1.

General properties of immune responses

Eff ectiveness of vaccines
Smallpox was an infectious disease.There were two clinical forms of smallpox. Variola major was the severe and
most common form, with a more extensive rash and higher fever. Variola minor was a less common presentation,
and a much less severe disease, with historical death rates of 1 percent or less. [19]
The incubation period between contraction and the first obvious symptoms of the disease is around 12 days. Once
inhaled, variola major virus invades the oropharyngeal (mouth and throat) or the respiratory mucosa, migrates to
regional lymph nodes, and begins to multiply. In the initial growth phase the virus seems to move from cell to cell,
but around the 12th day, lysis of many infected cells occurs and the virus is found in the bloodstream in large
numbers (this is called viremia), and a second wave of multiplication occurs in the spleen, bone marrow, and lymph
nodes. The initial or prodromal symptoms are similar to other viral diseases such as influenza and the common
cold:fever of at least 38.3 C (101 F), muscle pain, malaise, headache and prostration. As the digestive tract is
commonly involved, nausea and vomiting and backache often occur. The prodrome, or preeruptive stage, usually
lasts 24 days. By days 1215 the first visible lesionssmall reddish spots called enanthemappear on mucous
membranes of the mouth, tongue, palate, and throat, and temperature falls to near normal. These lesions rapidly
enlarge and rupture, releasing large amounts of virus into the saliva.[7]
Smallpox virus preferentially attacks skin cells, causing the characteristic pimples (called macules) associated with
the disease. A rash develops on the skin 24 to 48 hours after lesions on the mucous membranes appear. Typically
the macules first appear on the forehead, then rapidly spread to the whole face, proximal portions of extremities, the
trunk, and lastly to distal portions of extremities. The process takes no more than 24 to 36 hours, after which no new
lesions appear.[7] At this point variola major infection can take several very different courses, resulting in four types of
smallpox disease based on the Rao classification: [21] ordinary, modified, malignant (or flat), and hemorrhagic.
Historically, smallpox has an overall fatality rate of about 30 percent; however, the malignant and hemorrhagic forms
are usually fatal.[22]
The earliest procedure used to prevent smallpox was Inoculation (also known as variolation) was a historical
method for the prevention of smallpox by deliberate introduction into the skin of material from smallpox pustules.
This generally produced a less severe infection than naturally-acquired smallpox, but still induced immunity to it.
Variolation or inoculation was the method first used to immunize an individual against smallpox (Variola) with
material taken from a patient or a recently variolated individual in the hope that a mild, but protective infection would
result. The procedure was most commonly carried out by inserting/rubbing powdered smallpox scabs or fluid from
pustules into superficial scratches made in the skin. The patient would develop pustules identical to those caused by
naturally occurring smallpox, usually producing a less-severe disease than naturally-acquired smallpox. Eventually,
after about two to four weeks, these symptoms would subside, indicating successful recovery and immunity. The
method was first used in China and the Middle East before it was introduced into England and North America in the
1720s in the face of some opposition. The method is no longer used today. It was replaced by smallpox vaccine, a
safer alternative. This in turn paved the way for the development of the many vaccines now available.

Accounts of inoculation against smallpox in China can be found as early as the late 10th century, and the procedure
was widely practiced by the 16th century, during the Ming dynasty.[38] If successful, inoculation produced
lasting immunity to smallpox. However, because the person was infected with variola virus, a severe infection could
result, and the person could transmit smallpox to others. Variolation had a 0.52 percent mortality rate, considerably
less than the 2030 percent mortality rate of the disease.[20]
The latter term of vaccine was first used in 1800 soon after Edward Jenner discovered that immunity to smallpox
could be produced by inoculating a person with material from a cowpox lesion and introduced smallpox
vaccine derived from cowpox, an animal disease distinct from smallpox. (Cowpox is a poxvirus in the same family as
variola.) The procedure was much safer than variolation, and did not involve a risk of smallpox transmission.
Vaccination to prevent smallpox was soon practiced all over the world. During the 19th century, the cowpox virus
used for smallpox vaccination was replaced by vaccinia virus. Vaccinia is in the same family as cowpox and variola,
but is genetically distinct from both. The origin of vaccinia virus and how it came to be in the vaccine are not known.
[20]

in 1891, Louis Pasteur honoured Jenner by widening the terms vaccine/vaccination to refer to the artificial induction
of immunity against any infectious disease.
Historically, the vaccine has been effective in preventing smallpox infection in 95 percent of those vaccinated.
[41]

Smallpox vaccination provides a high level of immunity for three to five years and decreasing immunity thereafter.

If a person is vaccinated again later, immunity lasts even longer. Studies of smallpox cases in Europe in the 1950s
and 1960s demonstrated that the fatality rate among persons vaccinated less than 10 years before exposure was
1.3 percent; it was 7 percent among those vaccinated 11 to 20 years prior, and 11 percent among those vaccinated
20 or more years prior to infection. By contrast, 52 percent of unvaccinated persons died. [42]
here are side effects and risks associated with the smallpox vaccine. In the past, about 1 out of 1,000 people
vaccinated for the first time experienced serious, but non-life-threatening, reactions, including toxic or allergic
reaction at the site of the vaccination (erythema multiforme), spread of the vaccinia virus to other parts of the body,
and to other individuals. Potentially life-threatening reactions occurred in 14 to 500 people out of every 1 million
people vaccinated for the first time. Based on past experience, it is estimated that 1 or 2 people in 1 million
(0.000198

percent)

who

receive

the

vaccine

may

die

as

result,

most

often

the

result

of

postvaccinial encephalitis or severe necrosis in the area of vaccination (called progressive vaccinia). [41]
Given these risks, as smallpox became effectively eradicated and the number of naturally occurring cases fell below
the number of vaccine-induced illnesses and deaths, routine childhood vaccination was discontinued in the United
States in 1972, and was abandoned in most European countries in the early 1970s. [5][43] Routine vaccination of health
care workers was discontinued in the U.S. in 1976, and among military recruits in 1990 (although military personnel
deploying to the Middle East and Korea still receive the vaccination. [44]) By 1986, routine vaccination had ceased in
all countries.[5] It is now primarily recommended for laboratory workers at risk for occupational exposure. [20]
After vaccination campaigns throughout the 19th and 20th centuries, the WHO certified the eradication of smallpox
in 1979.[5]Smallpox is one of two infectious diseases to have been eradicated, the other being rinderpest, which was
declared eradicated in 2011.[16][17][18]

Immune System:
innate immunity
Microorganisms or toxins that successfully enter an organism encounter the cells and mechanisms of The innate
immune system, also known as the nonspecific 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, [15] or when damaged, injured or
stressed cells send out alarm signals, many of which (but not all) are recognized by the same receptors as those
that recognize pathogens.[16]
Innate immune defenses are non-specific, meaning these systems recognize and respond to pathogens in a generic
way. but, unlike the adaptive immune system (which is found only in vertebrates), it does not confer long-lasting or
protective immunity to the host against a pathogen. The innate immune system is the dominant system of host
defense in most organisms.[11]
Innate immune systems provide immediate defense against infection, and are found in all classes
of plant and animal life.They include both humoral immunity components and cell-mediated immunity components.
Anatomical barriers include physical, chemical and biological barriers.

Several barriers protect organisms from infection, including mechanical, chemical, and biological barriers.
The epithelial surfaces form a physical barrier that is impermeable to most infectious agents, acting as the first line
of defense against invading organisms. [4] Desquamation of skin epithelium also helps remove bacteria and other
infectious agents that have adhered to the epithelial surfaces. Lack of blood vessels and inability of the epidermis to
retain moisture, presence of sebaceous glands in the dermis provides an environment unsuitable for the survival of
microbes. [4] In the gastrointestinal and respiratory tract, movement due to peristalsis or cilia, respectively, helps
remove infectious agents.[4] Also, mucus traps infectious agents.[4]The gut flora can prevent the colonization of
pathogenic bacteria by secreting toxic substances or by competing with pathogenic bacteria for nutrients or
attachment to cell surfaces.[4] The flushing action of tears and saliva helps prevent infection of the eyes and mouth.
However, as organisms cannot be completely sealed from their environments, other 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.[17]
Chemical barriers also protect against infection. The skin and respiratory tract secrete antimicrobial peptides such
as the -defensins.[18] Enzymes such as lysozyme andphospholipase A2 in saliva, tears, and breast milk are
also antibacterials. Vaginal secretions serve as a chemical barrier following menarche, when they become slightly
acidic, while semen contains defensins and zinc to kill pathogens.[21][22] In the stomach, gastric
acid and proteases serve as powerful chemical defenses against ingested pathogens.
Within the genitourinary and gastrointestinal tracts, commensal flora serve as biological barriers by competing with
pathogenic bacteria for food and space and, in some cases, by changing the conditions in their environment, such
as pH or available iron.[23] This reduces the probability that pathogens will reach sufficient numbers to cause illness.

The mucus keeps the microbes trapped in, and that way we can avoid the infections.
Although the Epithelial cells are not immune cells, they protect us from the external medium the
most also secrete substances that protect us, for instance the sebum, which is a combination of
fatty acids
There are also the Defenses a light group of proteins which has the role to keep the microbes
away and which is found in the saliva or in the tears.
Other immune cells are located inside the body. They either does not exist and only appear when
an infection occur, either are present all the time, but when the infection occurs their
concentration raise.

In the body also exists other proteins which recognize the microbes (in general located in the
blood). These proteins are named Complement and consists of a group of enzymes that reacts
instantly against the microbes. In the blood, the complement proteins attack the bacteria, but as
the pathogenic bacteria are resistant, they only affect the nonpathogenic bacteria. (pathogenic
and nonpathogenic bacteria are differentiated by the way they are recognized by our immune
system). For example, Escherichia coli, which is a nonpathogenic bacteria found in the blood, is
phagocyte.
The complement system is a part of the immune system that helps or complements the ability
of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the innate immune system,
[1]

which is not adaptable and does not change over the course of an individual's lifetime. However, it can be

recruited and brought into action by the adaptive immune system.

The complement system consists of a number of small proteins found in the blood, in general synthesized by
the liver, and normally circulating as inactive precursors (pro-proteins). When stimulated by one of several
triggers, proteases in the system cleave specific proteins to release cytokines and initiate an amplifying cascade of
further cleavages. The end-result of this activation cascade is massive amplification of the response
and activation of the cell-killing membrane attack complex.
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.
Inflammation is one of the first responses of the immune system to infection or irritation.
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.

Inflammation is stimulated by chemical factors released by injured cells and serves to establish a physical barrier
against the spread of infection, and to promote healing of any damaged tissue following the clearance of pathogens.
[5]

Chemical factors produced during inflammation (histamine, bradykinin, serotonin, leukotrienes, and prostaglandins)
sensitize pain receptors, cause vasodilation of the blood vessels at the scene, and attract phagocytes, especially
neutrophils.[5] Neutrophils then trigger other parts of the immune system by releasing factors that summon other
leukocytes and lymphocytes.

Cytokines produced by macrophages and other cells of the innate immune system mediate the inflammatory
response, influencing the neighbor cells, the blood vessels. These cytokines include TNF, IL-1 and IL-6.(which occur
in the initiate phase of the inflammation.
The inflammatory response is characterized by the following symptoms:

redness of the skin, due to locally increased blood circulation;

heat, either increased local temperature, such as a warm feeling around a localized infection, or a
systemic fever;

swelling of affected tissues, such as the upper throat during the common cold or joints affected
by rheumatoid arthritis;

increased production of mucus, which can cause symptoms like a runny nose or a productive cough;

pain, either local pain, such as painful joints or a sore throat, or affecting the whole body, such as body
aches; and possible dysfunction of the organs or tissues involved.

In conclusion, the innate immunity is a rapid type of immunity, that action after a few hours and
which always action the same way.

Adaptive immune system

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. [50] 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.
Appears after about a week and is composed of highly specialized, systemic cells and processes that eliminate or
prevent pathogen growth. The adaptive immune system is one of the two main immunity strategies found
in vertebrates (the other being the innate immune system). Adaptive immunity creates immunological memory after
an initial response to a specific pathogen, leads to an enhanced response to subsequent encounters with that
pathogen. This process of acquired immunity is the basis of vaccination. Like the innate system, the adaptive
system includes both humoral immunity components and cell-mediated immunity components.
Unlike the innate immune system, the adaptive immune system is highly specific to a specific pathogen. Adaptive
immunity can also provide long-lasting protection: for example; someone who recovers from measles is now
protected against measles for their lifetime but in other cases it does not provide lifetime protection: for example;
chickenpox. The adaptive system response destroys invading pathogens and any toxic molecules they produce.
Sometimes the adaptive system is unable to distinguish foreign molecules, the effects of this may be hayfever,
asthma or any other allergies. Antigens are any substances that elicit the adaptive immune response. The cells that
carry out the adaptive immune response are white blood cells known as lymphocytes. There are two main broad
classes- antibody responses and cell mediated immune response which are also carried by two different
lymphocytes (B cells and T cells). In antibody responses, B cells are activated to secrete antibodies, which are

proteins also known as immunoglobulins. Antibodies travel through the bloodstream and bind to the foreign antigen
causing it to inactivate, which does not allow the antigen to bind to the host. [1]
In acquired immunity, pathogen-specific receptors are "acquired" during the lifetime of the organism (whereas in
innate immunity pathogen-specific receptors are already encoded in the germline). The acquired response is said to
be "adaptive" because it prepares the body's immune system for future challenges (though it can actually also be
maladaptive when it results in autoimmunity).[n 1]
The system is highly adaptable because of somatic hypermutation (a process of accelerated somatic mutations),
and V(D)J recombination (an irreversible genetic recombinationof antigen receptor gene segments). This
mechanism allows a small number of genes to generate a vast number of different antigen receptors, which are then
uniquely expressed on each individual lymphocyte. Because the gene rearrangement leads to an irreversible
change in the DNA of each cell, all of the progeny (offspring) of that cell will then inherit genes encoding the same
receptor specificity, including the memory B cells and memory T cells that are the keys to long-lived specific
immunity.
The major functions of the acquired immune system include:

Recognition of specific "non-self" antigens in the presence of "self", during the process of antigen
presentation.

Generation of responses that are tailored to maximally eliminate specific pathogens or pathogen-infected
cells.

Development of immunological memory, in which pathogens are "remembered" through memory B

cells and memory T cells.

In immunology, an antigen (Ag), abbreviation of antibody generator, is any structural substance which serves as a
target for the receptors of an adaptive immune response, TCR or BCR or its secreted form antibody, respectively.
[1]

Each antibody is specifically selected after binding to a certain antigen because of random somatic

diversification in the antibody complementarity determining regions (a common analogy used to describe this is the
fit between a lock and a key). Paul Ehrlich coined the term antibody in his side-chain theory at the end of 19th
century.[2]
In summary, an antigen is a molecule that binds to Ag-specific receptors but cannot induce an immune response in
the body by itself.[3] Antigen was originally a structural molecule that binds specifically to the antibody, but the term
now also refers to any molecule or a linear fragment that can be recognized by highly variable antigen receptors (Bcell receptor or T-cell receptor) of the adaptive immune system.
Antigens are any substances that elicit the adaptive immune response. The cells that carry out the adaptive immune response are white
blood cells known as lymphocytes. There are two main broad classes- antibody responses and cell mediated immune response which
is also carried by two different lymphocytes (B cells and T cells).
In antibody responses, B cells are activated to secrete antibodies, which are proteins also known as immunoglobulins. Antibodies travel
through the bloodstream and bind to the foreign antigen causing it to inactivate, which does not allow the antigen to bind to the host.

The antibodies are cells who memorize the microbes (memory cells). They keep under control the bacterial microflora from intestine;
are secreted in blood and mucosa. With their help we can control the population of bacteria from mouth, intestine etc. The cost of the
adaptive immunity consists in the necessity of the young cells to divides for grown the population. A lymphocyte cell can divide to obtain
105 cells in one day (ex: 10 cells 150.000 cells).

Dendritic cells (DCs) are antigen-presenting cells (also known as accessory cells) of the mammalian immune
system. Their main function is to process antigen material and present it on the cell surface to the T cells of the
immune system. They act as messengers between the innate and the adaptive immune systems.
Dendritic cells are present in those tissues that are in contact with the external environment, such as the skin (where
there is a specialized dendritic cell type called the Langerhans cell) and the inner lining of
the nose, lungs, stomach and intestines. They can also be found in an immature state in the blood. Once activated,
they migrate to the lymph nodes where they interact with T cells andB cells to initiate and shape the adaptive
immune response. At certain development stages they grow branched projections, the dendrites that give the cell its
name. While similar in appearance, these are structures distinct from the dendrites of neurons. Immature dendritic
cells are also called veiled cells, as they possess large cytoplasmic 'veils' rather than dendrites.
*they are not phagocyting hard the bacteria, form the T-cells (in a few days are dividing until form many copies and
finally in about a week give a response. In this time, our immune system is fighting the infection and for that reason
we get a fever.
Clonal selection theory is a scientific theory in immunology that explains the functions of cells (lymphocytes) of
the immune system in response to specific antigens invading the body.
The concept was in an attempt to explain the formation of a diversity of antibodies during initiation of the immune
response and The theory has become a widely accepted model for how the immune system responds
to infection and how certain types of B and T lymphocytes are selected for destruction of specific antigens.[3]
The theory states that in a pre-existing group of lymphocytes (specifically B cells), a specific antigen only activates
(i.e. selection) its counter-specific cell so that particular cell is induced to multiply (producing its clones) for antibody
production. In short the theory is an explanation of the mechanism for the generation of diversity of antibody
specificity.[4] The first experimental evidence came in 1958, when Gustav Nossaland Joshua Lederberg showed that
one B cell always produces only one antibody.[5] The idea turned out to be the foundation of molecular immunology,
especially in adaptive immunity.[6]
In 1900, Paul Ehrlich proposed the so-called side chain theory of antibody production. According to it, certain cells
exhibit on their surface different "side chains" (i.e. membrane-bound antibodies) able to react with different antigens.
When an antigen comes, it binds to a matching side chain. Then the cell stops producing all other side chains and
starts intensive synthesis and secretion of the antigen-binding side chain as a soluble antibody. This was a selection
(though not clonal selection) theory far more accurate than the instructive theories that dominated immunology in
the next decades.

*We already have T-cells before the infection so we already are prepared with millions of T and B
different cells (~1015). In reality the number of T and B-cells is about 10 6-107 (the number can be
found by an experiment in vitro). That way we can face any infection.
When the infection occurs, one or some of these cells interact with the antigen and form other
copies. In that case is developed a clone (are formed thousands of copies) and appears a B-cell
that secrete the antibody.
TCR and BCR contain pieces of gens and are formed by 3 parts A B C. By combining these parts,
we get more different types of these receptors.
In every cell exists mechanisms of repairing the DNA. For example, when we are sunbathing, the
solar radiations destroy the DNA, and these mechanisms remake it by detecting the mutations of
the DNA and forming different B and T-cells.
Paul Ehrlich made an experiment by injecting a rabbit with different substances and it observed
that the cells have a lots of receptors and that the more is stimulated, the more antibodies are
secreted.
Types of adaptive immunity

There are two classes of T-cells: Helper T-cells and

Cytotoxic T-cells
The Helper T-cells secret cytokines and determine
the immune response by producing cells that kills
the infectious cells with more efficiency
Cytotoxic T-cells kill directly the infectious cells.

Phases of the immune responses

Day 0 Some of the cells are stimulated
-

They start dividing so their number incrase. After

some of this divisions, it stops and the T-cells get
another function
- Appear specialized cells that eliminate infected
cells; The T-cells stop growing (the stimulus
disappear)
All the useless cells (after the microbe is gone) are dying in apoptosis because they dont
have sufficient space in the organism and for getting more space for other cells.
Only a few cells remain. These are called Memory cells and they recognize a future infection.
Only if the virus is modified a lot (is mutated) we
will need a stimulation again and other cells

The memory effect causes the apparition of a better response that is more efficient for the
infection because T and B-cell already have memory and recognize the infection

Lymphocyte

Active and passive immunity

When we are born, our immunity system is not completely developed and in that case we take
advantage of the antibodies of our mother (in the pregnancy) and that way, when we are born
we have the same amount of antibodies with the mother. These antibodies protect us for a few
months and this phenomenon is called Passive immunity.

Types of infectious organisms

Memory cells
B, T different types can live long time
Memory T-cells:
-

Live in the spleen which is a filter for the blood, maintaining the erythrocytes in good
condition
Migrate in the blood
In the absence of an infection they are in a sleep state
In the presence of the antigen start to divide