Immunology course - Introduction

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1. General properties of immune responsesEfectiveness o 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 smptoms of the disease is around 1! das. "nce

inhaled, variola major virus invades the oropharngeal #mouth and throat$ or the respirator mucosa, migrates to

regional lmph nodes, and begins to multipl. %n the initial growth phase the virus seems to move from cell to cell,

but around the 1!th da, lsis of man 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 lmph

nodes. The initial or prodromal smptoms are similar to other viral diseases such as influen&a and the common

cold'fever  of at least ().( *+ #11 *-$, muscle pain, malaise, headache and prostration. s the digestive tract is

commonl involved, nausea and vomiting and bac/ache often occur. The prodrome, or preeruptive stage, usuall

lasts !0 das. 2 das 1!013 the first visible lesions4small reddish spots called enanthem4appear on mucous

membranes of the mouth, tongue, palate, and throat, and temperature falls to near normal. These lesions rapidl

enlarge and rupture, releasing large amounts of virus into the saliva.[5]

6mallpox virus preferentiall attac/s s/in cells, causing the characteristic pimples #called macules$ associated with

the disease. rash develops on the s/in ! to ) hours after lesions on the mucous membranes appear. Tpicall

the macules first appear on the forehead, then rapidl spread to the whole face, proximal portions of extremities, the

trun/, and lastl to distal portions of extremities. The process ta/es no more than ! to (7 hours, after which no new

lesions appear.[5] t this point variola major infection can ta/e several ver different courses, resulting in four tpes of

smallpox disease based on the 8ao classification'[!1]

 ordinar, modified, malignant #or flat$, and hemorrhagicistoricall, smallpox has an overall fatalit rate of about ( percent: however, the malignant and hemorrhagic forms

are usuall fatal.[!!]

The earliest procedure used to prevent smallpox was  Inoculation #also /nown as variolation$ was a historica

method for the prevention of smallpox b deliberate introduction into the s/in of material from smallpox pustules

This generall produced a less severe infection than naturall;ac<uired smallpox, but still induced immunit to it.

Variolation or inoculation was the method first used to immuni&e an individual against smallpox #Variola$ with

material ta/en from a patient or a recentl variolated individual in the hope that a mild, but protective infection would

result. The procedure was most commonl carried out b inserting=rubbing powdered smallpox scabs or fluid frompustules into superficial scratches made in the s/in. The patient would develop pustules identical to those caused b

naturall occurring smallpox, usuall producing a less;severe disease than naturall;ac<uired smallpox. >ventuall,

after about two to four wee/s, these smptoms would subside, indicating successful recover and immunit. The

method was first used in +hina and the ?iddle >ast before it was introduced into >ngland and @orth merica in the

15!s in the face of some opposition. The method is no longer used toda. %t was replaced b smallpox vaccine, a

safer alternative. This in turn paved the wa for the development of the man vaccines now available.

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 ccounts of inoculation against smallpox in +hina can be found as earl as the late 1th centur, and the procedure

was widel practiced b the 17th centur, during the ?ing dnast.[()] %f successful, inoculation produced

lasting immunit to smallpox. owever, because the person was infected with variola virus, a severe infection could

result, and the person could transmit smallpox to others. Variolation had a .30! percent mortalit rate, considerabl

less than the !0( percent mortalit rate of the disease.[!]

The latter term of vaccine was first used in 1) soon after >dward Aenner  discovered that immunit to smallpox

could be produced b inoculating a person with material from a cowpox lesion and introduced smallpox

vaccine derived from cowpox, an animal disease distinct from smallpox. #+owpox is a poxvirus in the same famil as

variola.$ The procedure was much safer than variolation, and did not involve a ris/ of smallpox transmission.

Vaccination to prevent smallpox was soon practiced all over the world. Buring the 19th centur, the cowpox virus

used for smallpox vaccination was replaced b vaccinia virus. Vaccinia is in the same famil as cowpox and variola

but is geneticall distinct from both. The origin of vaccinia virus and how it came to be in the vaccine are not /nown.

[!]

in 1)91, Couis Dasteur  honoured Aenner b widening the terms vaccine/vaccination to refer to the artificial induction

of immunit against an infectious disease.

istoricall, the vaccine has been effective in preventing smallpox infection in 93 percent of those vaccinated.

[1] 6mallpox vaccination provides a high level of immunit for three to five ears and decreasing immunit thereafter

%f a person is vaccinated again later, immunit lasts even longer. 6tudies of smallpox cases in >urope in the 193s

and 197s demonstrated that the fatalit rate among persons vaccinated less than 1 ears before exposure was

1.( percent: it was 5 percent among those vaccinated 11 to ! ears prior, and 11 percent among those vaccinated

! or more ears prior to infection. 2 contrast, 3! percent of unvaccinated persons died. [!]

here are side effects and ris/s associated with the smallpox vaccine. %n the past, about 1 out of 1, peoplevaccinated for the first time experienced serious, but non;life;threatening, reactions, including toxic or allergic

reaction at the site of the vaccination #erthema multiforme$, spread of the vaccinia virus to other parts of the bod

and to other individuals. Dotentiall life;threatening reactions occurred in 1 to 3 people out of ever 1 million

people vaccinated for the first time. 2ased on past experience, it is estimated that 1 or ! people in 1 million

#.19) percent$ who receive the vaccine ma die as a result, most often the result of

postvaccinial encephalitis or severe necrosis in the area of vaccination #called progressive vaccinia$.[1]

Eiven these ris/s, as smallpox became effectivel eradicated and the number of naturall occurring cases fell below

the number of vaccine;induced illnesses and deaths, routine childhood vaccination was discontinued in the Fnited

6tates in 195!, and was abandoned in most >uropean countries in the earl 195s. [3][(] 8outine vaccination of health

care wor/ers was discontinued in the F.6. in 1957, and among militar recruits in 199 #although militar personnel

deploing to the ?iddle >ast and Gorea still receive the vaccination. []$ 2 19)7, routine vaccination had ceased in

all countries.[3] %t is now primaril recommended for laborator wor/ers at ris/ for occupational exposure. [!]

 fter vaccination campaigns throughout the 19th and !th centuries, the H" certified the eradication of smallpox

in 1959.[3]6mallpox is one of two infectious diseases to have been eradicated, the other being rinderpest, which was

declared eradicated in !11.[17][15][1)]

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Immune System:

innate immunity

?icroorganisms or toxins that successfull enter an organism encounter the cells and mechanisms of The innate

immune system, also /nown as the nonspecific immune system .

The innate response is usuall triggered when microbes are identified b pattern recognition receptors, which

recogni&e components that are conserved among broad groups of microorganisms, [13] or when damaged, injured or

stressed cells send out alarm signals, man of which #but not all$ are recogni&ed b the same receptors as those

that recogni&e pathogens.[17] 

%nnate immune defenses are non;specific, meaning these sstems recogni&e and respond to pathogens in a generic

wa. but, unli/e the adaptive immune sstem #which is found onl in vertebrates$, it does not confer long;lasting o

protective immunit to the host against a pathogen. The innate immune sstem is the dominant sstem of host

defense in most organisms.[11]

 %nnate immune sstems provide immediate defense against infection, and are found in all classes

of plant and animal life.The include both humoral immunit components and cell;mediated immunit components.

 natomical barriers include phsical, chemical and biological barriers.

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6everal barriers protect organisms from infection, including mechanical, chemical, and biological barriers.

The epithelial surfaces form a phsical barrier that is impermeable to most infectious agents, acting as the first line

of defense against invading organisms. [] Bes<uamation of s/in epithelium also helps remove bacteria and other

infectious agents that have adhered to the epithelial surfaces. Cac/ of blood vessels and inabilit of the epidermis to

retain moisture, presence of sebaceous glands in the dermis provides an environment unsuitable for the survival of

microbes. [] %n the gastrointestinal and respirator tract, movement due to peristalsis or cilia, respectivel, helps

remove infectious agents.[] lso, mucus traps infectious agents.[]The gut flora can prevent the coloni&ation o

pathogenic bacteria b secreting toxic substances or b competing with pathogenic bacteria for nutrients orattachment to cell surfaces.[] The flushing action of tears and saliva helps prevent infection of the ees and mouth.

owever, as organisms cannot be completel sealed from their environments, other sstems act to protect bod

openings such as the lungs, intestines, and the genitourinar tract. %n the lungs, coughing and

snee&ing mechanicall eject pathogens and other irritants from the respirator tract. The flushing action

of tears and urine also mechanicall expels pathogens, while mucus secreted b the respirator and gastrointestinal

tract serves to trap and entangle microorganisms.[15]

+hemical barriers also protect against infection. The s/in and respirator tract secrete antimicrobial peptides such

as the I;defensins.[1)]

 >n&mes such as lso&me andphospholipase ! in saliva, tears, and breast mil/ arealso antibacterials. Vaginal secretions serve as a chemical barrier following menarche, when the become slightl

acidic, while semen contains defensins and &inc to /ill pathogens.[!1][!!] %n the stomach, gastric

acid and proteases serve as powerful chemical defenses against ingested pathogens.

Hithin the genitourinar and gastrointestinal tracts, commensal flora serve as biological barriers b competing with

pathogenic bacteria for food and space and, in some cases, b changing the conditions in their environment, such

as p or available iron.[!(] This reduces the probabilit that pathogens will reach sufficient numbers to cause illness.

The mucus keeps the microbes trapped in, and that way we can avoid the inections.

 Althouh the Epithelial cells are not immune cells, they protect us rom the e!ternal medium the

most also secrete substances that protect us, or instance the sebum, which is a combination o

atty acids

There are also the "#eenses$ % a liht roup o proteins which has the role to keep the microbes

away and which is ound in the saliva or in the tears.

&ther immune cells are located inside the body. They either does not e!ist and only appear when

an inection occur, either are present all the time, but when the inection occurs their

concentration raise.

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In the body also e!ists other proteins which reconi'e the microbes (in eneral located in the

blood). These proteins are named "*omplement$ and consists o a roup o en'ymes that reacts

instantly aainst the microbes. In the blood, the complement proteins attack the bacteria, but as

the pathoenic bacteria are resistant, they only afect the nonpathoenic bacteria. (pathoenic

and nonpathoenic bacteria are diferentiated by the way they are reconi'ed by our immune

system). +or e!ample, Escherichia coli, which is a nonpathoenic bacteria ound in the blood, is

 phaocyte.

The complement system is a part of the immune sstem that helps or  complements the abilit

of antibodies and phagoctic cells to clear pathogens from an organism. %t is part of the innate immune sstem,

[1] which is not adaptable and does not change over the course of an individualJs lifetime. owever, it can be

recruited and brought into action b the adaptive immune sstem.

The complement sstem consists of a number of small proteins found in the blood, in general snthesi&ed b

the liver , and normall circulating as inactive precursors #pro;proteins$. Hhen stimulated b one of several

triggers, proteases in the sstem cleave specific proteins to release cto/ines and initiate an amplifing cascade of

further cleavages. The end;result of this activation cascade is massive amplification of the response

and activation of the cell;/illing membrane attac/ complex.

The complement sstem is a biochemical cascade that attac/s the surfaces of foreign cells. %t contains over !

different proteins and is named for its abilit to KcomplementK the /illing of pathogens b antibodies. +omplement is

the major humoral component of the innate immune response.

Inflammation is one of the first responses of the immune sstem to infection or irritation.

 The smptoms of inflammation are redness, swelling, heat, and pain, which are caused b increased blood flow into

tissue. %nflammation is produced b eicosanoids and cto/ines, which are released b injured or infected cells.

%nflammation is stimulated b chemical factors released b injured cells and serves to establish a phsical barrier

against the spread of infection, and to promote healing of an damaged tissue following the clearance of pathogens.

[3]

+hemical factors produced during inflammation #histamine, brad/inin, serotonin, leu/otrienes, and prostaglandins$

sensiti&e pain receptors, cause vasodilation of the blood vessels at the scene, and attract phagoctes, especiall

neutrophils.[3] @eutrophils then trigger other parts of the immune sstem b releasing factors that summon other

leu/octes and lmphoctes.

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 +to/ines produced b macrophages and other cells of the innate immune sstem mediate the inflammator

response, influencing the neighbor cells, the blood vessels. These cto/ines include T@-, %C;1 and %C;7.#which occur

in the initiate phase of the inflammation.

The inflammator response is characteri&ed b the following smptoms'

• redness of the s/in, due to locall increased blood circulation:

• heat, either increased local temperature, such as a warm feeling around a locali&ed infection, or a

sstemic fever :

• swelling of affected tissues, such as the upper throat during the common cold or joints affected

b rheumatoid arthritis:

• increased production of mucus, which can cause smptoms li/e a runn nose or a productive cough:

• pain, either local pain, such as painful joints or a sore throat, or affecting the whole bod, such as bod

aches: and possible dsfunction 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 sstem evolved in earl vertebrates and allows for a stronger immune response as well as

immunological memor, where each pathogen is KrememberedK b a signature antigen. [3] The adaptive immune

response is antigen;specific and re<uires the recognition of specific Knon;selfK antigens during a process

called antigen presentation. ntigen specificit allows for the generation of responses that are tailored to specific

pathogens or pathogen;infected cells. The abilit to mount these tailored responses is maintained in the bod b

Kmemor cellsK. 6hould a pathogen infect the bod more than once, these specific memor cells are used to <uic/l

eliminate it.

 ppears after about a wee/ and is composed of highl speciali&ed, sstemic cells and processes that eliminate or

prevent pathogen growth. The adaptive immune sstem is one of the two main immunit strategies found

in vertebrates #the other being the innate immune sstem$. daptive immunit creates immunological memor afte

an initial response to a specific pathogen, leads to an enhanced response to subse<uent encounters with that

pathogen. This process of ac<uired immunit is the basis of vaccination. Ci/e the innate sstem, the adaptive

sstem includes both humoral immunit components and cell;mediated immunit components.

Fnli/e the innate immune sstem, the adaptive immune sstem is highl specific to a specific pathogen. daptive

immunit 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:

chic/enpox. The adaptive sstem response destros invading pathogens and an toxic molecules the produce.

6ometimes the adaptive sstem is unable to distinguish foreign molecules, the effects of this ma be hafever,

asthma or an other allergies. ntigens are an substances that elicit the adaptive immune response. The cells that

carr out the adaptive immune response are white blood cells /nown as lmphoctes. There are two main broad

classes; antibod responses and cell mediated immune response which are also carried b two different

lmphoctes #2 cells and T cells$. %n antibod responses, 2 cells are activated to secrete antibodies, which are

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proteins also /nown as immunoglobulins. ntibodies 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]

%n ac<uired immunit, pathogen;specific receptors are Kac<uiredK during the lifetime of the organism #whereas in

innate immunit pathogen;specific receptors are alread encoded in the germline$. The ac<uired response is said to

be KadaptiveK because it prepares the bodJs immune sstem for future challenges #though it can actuall also be

maladaptive when it results in autoimmunit$.[n 1]

The sstem is highl adaptable because of  somatic hpermutation #a process of accelerated somatic mutations$,

and V#B$A recombination #an irreversible genetic recombinationof antigen receptor gene segments$. This

mechanism allows a small number of genes to generate a vast number of different antigen receptors, which are then

uni<uel expressed on each individual lmphocte. 2ecause the gene rearrangement leads to an irreversible

change in the B@ of each cell, all of the progen #offspring$ of that cell will then inherit genes encoding the same

receptor specificit, including the memor 2 cells and memor T cells that are the /es to long;lived specific

immunit.

The major functions of the ac<uired immune sstem include'

• 8ecognition of specific Knon;selfK antigens in the presence of KselfK, during the process of  antigen

presentation.

• Eeneration of responses that are tailored to maximall eliminate specific pathogens or pathogen;infected

cells.

• Bevelopment of  immunological memor, in which pathogens are KrememberedK through memor 2

cells and memor T cells.

%n immunolog, an antigen #g$, abbreviation of antibod generator, is an structural substance which serves as atarget for the receptors of an adaptive immune response, T+8 or 2+8 or its secreted form antibod, respectivel.

[1] >ach antibod is specificall selected after binding to a certain antigen because of  random somatic

diversification in the antibod complementarit determining regions #a common analog used to describe this is the

fit between a loc/ and a /e$. Daul >hrlich coined the term antibod in his side;chain theor at the end of 19th

centur.[!] 

%n summar, an antigen is a molecule that binds to g;specific receptors but cannot induce an immune response in

the bod b itself.[(]  ntigen was originall a structural molecule that binds specificall to the antibod, but the term

now also refers to an molecule or a linear fragment that can be recogni&ed b highl variable antigen receptors #2;

cell receptor  or  T;cell receptor $ of the adaptive immune sstem.

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.

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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 #B+s$ are antigen;presenting cells #also /nown as accessory cells$ of the mammalian immune

sstem. Their main function is to process antigen material and present it on the cell surface to the T cells of the

immune sstem. The act as messengers between the innate and the adaptive immune sstems.

Bendritic cells are present in those tissues that are in contact with the external environment, such as the s/in #where

there is a speciali&ed dendritic cell tpe called the Cangerhans cell$ and the inner lining of

the nose, lungs, stomach and intestines. The can also be found in an immature state in the blood. "nce activated,

the migrate to the lmph nodes where the interact with T cells and2 cells to initiate and shape the adaptive

immune response. t certain development stages the grow branched projections, the dendrites that give the cell its

name. Hhile similar in appearance, these are structures distinct from the dendrites of  neurons. %mmature dendritic

cells are also called veiled cells, as the possess large ctoplasmic JveilsJ rather than dendrites.

Lthe are not phagocting hard the bacteria, form the T;cells #in a few das are dividing until form man copies and

finall in about a wee/ give a response. %n this time, our immune sstem is fighting the infection and for that reason

we get a fever.

Clonal selection theory is a scientific theor in immunolog that explains the functions of cells #lmphoctes$ of

the immune sstem in response to specific antigens invading the bod.

The concept was in an attempt to explain the formation of a diversit of antibodies during initiation of the immune

response and The theor has become a widel accepted model for how the immune sstem responds

to infection and how certain tpes of  2 and T lmphoctes are selected for destruction of specific antigens.[(]

The theor states that in a pre;existing group of lmphoctes #specificall 2 cells$, a specific antigen onl activates

#i.e. selection$ its counter;specific cell so that particular cell is induced to multipl #producing its clones$ for antibod

production. %n short the theor is an explanation of the mechanism for the generation of diversit of antibod

specificit.[] The first experimental evidence came in 193), when Eustav @ossaland Aoshua Cederberg showed that

one 2 cell alwas produces onl one antibod.[3] The idea turned out to be the foundation of molecular immunolog,

especiall in adaptive immunit.[7]

%n 19, Daul >hrlich proposed the so;called side chain theor of antibod production. ccording to it, certain cells

exhibit on their surface different Kside chainsK #i.e. membrane;bound antibodies$ able to react with different antigens.Hhen an antigen comes, it binds to a matching side chain. Then the cell stops producing all other side chains and

starts intensive snthesis and secretion of the antigen;binding side chain as a soluble antibod. This was a selection

#though not clonal selection$ theor far more accurate than the instructive theories that dominated immunolog in

the next decades.

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*We already have T-cells before the infection so we already are prepared with millions of T and B

dierent cells (!"!#$. In reality the number of T and B-cells is about !"%-!"& (the number can be

found by an e'periment in vitro$. That way we can face any infection.

When the infection occurs, one or some of these cells interact with the antien 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.

 T) and B) contain pieces of ens and are formed by + parts B ). By combinin these parts,

we et more dierent types of these receptors.

In every cell e'ists mechanisms of repairin the . /or e'ample, when we are sunbathin, the

solar radiations destroy the , and these mechanisms rema0e it by detectin the mutations of 

the and formin dierent B and T-cells.

1aul 2hrlich made an e'periment by in3ectin a rabbit with dierent 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

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 There are two classes of T-cells4 5elper T-cells and

)ytoto'ic T-cells

 The 5elper T-cells secret cyto0ines and determine

the immune response by producin cells that 0ills

the infectious cells with more e6ciency

)ytoto'ic T-cells 0ill directly the infectious cells.

hases o the immune responses

ay " 7 8ome of the cells are stimulated

- They start dividin so their number incrase. fter

some of this divisions, it stops and the T-cells et

another function- ppear speciali9ed cells that eliminate infected

cells: The T-cells stop rowin (the stimulusdisappear$

- ll the useless cells (after the microbe is one$ are dyin in apoptosis because they don;t

have su6cient space in the oranism and for ettin more space for other cells.- <nly a few cells remain. These are called =emory cells and they reconi9e a future infection.

<nly if the virus is modi>ed a lot (is mutated$ we

will need a stimulation aain and other cells

 The memory eect 7 causes the apparition of a better response that is more e6cient for the

infection because T and B-cell already have memory and reconi9e the infection

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Lymphocyte

Active and passive immunityWhen we are born, our immunity system is not completely developed and in that case we ta0e

advantae of the antibodies of our mother (in the prenancy$ 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 1assive immunity.

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Types of infectious organisms

=emory cells

B, T 7 dierent types 7 can live lon time

=emory T-cells4

- ?ive in the spleen which is a >lter for the blood, maintainin the erythrocytes in ood

condition- =irate in the blood- In the absence of an infection they are in a sleep state- In the presence of the antien start to divide