-MHC
recognition (which, if too strong may contribute to autoimmune disease)
maintains the responsiveness of CD4+ T cells when foreign antigens are
absent.
Immunological tolerance
Pioneering work by Noel Rose and Ernst Witebsky in New York, and Roitt and Doniach at University College London
provided clear evidence that, at least in terms of antibody-producing B
cells (B lymphocytes), diseases such as rheumatoid arthritis and
thyrotoxicosis are associated with loss of immunological tolerance,
which is the ability of an individual to ignore "self", while reacting
to "non-self". This breakage leads to the immune system's mounting an
effective and specific immune response against self determinants. The
exact genesis of immunological tolerance is still elusive, but several
theories have been proposed since the mid-twentieth century to explain
its origin.
Three hypotheses have gained widespread attention among immunologists:
Clonal deletiontheory, proposed by Burnet,
according to which self-reactive lymphoid cells are destroyed during
the development of the immune system in an individual. For their work
Frank M. Burnet and Peter B. Medawar were awarded the 1960 Nobel Prize
in Physiology or Medicine "for discovery of acquired immunological
tolerance".
Clonal anergy theory, proposed by Nossal, in which self-reactive T- or B-cells become inactivated in the normal individual and cannot amplify the immune response.
Idiotype network theory, proposed by Jerne, wherein a network of antibodies capable of neutralizing self-reactive antibodies exists naturally within the body.
In addition, two other theories are under intense investigation:
Clonal ignorance theory, according to which autoreactive T
cells that are not represented in the thymus will mature and migrate to
the periphery, where they will not encounter the appropriate antigen
because it is inaccessible tissues. Consequently, auto-reactive B cells,
that escape deletion, cannot find the antigen or the specific helper T
cell.
Suppressor population or Regulatory T cell theory, wherein regulatory T-lymphocytes (commonly CD4+FoxP3+ cells, among others) function to prevent, downregulate, or limit autoaggressive immune responses in the immune system.
Tolerance can also be differentiated into "central" and "peripheral"
tolerance, on whether or not the above-stated checking mechanisms
operate in the central lymphoid organs (thymus and bone marrow) or the
peripheral lymphoid organs (lymph node, spleen, etc., where
self-reactive B-cells may be destroyed). It must be emphasised that
these theories are not mutually exclusive, and evidence has been
mounting suggesting that all of these mechanisms may actively contribute
to vertebrate immunological tolerance.
A puzzling feature of the documented loss of tolerance seen in
spontaneous human autoimmunity is that it is almost entirely restricted
to the autoantibody responses produced by B lymphocytes. Loss of
tolerance by T cells has been extremely hard to demonstrate, and where
there is evidence for an abnormal T cell response it is usually not to
the antigen recognised by autoantibodies. Thus, in rheumatoid arthritis
there are autoantibodies to IgG Fc but apparently no corresponding T
cell response. In systemic lupus there are autoantibodies to DNA, which
cannot evoke a T cell response, and limited evidence for T cell
responses implicates nucleoprotein antigens. In Celiac disease there are
autoantibodies to tissue transglutaminase but the T cell response is to
the foreign protein gliadin. This disparity has led to the idea that
human autoimmune disease is in most cases (with probable exceptions
including type I diabetes) based on a loss of B cell tolerance which
makes use of normal T cell responses to foreign antigens in a variety of
aberrant ways.
Immunodeficiency and autoimmunity
There
are a large number of immunodeficiency syndromes that present clinical
and laboratory characteristics of autoimmunity. The decreased ability of
the immune system to clear infections in these patients may be
responsible for causing autoimmunity through perpetual immune system
activation.
One example is common variable immunodeficiency
(CVID) where multiple autoimmune diseases are seen, e.g.: inflammatory
bowel disease, autoimmune thrombocytopenia and autoimmune thyroid
disease.
In addition to chronic and/or recurrent infections many
autoimmune diseases including arthritis, autoimmune hemolytic anemia,
scleroderma and type 1 diabetes mellitus are also seen in X-linked agammaglobulinemia (XLA).
Recurrent bacterial and fungal infections and chronic inflammation of the gut and lungs are seen in chronic granulomatous disease
(CGD) as well. CGD is a caused by decreased production of nicotinamide
adenine dinucleotide phosphate (NADPH) oxidase by neutrophils.
Hypomorphic RAG mutations are seen in patients with midline
granulomatous disease; an autoimmune disorder that is commonly seen in
patients with granulomatosis with polyangiitis and NK/T cell lymphomas.
Wiskott–Aldrich syndrome (WAS) patients also present with eczema, autoimmune manifestations, recurrent bacterial infections and lymphoma.
In autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy
(APECED) also autoimmunity and infections coexist: organ-specific
autoimmune manifestations (e.g. hypoparathyroidism and adrenocortical
failure) and chronic mucocutaneous candidiasis.
Finally, IgA deficiency is also sometimes associated with the development of autoimmune and atopic phenomena.
Genetic factors
Certain
individuals are genetically susceptible to developing autoimmune
diseases. This susceptibility is associated with multiple genes plus
other risk factors. Genetically predisposed individuals do not always
develop autoimmune diseases.
Three main sets of genes are suspected in many autoimmune diseases. These genes are related to:
The first two, which are involved in the recognition of antigens, are
inherently variable and susceptible to recombination. These variations
enable the immune system to respond to a very wide variety of invaders,
but may also give rise to lymphocytes capable of self-reactivity.
Fewer correlations exist with MHC class I molecules. The most
notable and consistent is the association between HLA B27 and
spondyloarthropathies like ankylosing spondylitis and reactive arthritis. Correlations may exist between polymorphisms within class II MHC promoters and autoimmune disease.
The contributions of genes outside the MHC complex remain the
subject of research, in animal models of disease (Linda Wicker's
extensive genetic studies of diabetes in the NOD mouse), and in patients
(Brian Kotzin's linkage analysis of susceptibility to SLE).
Recently, PTPN22
has been associated with multiple autoimmune diseases including Type I
diabetes, rheumatoid arthritis, systemic lupus erythematosus,
Hashimoto's thyroiditis, Graves’ disease, Addison's disease, Myasthenia
Gravis, vitiligo, systemic sclerosis juvenile idiopathic arthritis, and
psoriatic arthritis.
The reasons for the sex role in autoimmunity vary. Women appear
to generally mount larger inflammatory responses than men when their
immune systems are triggered, increasing the risk of autoimmunity.
Involvement of sex steroids
is indicated by that many autoimmune diseases tend to fluctuate in
accordance with hormonal changes, for example: during pregnancy, in the
menstrual cycle, or when using oral contraception. A history of
pregnancy also appears to leave a persistent increased risk for
autoimmune disease. It has been suggested that the slight, direct
exchange of cells between mothers and their children during pregnancy
may induce autoimmunity. This would tip the gender balance in the direction of the female.
Another theory suggests the female high tendency to get autoimmunity is due to an imbalanced X-chromosome inactivation.
The X-inactivation skew theory, proposed by Princeton University's Jeff
Stewart, has recently been confirmed experimentally in scleroderma and
autoimmune thyroiditis. Other complex X-linked genetic susceptibility mechanisms are proposed and under investigation.
Environmental factors
Infectious diseases and parasites
An
interesting inverse relationship exists between infectious diseases and
autoimmune diseases. In areas where multiple infectious diseases are
endemic, autoimmune diseases are quite rarely seen. The reverse, to some
extent, seems to hold true. The hygiene hypothesis
attributes these correlations to the immune-manipulating strategies of
pathogens. While such an observation has been variously termed as
spurious and ineffective, according to some studies, parasite infection
is associated with reduced activity of autoimmune disease.
The putative mechanism is that the parasite attenuates the host
immune response in order to protect itself. This may provide a
serendipitous benefit to a host that also suffers from autoimmune
disease. The details of parasite immune modulation are not yet known,
but may include secretion of anti-inflammatory agents or interference
with the host immune signaling.
A paradoxical observation has been the strong association of certain microbial organisms with autoimmune diseases.
For example, Klebsiella pneumoniae and coxsackievirus B have been strongly correlated with ankylosing spondylitis and diabetes mellitus type 1, respectively. This has been explained by the tendency of the infecting organism to produce super-antigens that are capable of polyclonal activation of B-lymphocytes, and production of large amounts of antibodies of varying specificities, some of which may be self-reactive (see below).
Chemical agents and drugs
Certain
chemical agents and drugs can also be associated with the genesis of
autoimmune conditions, or conditions that simulate autoimmune diseases.
The most striking of these is the drug-induced lupus erythematosus. Usually, withdrawal of the offending drug cures the symptoms in a patient.
Cigarette smoking is now established as a major risk factor for both incidence and severity of rheumatoid arthritis. This may relate to abnormal citrullination of proteins, since the effects of smoking correlate with the presence of antibodies to citrullinated peptides.
Pathogenesis of autoimmunity
Several
mechanisms are thought to be operative in the pathogenesis of
autoimmune diseases, against a backdrop of genetic predisposition and
environmental modulation. It is beyond the scope of this article to
discuss each of these mechanisms exhaustively, but a summary of some of
the important mechanisms have been described:
T-cell bypass – A normal immune system requires the activation of B cells by T cells
before the former can undergo differentiation into plasma B-cells and
subsequently produce antibodies in large quantities. This requirement of
a T cell can be bypassed in rare instances, such as infection by
organisms producing super-antigens,
which are capable of initiating polyclonal activation of B-cells, or
even of T-cells, by directly binding to the β-subunit of T-cell
receptors in a non-specific fashion.
T-cell–B-cell discordance – A normal immune response is
assumed to involve B and T cell responses to the same antigen, even if
we know that B cells and T cells recognise very different things:
conformations on the surface of a molecule for B cells and pre-processed
peptide fragments of proteins for T cells. However, there is nothing as
far as we know that requires this. All that is required is that a B
cell recognising antigen X endocytoses and processes a protein Y
(normally =X) and presents it to a T cell. Roosnek and Lanzavecchia
showed that B cells recognising IgGFc could get help from any T cell
responding to an antigen co-endocytosed with IgG by the B cell as part
of an immune complex. In coeliac disease it seems likely that B cells
recognising tissue transglutamine are helped by T cells recognising
gliadin.
Aberrant B cell receptor-mediated feedback – A feature of
human autoimmune disease is that it is largely restricted to a small
group of antigens, several of which have known signaling roles in the
immune response (DNA, C1q, IgGFc, Ro, Con. A receptor, Peanut agglutinin
receptor(PNAR)). This fact gave rise to the idea that spontaneous
autoimmunity may result when the binding of antibody to certain antigens
leads to aberrant signals being fed back to parent B cells through
membrane bound ligands. These ligands include B cell receptor (for
antigen), IgG Fc receptors, CD21, which binds complement C3d, Toll-like
receptors 9 and 7 (which can bind DNA and nucleoproteins) and PNAR. More
indirect aberrant activation of B cells can also be envisaged with
autoantibodies to acetyl choline receptor (on thymic myoid cells) and
hormone and hormone binding proteins. Together with the concept of
T-cell–B-cell discordance this idea forms the basis of the hypothesis of
self-perpetuating autoreactive B cells.
Autoreactive B cells in spontaneous autoimmunity are seen as surviving
because of subversion both of the T cell help pathway and of the
feedback signal through B cell receptor, thereby overcoming the negative
signals responsible for B cell self-tolerance without necessarily
requiring loss of T cell self-tolerance.
Molecular mimicry – An exogenous antigen
may share structural similarities with certain host antigens; thus, any
antibody produced against this antigen (which mimics the self-antigens)
can also, in theory, bind to the host antigens, and amplify the immune
response. The idea of molecular mimicry arose in the context of rheumatic fever, which follows infection with Group A beta-haemolytic streptococci.
Although rheumatic fever has been attributed to molecular mimicry for
half a century no antigen has been formally identified (if anything too
many have been proposed). Moreover, the complex tissue distribution of
the disease (heart, joint, skin, basal ganglia) argues against a
cardiac specific antigen. It remains entirely possible that the disease
is due to e.g. an unusual interaction between immune complexes,
complement components and endothelium.
Idiotype cross-reaction – Idiotypes are antigenic epitopes
found in the antigen-binding portion (Fab) of the immunoglobulin
molecule. Plotz and Oldstone presented evidence that autoimmunity can
arise as a result of a cross-reaction between the idiotype on an
antiviral antibody and a host cell receptor for the virus in question.
In this case, the host-cell receptor is envisioned as an internal image
of the virus, and the anti-idiotype antibodies can react with the host
cells.
Cytokine dysregulation – Cytokines
have been recently divided into two groups according to the population
of cells whose functions they promote: Helper T-cells type 1 or type 2.
The second category of cytokines, which include IL-4, IL-10 and TGF-β (to name a few), seem to have a role in prevention of exaggeration of pro-inflammatory immune responses.
Dendritic cell apoptosis – immune system cells called dendritic cells present antigens to active lymphocytes.
Dendritic cells that are defective in apoptosis can lead to
inappropriate systemic lymphocyte activation and consequent decline in
self-tolerance.
Epitope spreading or epitope drift – when the immune reaction changes from targeting the primary epitope to also targeting other epitopes. In contrast to molecular mimicry, the other epitopes need not be structurally similar to the primary one.
Epitope modification or Cryptic epitope exposure –
this mechanism of autoimmune disease is unique in that it does not
result from a defect in the hematopoietic system. Instead, disease
results from the exposure of cryptic N-glycan (polysaccharide) linkages
common to lower eukaryotes and prokaryotes on the glycoproteins of
mammalian non-hematopoietic cells and organs
This exposure of phylogenically primitive glycans activates one or
more mammalian innate immune cell receptors to induce a chronic sterile
inflammatory state. In the presence of chronic and inflammatory cell
damage, the adaptive immune system is recruited and self–tolerance is
lost with increased autoantibody production. In this form of the
disease, the absence of lymphocytes can accelerate organ damage, and
intravenous IgG administration can be therapeutic. Although this route
to autoimmune disease may underlie various degenerative disease states,
no diagnostics for this disease mechanism exist at present, and thus its
role in human autoimmunity is currently unknown.
The roles of specialized immunoregulatory cell types, such as regulatory T cells, NKT cells, γδ T-cells in the pathogenesis of autoimmune disease are under investigation.
Classification
Autoimmune diseases can be broadly divided into systemic and
organ-specific or localised autoimmune disorders, depending on the
principal clinico-pathologic features of each disease.
Using the traditional “organ specific” and “non-organ specific”
classification scheme, many diseases have been lumped together under the
autoimmune disease umbrella. However, many chronic inflammatory human
disorders lack the telltale associations of B and T cell driven
immunopathology. In the last decade it has been firmly established that tissue "inflammation against self" does not necessarily rely on abnormal T and B cell responses.
This has led to the recent proposal that the spectrum of
autoimmunity should be viewed along an “immunological disease
continuum,” with classical autoimmune diseases at one extreme and
diseases driven by the innate immune system at the other extreme.
Within this scheme, the full spectrum of autoimmunity can be included.
Many common human autoimmune diseases can be seen to have a substantial
innate immune mediated immunopathology using this new scheme. This new
classification scheme has implications for understanding disease mechanisms and for therapy development.
Diagnosis
Diagnosis
of autoimmune disorders largely rests on accurate history and physical
examination of the patient, and high index of suspicion against a backdrop of certain abnormalities in routine laboratory tests (example, elevated C-reactive protein).
In several systemic disorders, serological assays which can detect specific autoantibodies can be employed. Localised disorders are best diagnosed by immunofluorescence of biopsy specimens.
Autoantibodies are used to diagnose many autoimmune diseases. The levels of autoantibodies are measured to determine the progress of the disease.
Treatments
Treatments for autoimmune disease have traditionally been immunosuppressive, anti-inflammatory, or palliative. Managing inflammation is critical in autoimmune diseases.
Non-immunological therapies, such as hormone replacement in Hashimoto's
thyroiditis or Type 1 diabetes mellitus treat outcomes of the
autoaggressive response, thus these are palliative treatments. Dietary
manipulation limits the severity of celiac disease. Steroidal or NSAID
treatment limits inflammatory symptoms of many diseases. IVIG is used for CIDP and GBS. Specific immunomodulatory therapies, such as the TNFα antagonists (e.g. etanercept), the B cell depleting agent rituximab, the anti-IL-6 receptor tocilizumab and the costimulation blocker abatacept
have been shown to be useful in treating RA. Some of these
immunotherapies may be associated with increased risk of adverse
effects, such as susceptibility to infection.
Helminthic therapy is an experimental approach that involves inoculation of the patient with specific parasitic intestinal nematodes
(helminths). There are currently two closely related treatments
available, inoculation with either Necator americanus, commonly known as
hookworms, or Trichuris Suis Ova, commonly known as Pig Whipworm Eggs.
T-cell vaccination is also being explored as a possible future therapy for autoimmune disorders.
Nutrition and autoimmunity
Vitamin D/Sunlight
Because most human cells and tissues have receptors for
vitamin D, including T and B cells, adequate levels of vitamin D can aid
in the regulation of the immune system. Vitamin D plays a role in immune function by acting on T cells and natural killer cells. Research has demonstrated an association between low serum vitamin D and autoimmune diseases, including multiple sclerosis, type 1 diabetes, and Systemic Lupus Erythematosus (commonly referred to simply as lupus). However, since photosensitivity occurs in lupus, patients are advised to avoid sunlight which may be responsible for vitamin D deficiency seen in this disease. Polymorphisms in the vitamin D receptor gene
are commonly found in people with autoimmune diseases, giving one
potential mechanism for vitamin D's role in autoimmunity. There is mixed evidence on the effect of vitamin D supplementation in type 1 diabetes, lupus, and multiple sclerosis.
Omega-3 Fatty Acids
Studies have shown that adequate consumption of omega-3
fatty acids counteracts the effects of arachidonic acids, which
contribute to symptoms of autoimmune diseases. Human and animal trials
suggest that omega-3 is an effective treatment modality for many cases of Rheumatoid Arthritis, Inflammatory Bowel Disease, Asthma, and Psoriasis.
While major depression is not necessarily an autoimmune disease,
some of its physiological symptoms are inflammatory and autoimmune in
nature. Omega-3 may inhibit production of interferon gamma and other
cytokines which cause the physiological symptoms of depression. This
may be due to the fact that an imbalance in omega-3 and omega-6 fatty
acids, which have opposing effects, is instrumental in the etiology of
major depression.
Probiotics/Microflora
Various types of bacteria and microflora present in fermented dairy products, especially Lactobacillus casei,
have been shown to both stimulate immune response to tumors in mice and
to regulate immune function, delaying or preventing the onset of
nonobese diabetes. This is particularly true of the Shirota strain of L. casei (LcS). The LcS strain is mainly found in yogurt and similar products in Europe and Japan, and rarely elsewhere.
It has been theorized that free radicals contribute to
the onset of type-1 diabetes in infants and young children, and
therefore that the risk could be reduced by high intake of antioxidant
substances during pregnancy. However, a study conducted in a hospital in
Finland from 1997-2002 concluded that there was no statistically
significant correlation between antioxidant intake and diabetes risk.
This study involved monitoring of food intake through questionnaires,
and estimated antioxidant intake on this basis, rather than by exact
measurements or use of supplements.
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinters, distinguishing them from the organism's own healthy tissue. Many species have two major subsystems of the immune system. The innate immune system provides a preconfigured response to broad groups of situations and stimuli. The adaptive immune system provides a tailored response to each stimulus by learning to recognize molecules it has previously encountered. Both use molecules and cells to perform their functions.
Nearly all organisms have some kind of immune system. Bacteria have a rudimentary immune system in the form of enzymes that protect against virus infections. Other basic immune mechanisms evolved in ancient plants and animals and remain in their modern descendants. These mechanisms include phagocytosis, antimicrobial peptides called defensins, and the complement system. Jawed vertebrates,
including humans, have even more sophisticated defense mechanisms,
including the ability to adapt to recognize pathogens more efficiently.
Adaptive (or acquired) immunity creates an immunological memory
leading to an enhanced response to subsequent encounters with that same
pathogen. This process of acquired immunity is the basis of vaccination.
The immune system protects its host from infection with layered defenses of increasing specificity. Physical barriers prevent pathogens such as bacteria and viruses from entering the organism. If a pathogen breaches these barriers, the innate immune system provides an immediate, but non-specific response. Innate immune systems are found in all animals. If pathogens successfully evade the innate response, vertebrates possess a second layer of protection, the adaptive immune system, which is activated by the innate response.
Here, the immune system adapts its response during an infection to
improve its recognition of the pathogen. This improved response is then
retained after the pathogen has been eliminated, in the form of an immunological memory, and allows the adaptive immune system to mount faster and stronger attacks each time this pathogen is encountered.
Both innate and adaptive immunity depend on the ability of the immune system to distinguish between self and non-self molecules. In immunology, self molecules are components of an organism's body that can be distinguished from foreign substances by the immune system. Conversely, non-self
molecules are those recognized as foreign molecules. One class of
non-self molecules are called antigens (originally named for being antibody generators) and are defined as substances that bind to specific immune receptors and elicit an immune response.
Surface barriers
Several barriers protect organisms from infection, including mechanical, chemical, and biological barriers. The waxy cuticle of most leaves, the exoskeleton of insects, the shells and membranes of externally deposited eggs, and skin are examples of mechanical barriers that are the first line of defense against infection. Organisms cannot be completely sealed from their environments, so systems act to protect body openings such as the lungs, intestines, and the genitourinary tract. In the lungs, coughing and sneezing mechanically eject pathogens and other irritants from the respiratory tract. The flushing action of tears and urine also mechanically expels pathogens, while mucus secreted by the respiratory and gastrointestinal tract serves to trap and entangle microorganisms.
Within the genitourinary and gastrointestinal tracts, commensalflora
serve as biological barriers by competing with pathogenic bacteria for
food and space and, in some cases, changing the conditions in their
environment, such as pH or available iron. As a result, the probability that pathogens will reach sufficient numbers to cause illness is reduced.
Innate immune system
Microorganisms or toxins that successfully enter an organism
encounter the cells and mechanisms of the innate immune system. The
innate response is usually triggered when microbes are identified by pattern recognition receptors, which recognize components that are conserved among broad groups of microorganisms,
or when damaged, injured or stressed cells send out alarm signals, many
of which are recognized by the same receptors as those that recognize
pathogens. Innate immune defenses are non-specific, meaning these systems respond to pathogens in a generic way. This system does not confer long-lasting immunity against a pathogen. The innate immune system is the dominant system of host defense in most organisms, and the only one in plants.
Immune sensing
Cells in the innate immune system use pattern recognition receptors to recognize molecular structures that are produced by pathogens. They are proteins expressed, mainly, by cells of the innate immune system, such as dendritic cells, macrophages, monocytes, neutrophils and epithelial cells to identify two classes of molecules: pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens, and damage-associated molecular patterns (DAMPs), which are associated with components of host's cells that are released during cell damage or cell death.
Recognition of extracellular or endosomal PAMPs is mediated by transmembrane proteins known as toll-like receptors (TLRs). TLRs share a typical structural motif, the leucine rich repeats (LRR), which give them a curved shape. Toll-like receptors were first discovered in Drosophila and trigger the synthesis and secretion of cytokines
and activation of other host defense programs that are necessary for
both innate or adaptive immune responses. Ten toll-like receptors have
been described in humans.
Cells in the innate immune system have pattern recognition
receptors, which detect infection or cell damage, inside. Three major
classes of these "cytosolic" receptors are NOD–like receptors, RIG (retinoic acid-inducible gene)-like receptors, and cytosolic DNA sensors.
Phagocytosis
is an important feature of cellular innate immunity performed by cells
called phagocytes that engulf pathogens or particles. Phagocytes
generally patrol the body searching for pathogens, but can be called to
specific locations by cytokines. Once a pathogen has been engulfed by a phagocyte, it becomes trapped in an intracellular vesicle called a phagosome, which subsequently fuses with another vesicle called a lysosome to form a phagolysosome. The pathogen is killed by the activity of digestive enzymes or following a respiratory burst that releases free radicals into the phagolysosome.
Phagocytosis evolved as a means of acquiring nutrients, but this role was extended in phagocytes to include engulfment of pathogens as a defense mechanism.
Phagocytosis probably represents the oldest form of host defense, as
phagocytes have been identified in both vertebrate and invertebrate
animals.
Neutrophils and macrophages are phagocytes that travel throughout the body in pursuit of invading pathogens. Neutrophils are normally found in the bloodstream and are the most abundant type of phagocyte, representing 50% to 60% of total circulating leukocytes. During the acute phase of inflammation, neutrophils migrate toward the site of inflammation in a process called chemotaxis,
and are usually the first cells to arrive at the scene of infection.
Macrophages are versatile cells that reside within tissues and produce
an array of chemicals including enzymes, complement proteins, and cytokines, while they can also act as scavengers that rid the body of worn-out cells and other debris, and as antigen-presenting cells (APC) that activate the adaptive immune system.
Dendritic cells are phagocytes in tissues that are in contact
with the external environment; therefore, they are located mainly in the
skin, nose, lungs, stomach, and intestines. They are named for their resemblance to neuronaldendrites,
as both have many spine-like projections. Dendritic cells serve as a
link between the bodily tissues and the innate and adaptive immune
systems, as they present antigens to T cells, one of the key cell types of the adaptive immune system.
Granulocytes
are leukocytes that have granules in their cytoplasm. In this category
are neutrophils, mast cells, basophils, and eosinophils. Mast cells
reside in connective tissues and mucous membranes, and regulate the inflammatory response. They are most often associated with allergy and anaphylaxis. Basophils and eosinophils are related to neutrophils. They secrete chemical mediators that are involved in defending against parasites and play a role in allergic reactions, such as asthma.
Natural killer cells (NK) are lymphocytes and a component of the innate immune system which does not directly attack invading microbes.
Rather, NK cells destroy compromised host cells, such as tumor cells or
virus-infected cells, recognizing such cells by a condition known as
"missing self." This term describes cells with low levels of a
cell-surface marker called MHC I (major histocompatibility complex)—a situation that can arise in viral infections of host cells.
Normal body cells are not recognized and attacked by NK cells because
they express intact self MHC antigens. Those MHC antigens are recognized
by killer cell immunoglobulin receptors which essentially put the
brakes on NK cells.
Inflammation
Inflammation is one of the first responses of the immune system to infection.
The symptoms of inflammation are redness, swelling, heat, and pain,
which are caused by increased blood flow into tissue. Inflammation is
produced by eicosanoids and cytokines, which are released by injured or infected cells. Eicosanoids include prostaglandins that produce fever and the dilation of blood vessels associated with inflammation, and leukotrienes that attract certain white blood cells (leukocytes). Common cytokines include interleukins that are responsible for communication between white blood cells; chemokines that promote chemotaxis; and interferons that have anti-viral effects, such as shutting down protein synthesis in the host cell. Growth factors
and cytotoxic factors may also be released. These cytokines and other
chemicals recruit immune cells to the site of infection and promote
healing of any damaged tissue following the removal of pathogens. The pattern-recognition receptors called inflammasomes
are multiprotein complexes (consisting of an NLR, the adaptor protein
ASC, and the effector molecule pro-caspase-1) that form in response to
cytosolic PAMPs and DAMPs, whose function is to generate active forms of
the inflammatory cytokines IL-1β and IL-18.
Humoral defenses
The complement system is a biochemical cascade
that attacks the surfaces of foreign cells. It contains over 20
different proteins and is named for its ability to "complement" the
killing of pathogens by antibodies. Complement is the major humoral component of the innate immune response. Many species have complement systems, including non-mammals like plants, fish, and some invertebrates.
In humans, this response is activated by complement binding to
antibodies that have attached to these microbes or the binding of
complement proteins to carbohydrates on the surfaces of microbes. This recognition signal triggers a rapid killing response. The speed of the response is a result of signal amplification that occurs after sequential proteolytic
activation of complement molecules, which are also proteases. After
complement proteins initially bind to the microbe, they activate their
protease activity, which in turn activates other complement proteases,
and so on. This produces a catalytic cascade that amplifies the initial signal by controlled positive feedback. The cascade results in the production of peptides that attract immune cells, increase vascular permeability, and opsonize
(coat) the surface of a pathogen, marking it for destruction. This
deposition of complement can also kill cells directly by disrupting
their plasma membrane.
Adaptive immune system
Overview of the processes involved in the primary immune response
The adaptive immune system evolved in early vertebrates and allows for a stronger immune response as well as immunological memory, where each pathogen is "remembered" by a signature antigen.
The adaptive immune response is antigen-specific and requires the
recognition of specific "non-self" antigens during a process called antigen presentation.
Antigen specificity allows for the generation of responses that are
tailored to specific pathogens or pathogen-infected cells. The ability
to mount these tailored responses is maintained in the body by "memory
cells". Should a pathogen infect the body more than once, these specific
memory cells are used to quickly eliminate it.
Recognition of antigen
The cells of the adaptive immune system are special types of leukocytes, called lymphocytes. B cells and T cells are the major types of lymphocytes and are derived from hematopoietic stem cells in the bone marrow. B cells are involved in the humoral immune response, whereas T cells are involved in cell-mediated immune response. Killer T cells only recognize antigens coupled to Class I MHC molecules, while helper T cells and regulatory T cells only recognize antigens coupled to Class II MHC
molecules. These two mechanisms of antigen presentation reflect the
different roles of the two types of T cell. A third, minor subtype are
the γδ T cells that recognize intact antigens that are not bound to MHC receptors. The double-positive T cells are exposed to a wide variety of self-antigens in the thymus, in which iodine is necessary for its thymus development and activity.
In contrast, the B cell antigen-specific receptor is an antibody
molecule on the B cell surface and recognizes native (unprocessed)
antigen without any need for antigen processing. Such antigens may be large molecules found on the surfaces of pathogens, but can also be small haptens (such as penicillin) attached to carrier molecule.
Each lineage of B cell expresses a different antibody, so the complete
set of B cell antigen receptors represent all the antibodies that the
body can manufacture.
When B or T cells encounter their related antigens they multiply and
many "clones" of the cells are produced that target the same antigen.
This is called clonal selection.
Antigen presentation to T lymphocytes
Both
B cells and T cells carry receptor molecules that recognize specific
targets. T cells recognize a "non-self" target, such as a pathogen, only
after antigens (small fragments of the pathogen) have been processed
and presented in combination with a "self" receptor called a major
histocompatibility complex (MHC) molecule.
Killer
T cells are a sub-group of T cells that kill cells that are infected
with viruses (and other pathogens), or are otherwise damaged or
dysfunctional. As with B cells, each type of T cell recognizes a different antigen. Killer T cells are activated when their T-cell receptor
binds to this specific antigen in a complex with the MHC Class I
receptor of another cell. Recognition of this MHC:antigen complex is
aided by a co-receptor on the T cell, called CD8.
The T cell then travels throughout the body in search of cells where
the MHC I receptors bear this antigen. When an activated T cell contacts
such cells, it releases cytotoxins, such as perforin, which form pores in the target cell's plasma membrane, allowing ions, water and toxins to enter. The entry of another toxin called granulysin (a protease) induces the target cell to undergo apoptosis.
T cell killing of host cells is particularly important in preventing
the replication of viruses. T cell activation is tightly controlled and
generally requires a very strong MHC/antigen activation signal, or
additional activation signals provided by "helper" T cells (see below).
Helper T cells
Helper T cells
regulate both the innate and adaptive immune responses and help
determine which immune responses the body makes to a particular
pathogen.
These cells have no cytotoxic activity and do not kill infected cells
or clear pathogens directly. They instead control the immune response by
directing other cells to perform these tasks.
Helper T cells express T cell receptors that recognize antigen
bound to Class II MHC molecules. The MHC:antigen complex is also
recognized by the helper cell's CD4 co-receptor, which recruits molecules inside the T cell (such as Lck)
that are responsible for the T cell's activation. Helper T cells have a
weaker association with the MHC:antigen complex than observed for
killer T cells, meaning many receptors (around 200–300) on the helper T
cell must be bound by an MHC:antigen to activate the helper cell, while
killer T cells can be activated by engagement of a single MHC:antigen
molecule. Helper T cell activation also requires longer duration of
engagement with an antigen-presenting cell.
The activation of a resting helper T cell causes it to release
cytokines that influence the activity of many cell types. Cytokine
signals produced by helper T cells enhance the microbicidal function of
macrophages and the activity of killer T cells.
In addition, helper T cell activation causes an upregulation of
molecules expressed on the T cell's surface, such as CD40 ligand (also
called CD154), which provide extra stimulatory signals typically required to activate antibody-producing B cells.
Gamma delta T cells
Gamma delta T cells
(γδ T cells) possess an alternative T-cell receptor (TCR) as opposed to
CD4+ and CD8+ (αβ) T cells and share the characteristics of helper T
cells, cytotoxic T cells and NK cells. The conditions that produce
responses from γδ T cells are not fully understood. Like other
'unconventional' T cell subsets bearing invariant TCRs, such as CD1d-restricted natural killer T cells, γδ T cells straddle the border between innate and adaptive immunity. On one hand, γδ T cells are a component of adaptive immunity as they rearrange TCR genes
to produce receptor diversity and can also develop a memory phenotype.
On the other hand, the various subsets are also part of the innate
immune system, as restricted TCR or NK receptors may be used as pattern recognition receptors. For example, large numbers of human Vγ9/Vδ2 T cells respond within hours to common molecules produced by microbes, and highly restricted Vδ1+ T cells in epithelia respond to stressed epithelial cells.
Humoral immune response
An
antibody is made up of two heavy chains and two light chains. The
unique variable region allows an antibody to recognize its matching
antigen.
A B cell identifies pathogens when antibodies on its surface bind to a specific foreign antigen. This antigen/antibody complex is taken up by the B cell and processed by proteolysis
into peptides. The B cell then displays these antigenic peptides on its
surface MHC class II molecules. This combination of MHC and antigen
attracts a matching helper T cell, which releases lymphokines and activates the B cell. As the activated B cell then begins to divide, its offspring (plasma cells) secrete millions of copies of the antibody that recognizes this antigen. These antibodies circulate in blood plasma and lymph, bind to pathogens expressing the antigen and mark them for destruction by complement activation
or for uptake and destruction by phagocytes. Antibodies can also
neutralize challenges directly, by binding to bacterial toxins or by
interfering with the receptors that viruses and bacteria use to infect
cells.
Newborn infants have no prior exposure to microbes and are
particularly vulnerable to infection. Several layers of passive
protection are provided by the mother. During pregnancy, a particular
type of antibody, called IgG, is transported from mother to baby directly through the placenta, so human babies have high levels of antibodies even at birth, with the same range of antigen specificities as their mother. Breast milk or colostrum
also contains antibodies that are transferred to the gut of the infant
and protect against bacterial infections until the newborn can
synthesize its own antibodies. This is passive immunity because the fetus
does not actually make any memory cells or antibodies—it only borrows
them. This passive immunity is usually short-term, lasting from a few
days up to several months. In medicine, protective passive immunity can
also be transferred artificially from one individual to another.
Immunological memory
When B cells and T cells are activated and begin to replicate, some
of their offspring become long-lived memory cells. Throughout the
lifetime of an animal, these memory cells remember each specific
pathogen encountered and can mount a strong response if the pathogen is
detected again. This is "adaptive" because it occurs during the lifetime
of an individual as an adaptation to infection with that pathogen and
prepares the immune system for future challenges. Immunological memory
can be in the form of either passive short-term memory or active
long-term memory.
Physiological regulation
The
time-course of an immune response begins with the initial pathogen
encounter, (or initial vaccination) and leads to the formation and
maintenance of active immunological memory.
The immune system is involved in many aspects of physiological
regulation in the body. The immune system interacts intimately with
other systems, such as the endocrine and the nervous systems. The immune system also plays a crucial role in embryogenesis (development of the embryo), as well as in tissue repair and regeneration.
When a T-cell encounters a foreign pathogen, it extends a vitamin D receptor. This is essentially a signaling device that allows the T-cell to bind to the active form of vitamin D, the steroid hormone calcitriol.
T-cells have a symbiotic relationship with vitamin D. Not only does the
T-cell extend a vitamin D receptor, in essence asking to bind to the
steroid hormone version of vitamin D, calcitriol, but the T-cell
expresses the gene CYP27B1, which is the gene responsible for converting the pre-hormone version of vitamin D, calcidiol
into calcitriol. Only after binding to calcitriol can T-cells perform
their intended function. Other immune system cells that are known to
express CYP27B1 and thus activate vitamin D calcidiol, are dendritic cells, keratinocytes and macrophages.
Sleep and rest
The immune system is affected by sleep and rest, and sleep deprivation is detrimental to immune function. Complex feedback loops involving cytokines, such as interleukin-1 and tumor necrosis factor-α produced in response to infection, appear to also play a role in the regulation of non-rapid eye movement (REM) sleep. Thus the immune response to infection may result in changes to the sleep cycle, including an increase in slow-wave sleep relative to REM sleep.
In people suffering from sleep deprivation, active immunizations
may have a diminished effect and may result in lower antibody
production, and a lower immune response, than would be noted in a
well-rested individual. Additionally, proteins such as NFIL3, which have been shown to be closely intertwined with both T-cell differentiation and circadian rhythms,
can be affected through the disturbance of natural light and dark
cycles through instances of sleep deprivation. These disruptions can
lead to an increase in chronic conditions such as heart disease, chronic
pain, and asthma.
In addition to the negative consequences of sleep deprivation,
sleep and the intertwined circadian system have been shown to have
strong regulatory effects on immunological functions affecting both
innate and adaptive immunity. First, during the early slow-wave-sleep
stage, a sudden drop in blood levels of cortisol, epinephrine, and norepinephrine causes increased blood levels of the hormones leptin, pituitary growth hormone, and prolactin. These signals induce a pro-inflammatory state through the production of the pro-inflammatory cytokines interleukin-1, interleukin-12, TNF-alpha and IFN-gamma. These cytokines then stimulate immune functions such as immune cell activation, proliferation, and differentiation.
During this time of a slowly evolving adaptive immune response, there
is a peak in undifferentiated or less differentiated cells, like naïve
and central memory T cells. In addition to these effects, the milieu of
hormones produced at this time (leptin, pituitary growth hormone, and
prolactin) supports the interactions between APCs and T-cells, a shift
of the Th1/Th2 cytokine balance towards one that supports Th1, an increase in overall Th
cell proliferation, and naïve T cell migration to lymph nodes. This is
also thought to support the formation of long-lasting immune memory
through the initiation of Th1 immune responses.
During wake periods, differentiated effector cells, such as
cytotoxic natural killer cells and cytotoxic T lymphocytes, peak to
elicit an effective response against any intruding pathogens.
Anti-inflammatory molecules, such as cortisol and catecholamines,
also peak during awake active times. Inflammation would cause serious
cognitive and physical impairments if it were to occur during wake
times, and inflammation may occur during sleep times due to the presence
of melatonin. Inflammation causes a great deal of oxidative stress and the presence of melatonin during sleep times could actively counteract free radical production during this time.
Repair and regeneration
The immune system, particularly the innate component, plays a decisive role in tissue repair after an insult. Key actors include macrophages and neutrophils, but other cellular actors, including γδ T cells, innate lymphoid cells (ILCs), and regulatory T cells
(Tregs), are also important. The plasticity of immune cells and the
balance between pro-inflammatory and anti-inflammatory signals are
crucial aspects of efficient tissue repair. Immune components and
pathways are involved in regeneration as well, for example in
amphibians. According to one hypothesis, organisms that can regenerate
could be less immunocompetent than organisms that cannot regenerate.
Disorders of human immunity
Failures of host defense occur and fall into three broad categories: immunodeficiencies, autoimmunity, and hypersensitivities.
Immunodeficiencies
Immunodeficiencies
occur when one or more of the components of the immune system are
inactive. The ability of the immune system to respond to pathogens is
diminished in both the young and the elderly, with immune responses beginning to decline at around 50 years of age due to immunosenescence. In developed countries, obesity, alcoholism, and drug use are common causes of poor immune function, while malnutrition is the most common cause of immunodeficiency in developing countries. Diets lacking sufficient protein are associated with impaired cell-mediated immunity, complement activity, phagocyte function, IgA antibody concentrations, and cytokine production. Additionally, the loss of the thymus at an early age through genetic mutation or surgical removal results in severe immunodeficiency and a high susceptibility to infection. Immunodeficiencies can also be inherited or 'acquired'. Severe combined immunodeficiency is a rare genetic disorder characterized by the disturbed development of functional T cells and B cells caused by numerous genetic mutations. Chronic granulomatous disease, where phagocytes have a reduced ability to destroy pathogens, is an example of an inherited, or congenital, immunodeficiency. AIDS and some types of cancer cause acquired immunodeficiency.
Autoimmunity
Joints of a hand swollen and deformed by rheumatoid arthritis, an autoimmune disorder
Overactive immune responses form the other end of immune dysfunction, particularly the autoimmune disorders. Here, the immune system fails to properly distinguish between self and non-self, and attacks part of the body. Under normal circumstances, many T cells and antibodies react with "self" peptides. One of the functions of specialized cells (located in the thymus and bone marrow) is to present young lymphocytes with self antigens produced throughout the body and to eliminate those cells that recognize self-antigens, preventing autoimmunity. Common autoimmune diseases include Hashimoto's thyroiditis, rheumatoid arthritis, diabetes mellitus type 1, and systemic lupus erythematosus.
Hypersensitivity
Hypersensitivity
is an immune response that damages the body's own tissues. It is
divided into four classes (Type I – IV) based on the mechanisms involved
and the time course of the hypersensitive reaction. Type I
hypersensitivity is an immediate or anaphylactic
reaction, often associated with allergy. Symptoms can range from mild
discomfort to death. Type I hypersensitivity is mediated by IgE, which triggers degranulation of mast cells and basophils when cross-linked by antigen.
Type II hypersensitivity occurs when antibodies bind to antigens on the
individual's own cells, marking them for destruction. This is also
called antibody-dependent (or cytotoxic) hypersensitivity, and is
mediated by IgG and IgM antibodies. Immune complexes
(aggregations of antigens, complement proteins, and IgG and IgM
antibodies) deposited in various tissues trigger Type III
hypersensitivity reactions. Type IV hypersensitivity (also known as cell-mediated or delayed type hypersensitivity)
usually takes between two and three days to develop. Type IV reactions
are involved in many autoimmune and infectious diseases, but may also
involve contact dermatitis. These reactions are mediated by T cells, monocytes, and macrophages.
Idiopathic inflammation
Inflammation is one of the first responses of the immune system to infection, but it can appear without known cause.
Inflammation is produced by eicosanoids and cytokines, which are released by injured or infected cells. Eicosanoids include prostaglandins that produce fever and the dilation of blood vessels associated with inflammation, and leukotrienes that attract certain white blood cells (leukocytes). Common cytokines include interleukins that are responsible for communication between white blood cells; chemokines that promote chemotaxis; and interferons that have anti-viral effects, such as shutting down protein synthesis in the host cell. Growth factors
and cytotoxic factors may also be released. These cytokines and other
chemicals recruit immune cells to the site of infection and promote
healing of any damaged tissue following the removal of pathogens.
The immune response can be manipulated to suppress unwanted responses resulting from autoimmunity, allergy, and transplant rejection, and to stimulate protective responses against pathogens that largely elude the immune system (see immunization) or cancer.
Cytotoxic drugs inhibit the immune response by killing dividing cells such as activated T cells. This killing is indiscriminate and other constantly dividing cells and their organs are affected, which causes toxic side effects. Immunosuppressive drugs such as cyclosporin prevent T cells from responding to signals correctly by inhibiting signal transduction pathways.
Long-term active memory is acquired following infection by
activation of B and T cells. Active immunity can also be generated
artificially, through vaccination. The principle behind vaccination (also called immunization) is to introduce an antigen from a pathogen to stimulate the immune system and develop specific immunity against that particular pathogen without causing disease associated with that organism.
This deliberate induction of an immune response is successful because
it exploits the natural specificity of the immune system, as well as its
inducibility. With infectious disease remaining one of the leading
causes of death in the human population, vaccination represents the most
effective manipulation of the immune system mankind has developed.
Many vaccines are based on acellular components of micro-organisms, including harmless toxin components.
Since many antigens derived from acellular vaccines do not strongly
induce the adaptive response, most bacterial vaccines are provided with
additional adjuvants that activate the antigen-presenting cells of the innate immune system and maximize immunogenicity.
Tumor immunology
Another important role of the immune system is to identify and eliminate tumors. This is called immune surveillance. The transformed cells of tumors express antigens
that are not found on normal cells. To the immune system, these
antigens appear foreign, and their presence causes immune cells to
attack the transformed tumor cells. The antigens expressed by tumors
have several sources; some are derived from oncogenic viruses like human papillomavirus, which causes cancer of the cervix, vulva, vagina, penis, anus, mouth, and throat,
while others are the organism's own proteins that occur at low levels
in normal cells but reach high levels in tumor cells. One example is an
enzyme called tyrosinase that, when expressed at high levels, transforms certain skin cells (for example, melanocytes) into tumors called melanomas. A third possible source of tumor antigens are proteins normally important for regulating cell growth and survival, that commonly mutate into cancer inducing molecules called oncogenes.
Macrophages
have identified a cancer cell (the large, spiky mass). Upon fusing with
the cancer cell, the macrophages (smaller white cells) inject toxins
that kill the tumor cell. Immunotherapy for the treatment of cancer is an active area of medical research.
The main response of the immune system to tumors is to destroy the
abnormal cells using killer T cells, sometimes with the assistance of
helper T cells.
Tumor antigens are presented on MHC class I molecules in a similar way
to viral antigens. This allows killer T cells to recognize the tumor
cell as abnormal.
NK cells also kill tumorous cells in a similar way, especially if the
tumor cells have fewer MHC class I molecules on their surface than
normal; this is a common phenomenon with tumors. Sometimes antibodies are generated against tumor cells allowing for their destruction by the complement system.
Some tumors evade the immune system and go on to become cancers. Tumor cells often have a reduced number of MHC class I molecules on their surface, thus avoiding detection by killer T cells. Some tumor cells also release products that inhibit the immune response; for example by secreting the cytokine TGF-β, which suppresses the activity of macrophages and lymphocytes. In addition, immunological tolerance may develop against tumor antigens, so the immune system no longer attacks the tumor cells.
Paradoxically, macrophages can promote tumor growth when tumor cells send out cytokines that attract macrophages, which then generate cytokines and growth factors such as tumor-necrosis factor alpha that nurture tumor development or promote stem-cell-like plasticity.
In addition, a combination of hypoxia in the tumor and a cytokine
produced by macrophages induces tumor cells to decrease production of a
protein that blocks metastasis and thereby assists spread of cancer cells.
Anti-tumor M1 macrophages are recruited in early phases to tumor
development but are progressively differentiated to M2 with pro-tumor
effect, an immunosuppressor switch. The hypoxia reduces the cytokine
production for the anti-tumor response and progressively macrophages
acquire pro-tumor M2 functions driven by the tumor microenvironment,
including IL-4 and IL-10. Cancer immunotherapy covers the medical ways to stimulate the immune system to attack cancer tumors.
Predicting immunogenicity
Some drugs can cause a neutralizing immune response, meaning that the immune system produces neutralizing antibodies
that counteract the action of the drugs, particularly if the drugs are
administered repeatedly, or in larger doses. This limits the
effectiveness of drugs based on larger peptides and proteins (which are
typically larger than 6000 Da).
In some cases, the drug itself is not immunogenic, but may be
co-administered with an immunogenic compound, as is sometimes the case
for Taxol.
Computational methods have been developed to predict the immunogenicity
of peptides and proteins, which are particularly useful in designing
therapeutic antibodies, assessing likely virulence of mutations in viral
coat particles, and validation of proposed peptide-based drug
treatments. Early techniques relied mainly on the observation that hydrophilicamino acids are overrepresented in epitope regions than hydrophobic amino acids; however, more recent developments rely on machine learning techniques using databases of existing known epitopes, usually on well-studied virus proteins, as a training set.
A publicly accessible database has been established for the cataloguing
of epitopes from pathogens known to be recognizable by B cells. The emerging field of bioinformatics-based studies of immunogenicity is referred to as immunoinformatics. Immunoproteomics is the study of large sets of proteins (proteomics) involved in the immune response.
Evolution and other mechanisms
Evolution of the immune system
It is likely that a multicomponent, adaptive immune system arose with the first vertebrates, as invertebrates do not generate lymphocytes or an antibody-based humoral response.
Many species, however, use mechanisms that appear to be precursors of
these aspects of vertebrate immunity. Immune systems appear even in the
structurally simplest forms of life, with bacteria using a unique
defense mechanism, called the restriction modification system to protect themselves from viral pathogens, called bacteriophages. Prokaryotes also possess acquired immunity, through a system that uses CRISPR
sequences to retain fragments of the genomes of phage that they have
come into contact with in the past, which allows them to block virus
replication through a form of RNA interference. Prokaryotes also possess other defense mechanisms. Offensive elements of the immune systems are also present in unicellular eukaryotes, but studies of their roles in defense are few.
Pattern recognition receptors are proteins used by nearly all organisms to identify molecules associated with pathogens. Antimicrobial peptides
called defensins are an evolutionarily conserved component of the
innate immune response found in all animals and plants, and represent
the main form of invertebrate systemic immunity. The complement system and phagocytic cells are also used by most forms of invertebrate life. Ribonucleases and the RNA interference pathway are conserved across all eukaryotes, and are thought to play a role in the immune response to viruses.
Unlike animals, plants lack phagocytic cells, but many plant
immune responses involve systemic chemical signals that are sent through
a plant. Individual plant cells respond to molecules associated with pathogens known as pathogen-associated molecular patterns or PAMPs. When a part of a plant becomes infected, the plant produces a localized hypersensitive response, whereby cells at the site of infection undergo rapid apoptosis to prevent the spread of the disease to other parts of the plant. Systemic acquired resistance is a type of defensive response used by plants that renders the entire plant resistant to a particular infectious agent. RNA silencing mechanisms are particularly important in this systemic response as they can block virus replication.
Alternative adaptive immune system
Evolution of the adaptive immune system occurred in an ancestor of the jawed vertebrates. Many of the classical molecules of the adaptive immune system (for example, immunoglobulins and T-cell receptors) exist only in jawed vertebrates. A distinct lymphocyte-derived molecule has been discovered in primitive jawless vertebrates, such as the lamprey and hagfish. These animals possess a large array of molecules called Variable lymphocyte receptors (VLRs) that, like the antigen receptors of jawed vertebrates, are produced from only a small number (one or two) of genes. These molecules are believed to bind pathogenic antigens in a similar way to antibodies, and with the same degree of specificity.
Manipulation by pathogens
The
success of any pathogen depends on its ability to elude host immune
responses. Therefore, pathogens evolved several methods that allow them
to successfully infect a host, while evading detection or destruction by
the immune system. Bacteria often overcome physical barriers by secreting enzymes that digest the barrier, for example, by using a type II secretion system. Alternatively, using a type III secretion system,
they may insert a hollow tube into the host cell, providing a direct
route for proteins to move from the pathogen to the host. These proteins
are often used to shut down host defenses.
An evasion strategy used by several pathogens to avoid the innate
immune system is to hide within the cells of their host (also called intracellularpathogenesis). Here, a pathogen spends most of its life-cycle
inside host cells, where it is shielded from direct contact with immune
cells, antibodies and complement. Some examples of intracellular
pathogens include viruses, the food poisoning bacterium Salmonella and the eukaryotic parasites that cause malaria (Plasmodium spp.) and leishmaniasis (Leishmania spp.). Other bacteria, such as Mycobacterium tuberculosis, live inside a protective capsule that prevents lysis by complement. Many pathogens secrete compounds that diminish or misdirect the host's immune response. Some bacteria form biofilms
to protect themselves from the cells and proteins of the immune system.
Such biofilms are present in many successful infections, such as the
chronic Pseudomonas aeruginosa and Burkholderia cenocepacia infections characteristic of cystic fibrosis. Other bacteria generate surface proteins that bind to antibodies, rendering them ineffective; examples include Streptococcus (protein G), Staphylococcus aureus (protein A), and Peptostreptococcus magnus (protein L).
The mechanisms used to evade the adaptive immune system are more
complicated. The simplest approach is to rapidly change non-essential epitopes (amino acids and/or sugars) on the surface of the pathogen, while keeping essential epitopes concealed. This is called antigenic variation. An example is HIV, which mutates rapidly, so the proteins on its viral envelope
that are essential for entry into its host target cell are constantly
changing. These frequent changes in antigens may explain the failures of
vaccines directed at this virus. The parasite Trypanosoma brucei
uses a similar strategy, constantly switching one type of surface
protein for another, allowing it to stay one step ahead of the antibody
response.
Masking antigens with host molecules is another common strategy for
avoiding detection by the immune system. In HIV, the envelope that
covers the virion
is formed from the outermost membrane of the host cell; such
"self-cloaked" viruses make it difficult for the immune system to
identify them as "non-self" structures.
History of immunology
Paul Ehrlich (1854–1915) was awarded a Nobel Prize in 1908 for his contributions to immunology.
Immunology is a science that examines the structure and function of the immune system. It originates from medicine and early studies on the causes of immunity to disease. The earliest known reference to immunity was during the plague of Athens in 430 BC. Thucydides
noted that people who had recovered from a previous bout of the disease
could nurse the sick without contracting the illness a second time. In the 18th century, Pierre-Louis Moreau de Maupertuis experimented with scorpion venom and observed that certain dogs and mice were immune to this venom. In the 10th century, Persian physician al-Razi (also known as Rhazes) wrote the first recorded theory of acquired immunity, noting that a smallpox
bout protected its survivors from future infections. Although he
explained the immunity in terms of "excess moisture" being expelled from
the blood—therefore preventing a second occurrence of the disease—this
theory explained many observations about smallpox known during this
time.
These and other observations of acquired immunity were later exploited by Louis Pasteur in his development of vaccination and his proposed germ theory of disease. Pasteur's theory was in direct opposition to contemporary theories of disease, such as the miasma theory. It was not until Robert Koch's 1891 proofs, for which he was awarded a Nobel Prize in 1905, that microorganisms were confirmed as the cause of infectious disease. Viruses were confirmed as human pathogens in 1901, with the discovery of the yellow fever virus by Walter Reed.
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