The germ theory of disease is the currently accepted scientific theory for many diseases. It states that microorganisms known as pathogens
or "germs" can lead to disease. These small organisms, too small to see
without magnification, invade humans, other animals, and other living
hosts. Their growth and reproduction within their hosts can cause
disease. "Germ" may refer to not just a bacterium but to any type of microorganism, such as protists or fungi, or even non-living pathogens that can cause disease, such as viruses, prions, or viroids. Diseases caused by pathogens are called infectious diseases.
Even when a pathogen is the principal cause of a disease, environmental
and hereditary factors often influence the severity of the disease, and
whether a potential host individual becomes infected when exposed to
the pathogen.
Basic forms of germ theory were proposed in the late Middle Ages by physicians including Ibn Sina in 1025, Ibn Khatima and Ibn al-Khatib in the 14th century, Girolamo Fracastoro in 1546, and expanded upon by Marcus von Plenciz in 1762. However, such views were held in disdain in Europe, where Galen'smiasma theory remained dominant among scientists and doctors.
By the early 19th century, smallpox vaccination
was commonplace in Europe, though doctors were unaware of how it worked
or how to extend the principle to other diseases. Similar treatments
had been prevalent in India from just before AD 1000. A transitional period began in the late 1850s with the work of Louis Pasteur. This work was later extended by Robert Koch
in the 1880s. By the end of that decade, the miasma theory was
struggling to compete with the germ theory of disease. Viruses were
initially discovered in the 1890s. Eventually, a "golden era" of bacteriology ensued, during which the germ theory quickly led to the identification of the actual organisms that cause many diseases.
Miasma theory
A representation by Robert Seymour of the cholera epidemic depicts the spread of the disease in the form of poisonous air.
The miasma theory was the predominant theory of disease transmission
before the germ theory took hold towards the end of the 19th century,
and it is no longer accepted as a scientific theory of disease. It held
that diseases such as cholera, chlamydia infection, or the Black Death were caused by a miasma (μίασμα, Ancient Greek: "pollution"), a noxious form of "bad air" emanating from rotting organic matter.
Miasma was considered to be a poisonous vapor or mist filled with
particles from decomposed matter (miasmata) that was identifiable by its
foul smell. The theory posited that diseases were the product of
environmental factors such as contaminated water, foul air, and poor
hygienic conditions. Such infections, according to the theory, were not
passed between individuals but would affect those within a locale that
gave rise to such vapors.
Development
Ancient Israel
The Mosaic Law,
within the first five books of the Hebrew Bible, contains the earliest
recorded thoughts of contagion in the spread of disease, standing in
contrast with classical medical tradition and the Hippocratic writings.
Specifically, it presents instructions on quarantine and washing in
relation to leprosy and venereal disease.
Greece and Rome
In Antiquity, the Greek historian Thucydides (c. 460 – c. 400 BC) was the first person to write, in his account of the plague of Athens, that diseases could spread from an infected person to others.
One theory of the spread of contagious diseases that were not spread by direct contact was that they were spread by spore-like "seeds" (Latin: semina) that were present in and dispersible through the air. In his poem, De rerum natura (On the Nature of Things, c. 56 BC), the Roman poet Lucretius
(c. 99 BC – c. 55 BC) stated that the world contained various "seeds",
some of which could sicken a person if they were inhaled or ingested.
The Roman statesman Marcus Terentius Varro (116–27 BC) wrote, in his Rerum rusticarum libri III
(Three Books on Agriculture, 36 BC): "Precautions must also be taken in
the neighborhood of swamps […] because there are bred certain minute
creatures which cannot be seen by the eyes, which float in the air and
enter the body through the mouth and nose and there cause serious
diseases."
The Greek physician Galen (AD 129 – c. 200/c. 216) speculated in his On Initial Causes (c. AD 175) that some patients might have "seeds of fever". In his On the Different Types of Fever (c. AD 175), Galen speculated that plagues were spread by "certain seeds of plague", which were present in the air. And in his Epidemics
(c. AD 176–178), Galen explained that patients might relapse during
recovery from fever because some "seed of the disease" lurked in their
bodies, which would cause a recurrence of the disease if the patients
didn't follow a physician's therapeutic regimen.
Ancient India
In the Sushruta Samhita, the ancient Indian physician Sushruta
theorized: "Leprosy, fever, consumption, diseases of the eye, and other
infectious diseases spread from one person to another by sexual union,
physical contact, eating together, sleeping together, sitting together,
and the use of same clothes, garlands and pastes." The book has been dated to about the sixth century BC.
The Middle Ages
A basic form of contagion theory dates back to medicine in the medieval Islamic world, where it was proposed by Persian physicianIbn Sina (known as Avicenna in Europe) in The Canon of Medicine (1025), which later became the most authoritative medical textbook in Europe up until the 16th century. In Book IV of the El-Kanun, Ibn Sina discussed epidemics, outlining the classical miasma theory
and attempting to blend it with his own early contagion theory. He
mentioned that people can transmit disease to others by breath, noted
contagion with tuberculosis, and discussed the transmission of disease through water and dirt.
The concept of invisible contagion was later discussed by several Islamic scholars in the Ayyubid Sultanate who referred to them as najasat ("impure substances"). The fiqh scholar Ibn al-Haj al-Abdari (c. 1250–1336), while discussing Islamic diet and hygiene,
gave warnings about how contagion can contaminate water, food, and
garments, and could spread through the water supply, and may have
implied contagion to be unseen particles. When the Black Deathbubonic plague reached Al-Andalus in the 14th century, the Arab physicians Ibn Khatima (c. 1369) and Ibn al-Khatib
(1313–1374) hypothesised that infectious diseases were caused by
"minute bodies" and described how they can be transmitted through
garments, vessels and earrings.
During the early Middle Ages, Isidore of Seville (c. 560–636) mentioned "plague-bearing seeds" (pestifera semina) in his On the Nature of Things (c. AD 613). Later in 1345, Tommaso del Garbo (c. 1305–1370) of Bologna, Italy mentioned Galen's "seeds of plague" in his work Commentaria non-parum utilia in libros Galeni (Helpful commentaries on the books of Galen).
The Italian scholar and physician Girolamo Fracastoro proposed in 1546 in his book De Contagione et Contagiosis Morbis that epidemic diseases are caused by transferable seed-like entities (seminaria morbi)
that transmit infection by direct or indirect contact, or even without
contact over long distances. The diseases were categorised based on how
they were transmitted, and how long they could lie dormant.
The Early Modern Period
Italian physician Francesco Redi provided early evidence against spontaneous generation. He devised an experiment in 1668 in which he used three jars. He placed a meatloaf
and egg in each of the three jars. He had one of the jars open, another
one tightly sealed, and the last one covered with gauze. After a few
days, he observed that the meatloaf in the open jar was covered with
maggots, and the jar covered with gauze had maggots on the surface of
the gauze. However, the tightly sealed jar had no maggots inside or
outside it. He also noticed that the maggots were found only on surfaces
that were accessible by flies. From this he concluded that spontaneous
generation is not a plausible theory.
Microorganisms are said to have been first directly observed in the 1670s by Anton van Leeuwenhoek, an early pioneer in microbiology,
considered "the Father of Microbiology". Leeuwenhoek is said to be the
first to see and describe bacteria (1674), yeast cells, the teeming life
in a drop of water (such as algae), and the circulation of blood
corpuscles in capillaries. The word "bacteria" didn't exist yet, so he
called these microscopic living organisms "animalcules", meaning "little
animals." Those "very little animalcules" he was able to isolate from
different sources, such as rainwater, pond and well water, and the human
mouth and intestine. Yet German Jesuit priest and scholar Athanasius Kircher
may have observed such microorganisms prior to this. One of his books
written in 1646 contains a chapter in Latin, which reads in translation
"Concerning the wonderful structure of things in nature, investigated by
Microscope", stating "who would believe that vinegar and milk abound
with an innumerable multitude of worms." Kircher defined the invisible
organisms found in decaying bodies, meat, milk, and secretions as
"worms." His studies with the microscope led him to the belief, which he
was possibly the first to hold, that disease and putrefaction (decay)
were caused by the presence of invisible living bodies. In 1646, Kircher
(or "Kirchner", as it is often spelled), wrote that "a number of things
might be discovered in the blood of fever patients." When Rome was
struck by the bubonic plague in 1656, Kircher investigated the blood of
plague victims under the microscope. He noted the presence of "little
worms" or "animalcules" in the blood and concluded that the disease was
caused by microorganisms. He was the first to attribute infectious
disease to a microscopic pathogen, inventing the germ theory of disease,
which he outlined in his Scrutinium Physico-Medicum (Rome 1658).
Kircher's conclusion that disease was caused by microorganisms was
correct, although it is likely that what he saw under the microscope
were in fact red or white blood cells and not the plague agent itself.
Kircher also proposed hygienic measures to prevent the spread of
disease, such as isolation, quarantine, burning clothes worn by the
infected, and wearing facemasks to prevent the inhalation of germs. It
was Kircher who first proposed that living beings enter and exist in the
blood.
In 1700, physician Nicolas Andry argued that microorganisms he called "worms" were responsible for smallpox and other diseases.
In 1720, Richard Bradley
theorised that the plague and 'all pestilential distempers' were caused
by 'poisonous insects', living creatures viewable only with the help of
microscopes.
In 1762, the Austrian physician Marcus Antonius von Plenciz (1705–1786) published a book titled Opera medico-physica. It outlined a theory of contagion stating that specific animalcules
in the soil and the air were responsible for causing specific diseases.
Von Plenciz noted the distinction between diseases which are both
epidemic and contagious (like measles and dysentery), and diseases which
are contagious but not epidemic (like rabies and leprosy).
The book cites Anton van Leeuwenhoek to show how ubiquitous such
animalcules are and was unique for describing the presence of germs in
ulcerating wounds. Ultimately, the theory espoused by von Plenciz was
not accepted by the scientific community.
19th and 20th centuries
Agostino Bassi, Italy
The Italian Agostino Bassi
was the first person to prove that a disease was caused by a
microorganism when he conducted a series of experiments between 1808 and
1813, demonstrating that a "vegetable parasite" caused a disease in
silkworms known as calcinaccio which was devastating the French
silk industry at the time. The "vegetable parasite" is now known to be a
fungus pathogenic to insects called Beauveria bassiana (named after Bassi).
Ignaz Semmelweis, Austria
Ignaz Semmelweis, a Hungarianobstetrician working at the Vienna General Hospital (Allgemeines Krankenhaus) in 1847, noticed the dramatically high maternal mortality from puerperal fever following births assisted by doctors and medical students. However, those attended by midwives
were relatively safe. Investigating further, Semmelweis made the
connection between puerperal fever and examinations of delivering women
by doctors, and further realized that these physicians had usually come
directly from autopsies. Asserting that puerperal fever was a contagious disease
and that matter from autopsies were implicated in its development,
Semmelweis made doctors wash their hands with chlorinated lime water
before examining pregnant women. He then documented a sudden reduction
in the mortality rate from 18% to 2.2% over a period of a year. Despite
this evidence, he and his theories were rejected by most of the contemporary medical establishment.
Gideon Mantell, UK
Gideon Mantell, the Sussex doctor more famous for discovering dinosaur fossils, spent time with his microscope, and speculated in his Thoughts on Animalcules
(1850) that perhaps "many of the most serious maladies which afflict
humanity, are produced by peculiar states of invisible animalcular
life".
John Snow, UK
John Snow was a skeptic of the then-dominant miasma theory.
Even though the germ theory of disease pioneered by Girolamo Fracastoro
had not yet achieved full development or widespread currency, Snow
demonstrated a clear understanding of germ theory in his writings. He
first published his theory in an 1849 essay On the Mode of Communication of Cholera, in which he correctly suggested that the fecal-oral route
was the mode of communication, and that the disease replicated itself
in the lower intestines. He even proposed in his 1855 edition of the
work, that the structure of cholera was that of a cell.
Snow's 1849 recommendation that water be "filtered and boiled
before it is used" is one of the first practical applications of germ
theory in the area of public health and is the antecedent to the modern boil-water advisory.
In 1855 he published a second edition of his article, documenting his
more elaborate investigation of the effect of the water supply in the Soho, London epidemic of 1854.
By talking to local residents, he identified the source of the outbreak as the public water pump on Broad Street (now Broadwick Street). Although Snow's chemical and microscope examination of a water sample from the Broad Street pump
did not conclusively prove its danger, his studies of the pattern of
the disease were convincing enough to persuade the local council to
disable the well pump by removing its handle. This action has been
commonly credited as ending the outbreak, but Snow observed that the
epidemic may have already been in rapid decline.
Snow's study was a major event in the history of public health and
geography. It is regarded as one of the founding events of the science
of epidemiology.
After the cholera epidemic had subsided, government officials
replaced the handle on the Broad Street pump. They had responded only to
the urgent threat posed to the population, and afterward, they rejected
Snow's theory. To accept his proposal would have meant accepting the
fecal-oral method transmission of disease, which they dismissed.
Louis Pasteur, France
Louis
Pasteur's pasteurization experiment illustrates the fact that the
spoilage of liquid was caused by particles in the air rather than the
air itself. These experiments were important pieces of evidence
supporting the idea of germ theory of disease.
The more formal experiments on the relationship between germ and disease were conducted by Louis Pasteur between the years 1860 and 1864. He discovered the pathology of the puerperal fever and the pyogenic vibrio in the blood, and suggested using boric acid to kill these microorganisms before and after confinement.
Pasteur further demonstrated between 1860 and 1864 that fermentation and the growth of microorganisms in nutrient broths
did not proceed by spontaneous generation. He exposed freshly boiled
broth to air in vessels that contained a filter to stop all particles
passing through to the growth medium, and even with no filter at all,
with air being admitted via a long tortuous tube that would not pass
dust particles. Nothing grew in the broths: therefore the living
organisms that grew in such broths came from outside, as spores on dust,
rather than being generated within the broth.
Pasteur discovered that another serious disease of silkworms, pébrine, was caused by a microscopic organism now known as Nosema bombycis
(1870). Pasteur saved France's silk industry by developing a method to
screen silkworms eggs for those that were not infected, a method that is
still used today to control this and other silkworm diseases.
Robert Koch, Germany
Robert Koch is known for developing four basic criteria (known as Koch's postulates)
for demonstrating, in a scientifically sound manner, that a disease is
caused by a particular organism. These postulates grew out of his
seminal work with anthrax using purified cultures of the pathogen that had been isolated from diseased animals.
Koch's postulates were developed in the 19th century as general
guidelines to identify pathogens that could be isolated with the
techniques of the day.
Even in Koch's time, it was recognized that some infectious agents were
clearly responsible for disease even though they did not fulfill all of
the postulates.
Attempts to rigidly apply Koch's postulates to the diagnosis of viral
diseases in the late 19th century, at a time when viruses could not be
seen or isolated in culture, may have impeded the early development of
the field of virology.
Currently, a number of infectious agents are accepted as the cause of
disease despite their not fulfilling all of Koch's postulates.
Therefore, while Koch's postulates retain historical importance and
continue to inform the approach to microbiologic diagnosis, fulfillment
of all four postulates is not required to demonstrate causality.
Koch's postulates have also influenced scientists who examine
microbial pathogenesis from a molecular point of view. In the 1980s, a molecular version of Koch's postulates was developed to guide the identification of microbial genes encoding virulence factors.
Koch's postulates:
The microorganism must be found in abundance in all organisms
suffering from the disease, but should not be found in healthy
organisms.
The microorganism must be isolated from a diseased organism and grown in pure culture.
The cultured microorganism should cause disease when introduced into a healthy organism.
The microorganism must be reisolated from the inoculated, diseased
experimental host and identified as being identical to the original
specific causative agent.
However, Koch abandoned the universalist requirement of the first
postulate altogether when he discovered asymptomatic carriers of cholera and, later, of typhoid fever. Asymptomatic or subclinical infection carriers are now known to be a common feature of many infectious diseases, especially viruses such as polio, herpes simplex, HIV, and hepatitis C. As a specific example, all doctors and virologists agree that poliovirus causes paralysis in just a few infected subjects, and the success of the polio vaccine in preventing disease supports the conviction that the poliovirus is the causative agent.
The third postulate specifies "should", not "must", because as Koch himself proved in regard to both tuberculosis and cholera,
not all organisms exposed to an infectious agent will acquire the
infection. Noninfection may be due to such factors as general health and
proper immune functioning; acquired immunity from previous exposure or
vaccination; or genetic immunity, as with the resistance to malaria
conferred by possessing at least one sickle cell allele.
The second postulate may also be suspended for certain
microorganisms or entities that cannot (at the present time) be grown in
pure culture, such as prions responsible for Creutzfeldt–Jakob disease.
In summary, a body of evidence that satisfies Koch's postulates is sufficient but not necessary to establish causation.
Joseph Lister, UK
In the 1870s, Joseph Lister
was instrumental in developing practical applications of the germ
theory of disease with respect to sanitation in medical settings and
aseptic surgical techniques—partly through the use of carbolic acid (phenol) as an antiseptic.
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
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 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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