Candice Arnaud, Roxane Jannin, Julie Sitolle, Joachim Taieb

https://fdvbio.wordpress.com/2019/01/25/premier-article-de-blog/?fbclid=IwAR3uXCyTTOl

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Immune system

Introduction

I. Innate/ non-specific immune system

II. Adaptive/ specific system

III. The story of immune cells and where to find them : from birth to death

IV. Deficiencies, disabilities and difficulties of the I.S

V. Research and Discoveries about the Immune System

Introduction

In almost every living organism, you can find a protective system against infections.

It goes from very rudimentary systems only composed of protection enzymes, to complex

organizations such as the ones we can find in mammals.

An Antigen is a molecule that is recognizable by our immune system, and triggers an

immune response. It can be proteins or other substances produced by a pathogen (for

instance polysaccharides), and more generally by any individual. To put it simple, antigens

are tags that notify pathogen and foreign bodies presence to immune system.

They are classified by the system as immunogens, tolerogens, or allergens according to

whether the molecules in question activate the immune response, are tolerated by the

immune system (as for molecules of our own body that belong to “self”), or trigger an

allergic response.

Pathogens inhabit a body to shelter from eventual dangers, and feed upon the wide range

of nutrients it offers. All of this is in the prospect of growth and reproduction. Hence it is a

survival instinct that motivates pathogens to invade another living body. There are different

types of attackers : parasites, bacteria, viruses (we invite you to check on the Viruses

chapter), fungi. In this chapter we won’t go in the details of attack mechanisms specific to

these types of pathogens. However, we will describe the variety of immune responses the

body is able to render according to the type of attacks it endures.

Our immune system englobes a variety of tissues, organs and other systems that

generate and spread defense cells molecules. Immune system acts upon a 3 parts policy :

detection (identification), deflection (transformation) and destruction. Detection is an essential mechanism of our immune system. Before actually acting on the

invasion our immune system heavily relies on its capacity to recognize what belongs to the

body and what does not. The foreigners can either be noticed with the antigens they

present, or because of the unfamiliar activity they trigger when infecting a cell. Recognition

of self, modified-self, non-self and safe non-self (such as foetus) stands as the paramount

job of our immune system.

We divide the immune system according to the main features of its actors. The first

lines of defenses form our innate immune system. It is a quick non specific response from

the body towards any invasion from a pathogen. The second part of our immune system

forms our adaptive, or specific defenses. They act less swiftly but accordingly to the type of

invaders the body faces.

I. Innate / non specific immune system

There are a few differences between vertebrates and invertebrates, but the overall

mechanism is the same. All animals have the ability to recognize a foreign body within their

system, and have built a variety of barriers and defense to either prevent those pathogens

to enter the body, or fight/ destruct them when they manage to come in. Innate defenses

stand for the first protection mechanism of the immune system. Innate immunity is a quick,

non specific system who’s constantly patrolling and protecting the body from various

invaders.

Innate defenses rely on antigens that are common to all or almost all pathogens. In this

section we will expose some innate mechanisms of defenses, sometimes common to all

animals (vertebrates and invertebrates), and sometimes specific to one of its subclasses.

1) External defenses

a) physical barriers

Our body puts up a whole variety of defenses to prevent foreign beings from

invading. The very first line of that particular army is your skin. It serves as a huge wall to

cover your whole body, and restricts exchanges with environment to the survival minimum

(by minimizing mouth and nose’s openings).

Moreover, your organs are covered of epithelial membranes that act in the same way the

skin does (protection and exchanges regulation). If you want additional information on the

mechanisms of exchanges between a body and its environment, and within the body, we

recommend you check on Circulation and gas exchanges page of the same website !

For insects, the principle remains the same : the exoskeleton is made of chitin,

amino-polysaccharide. Accumulation of chitin chains creates a resistant shell to protect

insects and crustaceans.

Hairs and eyelashes cover skin or other protective layers to enhance their protective

function by retaining foreign bodies, hence preventing them from entering a body.

Another type of physical barrier are mucous membranes in respiratory, digestive and

reproductive systems. In addition of physically blocking pathogens’ way in various organs

(lungs, stomach, gut), mucous substances enclose some chemicals that repel germs.

b) chemical barriers

Our body need an enormous amount of chemical substances to perform its

metabolism. Some of those have the ability to repel, incapacitate or destroy molecules or

cells identified as part of the non-self.

For instance, mammals stomach is filled with gastric acid. Although some parasites are able

to subsist in those conditions, most of pathogens can’t survive such a harsh environment

and die. Our respiratory and reproductive systems secrete mucus containing acidic

chemicals that prevent bacteria and other pathogens from flourishing (performing their

metabolism), and repel them.

Some in-body-secreted liquids enclose enzymes that fight pathogens and strike more

directly eventual invaders. For instance, lysozyme is involved in bacterial infections : it

destroys the membrane components of Gram-positive bacteria by catalyzing

peptidoglycans’ hydrolysis. Peptidoglycans are the main components of bacterial walls.

When the membrane (which is thick) of a gram-positive bacterium is destroyed, the cell no

longer has protection and is crushed under osmotic pressure. Lysozymes are produced by

granulocytes (a type of immune cells we will detail later in this section), and are mainly

found in saliva, eye fluids and mucus.

Let’s talk a little bit about antimicrobial peptides. Although it is a common

mechanism to invertebrates and vertebrates, their action is notably significant in insects

immune system. Specific pathways requiring information to be conducted to nucleus’s cells

trigger their production. For instance, the binding of antigens to receptor proteins like Toll,

located on the surface of hemocytes (immune cells of insects) provokes the synthesis of

antimicrobial peptides called defensins. Defensins are actually short amino acid chains. They

circulate within hemolymph or blood in order to inactivate bacteria and eumycetes by

impairing their plasma membrane.

Interferons (found among vertebrates only) are proteins naturally produced by immune

cells in response of a double stranded foreign RNA, thus testifying of viral/ bacterial/

parasite/ tumoral infection. Interferons induce antimicrobial proteins production and alert

Natural Killer cells and macrophages, both of these being special types of immune cells we

will detail later in this section. Interferons’ action results in the destruction of the pathogen

or infected cell in case of a tumour infection. Note that interferons also have a role in the

activation of macrophages differentiation (for more information see part III).

2) Internal defenses

a) Recognition proteins

Remember Toll, the receptor protein found in invertebrates immune cells. Toll

receptors recognizes peptidoglycan, which is a prevailing component of

pathogens’membrane. Therefore, Toll receptor permits the identification of almost every

type of pathogen, and plays a major role in innate immunity because of its scope.

Among vertebrates, Toll receptors come in various forms, and are called TLRs (Toll Like

Receptors). We can found them on almost every immune cell’s membrane.

Just as invertebrates Toll receptor, TLRs

detect a variety of molecular components

that are common to almost every pathogen

but absent in vertebrates. For instance,

TLR4 binds with lipopolysaccharide, TLR5

with flagellin (protein responsible for

flagella beat), TLR9 with CpG DNA (non

methylated G and C nucleotides), or TLR3

with double-stranded DNA (characteristic of

viruses). As you can see on Figure 1, once

the epitope (part of antigen) binds with the

receptor, the latter conducts a message to

the nucleus which will causes an immune

response like producing antimicrobial

peptides, or chemical mediators to bring

other immune cells to site.

Figure 1 : TLR protein functioning @Candice Arnaud

b) immune cells

Animals body has developed diverse defensive strategies requiring a large panel of

cells able to neutralize hazardous molecules. Immune cells are indeed the most effective

actors of our immune system. Some of them play a role in both innate and adaptive

immunity. The table below presents the most important innate immunity cells as well as

their respective abilities and functions.

Class Cell Function Image

Granulocyte Mast cell ● lives in connective tissues

and mucous membranes

● active role in inflammatory

response

releases histamine and

cytokines

Neutrophil ● most abundant white blood

cell

● circulates within body

● first to arrive on infection site

● phagocyte, dies after

performing phagocytosis

Dendritic

cell

● fixed (located in tissues likely

to suffer infections)

● phagocyte

● outgrowth-armed shaped

● identifies pathogen with TLR

● active role as Antigen

Presenting Cell (APC) after

digesting a pathogen

Monocyte Macrophage ● free and fixed type

(for eg : in liver)

● bigger, tougher phagocyte

Can repeatedly perform

phagocytosis

● ability to release cytokines to

draw other immune cells

Lymphocyte NK cell ● Patrols blood and lymph

● looks for abnormal cells

● injects enzymes that trigger

apoptosis

Table 1 : Innate immunity cells @Candice Arnaud

Nota Bene : Dendritic cells ‘s name comes from the fact that they look like they have

dendrites. They are not related in any kind to the Nervous system.

Neutrophils, dendritic cells and macrophages are phagocytes. They have the ability to

identify intruders with their TLRs or other receptors, and “eat” them. Phagocytic cells are

present within all animals, but the cells we introduced in the table above are specific to

vertebrates. You may wonder how does a cell swallow another ? Take a look at Figure 2

below to understand this vital process.

Figure 2 : A macrophage performing Phagocytosis. The process is the same for any phagocyte

mentioned above @Candice Arnaud

1. After recognizing an antigen on a pathogen, the phagocyte grabs it with its

cytoplasmic extensions called pseudopods ;

2. It engulfs the pathogen into it cytoplasm. This process is known as Endocytosis ; 3. The absorbed pathogen is enclosed in a vesicle called phagosome and lingers in the

cytoplasm while a lysosome (cell organelle) containing digestive enzymes draws near

the phagosome ;

4. Phagosome and lysosome fuse together. The newly-formed phagolysosome can use

different techniques to neutralize the pathogen ;

5. Lowering the pH inside its structure to create a hostile acidic environment or

mobilizing proteases (enzymes that destroy peptidic bonds of proteins) are two

mechanisms that will result in the decay of the pathogen ;

6. Once the pathogen is destroys, the phagocytes need to expulse what is left of the

pathogen via Exocytosis. Some cells will preserve a tiny piece of an antigen and

begin a journey to present it to other immune cells involved in adaptive immunity,

but you’ll learn all about this process in part II.

Natural Killer cells (vertebrate species only) belong to lymphocytes. They can’t

perform phagocytosis, and do not directly attack pathogens. But unlike other lymphocytes,

they don’t to be activated by antigen-presenting cell (ACP), they freely they patrol both

blood and lymph, looking for infected / tumoural cells. How do they detect it ? A healthy cell

produces a protein called MHC I (Major Histocompatibility Complex I), whereas a

dysfunctional cell does not. NK cells possess inhibitory receptors that are complementary to

MHC I. Thus the binding of only one receptor to MHC I prevents NK cells to attack.

In addition of those receptors, NK cells need several activating receptors to be activated by

special ligands present on defectuous cells. They will proceed if and only if no receptor binds

to MHC I, and receptors bind to activating ligands. Once these two conditions are fulfilled,

NK cells release two types of enzymes : perforins pierce the membrane of targeted cell to let

granzymes come in and trigger apoptosis. They also release cytokines to draw phagocytes

that will dispose of cell remains.

Figure 3 : NK cell activation and inhibition @Candice Arnaud

c) The complement system

The complement system is a supplemental set of proteins that assist the innate

immune system (and sometimes the adaptive system). Those proteins either mark

pathogens for destruction or directly initiate their decay (by drilling their membrane). They

remain inactive as they circulate in blood and are trigger whenever they receive a signal

requiring for their help.

Here is the different types of mechanisms that belong to the complement system :

- Opsonization : Proteins (sometimes antibodies) detect cells that present antigens, wrap up their

membrane. In this way they mark the infected cells for future phagocytosis or other

destruction method.

Figure 4 : Opsonization facilitates phagocytosis @Candice Arnaud

- Chemotaxis : It is the attraction or movement of phagocytic cells like neutrophils and

macrophages in response to the release of chemical signals by immune cells fighting

an infection. Those chemicals are mainly produced by mastocytes and surrounding

immune cells, thus enhancing the signal.

- Cell Lysis : This process results in the destruction of cell membrane. Proteins

perforate the membrane of foreign cells, weakening the pathogen in the process. It

is used to stop an infection progression.

- Agglutination : This mechanism requires antibodies for clustering pathogens and

binding them together. It facilitates the action of immune cells, allowing them to

process in a fixed area, thus preventing the infection from spreading.

3) Strategy : Inflammatory response

Inflammation is a defense mechanism common to all animals. It is an alert

mechanism, an alarm to mobilize a massive amount of innate defenses. Inflammation can

be a response to pathogens invading (e.g : due to an injury), but it can also be caused by

autoimmune deficiencies or allergies. If you are interested in learning about these two

conditions, we recommend you take a look to Part IV.

a) clinical signs

Giving the fact that it is the initial field of battle, inflammatory response causes some

visible signs. Those symptoms show that the innate system is actually performing its

functions, and strives for the preservation of body’s well being. Therefore you should not

worry too much about these physical changes as they testify a healing process.

The 4 main signs are redness, swelling, heat, and pain. In addition of these, the infected

limb or organ sometimes suffers from a temporary loss of function.

Those are the macro symptoms of the inflammatory response. What happens at a cellular

level ?

b) mechanism

In this section, we will take a close look to the running of a local inflammatory

response. Let’s take the example of inflammation caused by skin injury.

The starting mechanism right after infection is clotting. The coagulation of platelets inhibits

blood dispersion and at the same time prevents the infection from spreading. The redness

of injured skin comes from the action of platelets.

Meanwhile, damaged skin cells release chemokines (soluble proteins or molecules that act

as messenger in cellular signalisation) to notify the body about the upcoming infection. This

will trigger an innate response as well as alert nearby neurons.

Neurons will carry on a message through the nervous system, the final result being the body

experiencing pain.

Mastocytes (see immune cells in the precedent section) arrive to the infection site in

response of the chemokines signal to diffuse other chemical mediators, including cytokine

and histamine (see Figure 5, step 1 below). Cytokine acts as a paracrine (nearby) and

endocrine (far away) messenger, emphasizes the signal released by damaged cells and

attracts immune cells the infection site. Histamine has two major effects : First, it relaxes

local muscles, which causes a swelling of blood vessels and an increase of its flow (as well as

red and white blood cells’ mobility). That is vasodilation. Heat testifies of the increase in

cells’ mobility. As a second effect, histamine causes capillary weakening, allowing fluids to

infiltrate in the wound, and phagocytes to cross in order to fight the pathogens on infection

site.

Figure 5 : Local inflammatory response after a skin injury (step 1 and 2) @Candice Arnaud

Leukocytosis is the release of neutrophils in the bloodstream. The latter arrive on the

infection site by crossing the vessels, permeable thanks to vasodilation (see Figure 5, step

2). Neutrophils are the first phagocytic cells to arrive. They neutralize cells while continuing

to produce cytokine molecules to draw other immune cells (Figure 6).

Figure 6 : Local inflammatory response after a skin injury (step 3) @Candice Arnaud

As neutrophils activity is ephemeral, their concentration decline overtime. The second line

of defenses composed of monocytes (macrophages) and dendritic cells arrive later on to

clean the remaining pathogens with phagocytosis.

c) generalized inflammatory reaction

We have just seen how innate immunity drives a local inflammatory reaction.

Although it is a powerful systematic mechanism, it is not a flawless one and there are times

where infection takes over from its initial area and expand to the entire body. As a

response, innate defenses continues to fight pathogens.

Mastocytes and phagocytes continue to perform their functions and produce significant

amounts of cytokines, causing a “cytokine storm”. As you know, cytokines draw immune

cells to pathogen-infested areas, and cause a increase in the the blood flow to facilitate their

journey. So the more cytokines your cells produce, the stronger swelling, heat and redness

will be. Massive continuous release of cytokines and increase of body temperature to

enhance cells metabolism cause a well-known symptom : fever. In addition of being a

symptom of an intense immune activity, fever also serves as a signal for liver and spleen to

retain iron and zinc (both are essential molecules for bacteria growth).

Therefore fever is a sign that immune system properly works as much as it is a mechanism

helping in its functioning.

4) Innate Immunity prepares adaptive response

In addition of assuring the primary response to a pathogen’s attack, innate immune

cells have a role on preparing the adaptive response that follows in case of a fierce

infection. Remember that during phagocytosis, an antigen is captured and processed by the

cell : enzymes split it up into harmless immunogenic peptides.

After a pathogen digestion, some phagocytic cells expose those antigenic peptides are their

membrane thanks to the major histocompatibility complex (MHC).

Let’s take the example of dendritic cells. Once they have incorporated immunogenic

peptides in their membrane, they undergo some changes that prevent them from

performing endocytosis (and thus phagocytosis), and they gain new receptors that draw

them to lymph nodes. This process called maturation, Part III will tell you more about it. But

for now let’s focus on the conducting of the adaptive response. Once dendritic cells have

migrated to the lymph nodes, they present the antigen they display to other cells involved in

the adaptive immune response. Unlike innate immunity, it is a much more specific

mechanism (directed towards a targeted type of pathogen) which requires a longer time to

set up.

II. Adaptive / specific immune system

Vertebrates have a unique immune system : in addition to their innate defenses,

they have developed adaptive immune defenses. Adaptive immune system is a dynamical

phenomenon. It is necessarily prepared by innate immunity. This response is allowed by two

types of lymphocytes : T lymphocytes and B lymphocytes, respectively responsible for

cell-mediated and humoral responses. Where specialized T cells directly destroy infected

cells, antibodies help to neutralize toxins or pathogens present in the blood and the lymph.

1) Helper T cell for both responses

One type of T lymphocyte, called the helper T cell, triggers both humoral and cellular

reactions. Helper T cells are the most important cells in adaptive immunity, as they are

required for almost all adaptive responses. They help activate B cells to secrete antibodies,

macrophages to destroy ingested microbes, and cytotoxic T cells to kill infected target cells.

However, they can only function when activated to become effector cells. The

activation of helper T cells needs the involvement of antigen-presenting cells (APC). These

cells mature during the innate immune response. The antigen-presenting-cell may be a

dendritic cell, a macrophage or a B cell. When cells are infected, they also expose the

antigens to their surface but they are not considered as APCs. The difference lies in the

existence of two classes of MHC molecules. MHC means Major Histocompatibility Complex.

It is a complex of surface proteins that enables the recognition of foreign molecules.

Most body cells only have MHC class I, while antigen-presenting cells have both class I and

class II MHC molecules. It is MHC class II that gives the antigen-presenting cell a recognizable

molecular signature. An APC digests an antigenic protein, takes a fraction of it, the epitope,

and displays it on its surface once it is coupled with a MHC class II. Helper T cells have the

ability to identify antigen fragments (the epitope).

T cells surface antigen receptors (TCR) bind to an epitope displayed by MHC class II

on the antigen-presenting cell. At the same time, a helper T cell surface protein, called CD4,

binds to MHC class II to stabilize the interaction and reinforce the binding. This activating

pathway is known as T cell activation signal 1, as it is the first pro-activation signal for helper

T cells. During this interaction between helper T cell and APC, both cells release cytokines.

After having received the signal, the naïve T cell must activate a second biochemical

pathway, signal 2. This signal, independent of the first one, involves an interaction between

proteins of both cells called co-stimulatory molecules. Once the two-signal activation is

complete the helper T cell is able to proliferate. It releases a growth factor called

interleukin-2 (IL-2), which is actually a type of cytokine. Interleukin-2 then binds to that

same helper T cell and thus drives clonal proliferation and expansion.

Figure 7 : Antigen- presenting Cell delivers three kinds of signal to naive T cell @Roxane Jannin

The interaction between an APC and a helper T cell varies depending on the type of

antigen-presenting cell. For instance, presenting an antigen by dendritic cells or

macrophages activates a helper T cell and induces it to divide into effector T cells.

Antigen-presenting B cells only interact with already enabled T cells, subsequently

responsible for activating B lymphocytes (we’ll detail this process in the humoral response).

Activated Effector T cells can be placed into three functioning classes, the first class being

Cytotoxic T cells (directly kill targeted cells), the second class being TH1 cells (which function

is essentially to activate macrophages) and the third class being TH2 cells (which primary

function is to stimulate B cells into producing antibodies).

2) The cell-mediated immune response

Cell-mediated response does not need antibodies action. It rather involves the

activation of macrophages and NK cells (both cells are introduced in innate immunity, Part

I), the production of antigen-specific cytotoxic T cells, and the release of cytokines in

response to an antigen. Let’s focus on cytotoxic T cells activation and action.

a) Cytotoxic T cell activation

Cytotoxic T lymphocytes are the most important effectors of cell-mediated

response. To be activated, they have to receive molecular stimuli (cytokines) released by

helper T cells. They also need to link with an antigen-presenting cell. Once activated,

cytotoxic T cells have the ability to kill infected cells.

The activation of cytotoxic T cells requires interactions between T cell surface receptors and

APC surface molecules. The first interaction is the bound between TCR and MHC class I. Just

like helper T cells, cytotoxic T cells possess a surface protein which helps stabilizing the

interaction between both cells. The difference is that this CD8 protein binds to the MHC

class I molecule, whereas helper T cells’ CD4 binds with MHC class II (as we have seen

previously).

There is a second interaction, driven by co-stimulatory molecules (principle remains the

same as for the one explained above). This signal may require helper T cells to release

cytokines for assisting the co-stimulatory molecules.

Once it is activated, a cytotoxic T cell starts to multiply (clonal expansion) with the help

Interleukin-2 released by close helper T cells.

b) To kill and infected cell

A cytotoxic T cell attaches to the complex formed by the MHC class I and the

fragment of antigen on an infected cell. Cytotoxic T cell’s protein (CD8) binds to the MHC

class I molecule to help keep both cells in contact. Then, T cell releases perforins, enzymes

which creates pores in the membrane of the infected cell. Indeed, perforins insert into the

plasma membrane of the targeted cell and form a channel by polymerizing. However, this is

not enough to cause apoptosis of the target cells. Granzymes are other enzymes released by

cytotoxic T cells which degrade proteins. They enter the infected cell through the pores

created by perforin. Granzymes initiate apoptosis in the infected cell. The death of the

infected cell deprives the pathogen of its site of growth and exposes it to circulating

antibodies and phagocytes. The linkage between antibodies and antigens facilitates the

elimination of the pathogen.

After destroying the infected cell, the cytotoxic T cell attacks other infected cells by the

same pathogen.

Figure 8 : Destruction of an infected cell by a cytotoxic T cell @Roxane Jannin

3) The humoral immune response

a) B Lymphocytes activation

The humoral response involves B cells that recognize antigens or pathogens

circulating in the lymph or blood. First, an antigenic molecule binds to a specific surface

receptor of B lymphocyte, called BCR. Those receptors control the activating of B cells. BCRs

and antibodies belong to immunoglobulins (major protein family for cellular communication

and metabolism). BCRs and antibodies have a "Y" form, which means that they have two

antigen binding sites. Each B cell expresses on its surface only one type of BCR in several

copies. When a BCR bonds with its complementary antigen, the B cell absorbs the antigen

by endocytosis.

To activate a B cell, there must be a B - T cell interaction in the secondary lymphoid organs

(see part III for more information on these). The interaction is most of the time

antigen-dependent and therefore specific. B cell plays the role of an antigen-presenting cell

for the T lymphocyte previously activated by a dendritic cell or a macrophage. Remember

that this T cell called TH2 is responsible for activating B cells, and therefore the humoral

response.

A fragment of this antigen, after being absorbed by endocytosis and associated to a MHC

class II is presented by the B cell (note that B cells only present the antigen to which they

specifically bind). A functional helper T cell with specific receptors to the same antigen binds

to the B cell, and releases interleukins to stimulate the B cell. Most of the time antigen and

stimulator are both required to activate the B cell and initiate its proliferation. Interleukins induce B cells to divide rapidly, making thousands of identical clones of B cell.

Enabled B cells proliferate and differentiate into memory B lymphocytes, and plasmocytes

(plasma cells) secreting antibodies. Memory B cells remain inactive and wander within the

body until they encounter the antigen they bond with for the second time (case of

reinfection). This causes them to divide and form effective plasma cells. These cells stop

expressing their particular BCR on their membrane, and begin instead to secrete in large

quantity a soluble form of the receptor : antibodies. Keep in mind that antibodies are

complementary to the very same antigen than the one that initiated the reaction.

Figure 9 : Activation, proliferation and differentiation of B cells @Roxane Jannin

b) Antibodies

Each antibody recognizes one specific antigen. Each plasma cell produces one kind of

antibody. Antibodies do not destroy pathogens.

One of their action is to immobilize virus and toxins (by bonding to them) to prevent them

from infecting new cells, and stop the infection. This process is called neutralization :

antibodies block the site(s) viruses use to enter into targeted cells.

Antibodies are involved in another process called opsonization (see part I).

Antibodies recognize bacterial antigen and make a link with it. Indeed, a specific portion of

an antibody has the ability to bind the epitope of a pathogen. The antibody-antigen binding

alerts white blood cells that this antigen has been spotted. Antibodies enhance phagocytosis

as they form aggregates of neutralized pathogens, before the arrival of phagocytes. After

the antibody-antigen binding, phagocytes are attracted to the pathogen. When a phagocyte

has arrived, another portion of each antibody binds to a specific receptor on the phagocyte,

thus facilitating endocytosis of the pathogen.

This feedback between innate immunity and adaptive immunity allows for the deployment

of an effective and coordinated response against the infection.

As we saw in the first part about the innate immune system, antibodies sometimes work

with the complement system to eliminate pathogens. If you want additional information

about it, please scroll up to the complement system section in part I.

Figure 10 : principle of Neutralization, Opsonization and Complement recruitment by antibodies

@Roxane Jannin

Another reaction led by antibodies relies on a more aggressive strategy, in which antibodies

directly destroy infected cells. This mechanism does not involve phagocytosis.

When a virus produces viral proteins by using its host cell, patrolling antibodies gather to

the surface of the infected cell. If antibodies are specific of the epitope, they can make a

bond with it. This is the antibody-dependent cell-mediated cytotoxicity (ADCC) : the killing

of an antibody-coated targeted cell by a cytotoxic effector cell through a process that does

not involve phagocytose. Cytotoxic effector cell links with antibodies (themselves attached

to targeted cell) thanks to receptors present on the cytotoxic effector cell. These receptors

recognize a specific region of the antibodies and thus make bonds. Effector cells that

mediate ADCC include natural killer (NK) cells, monocytes, macrophages, neutrophils,

eosinophils and dendritic cells.

Figure 11 : An example of ADCC (Antibody-Dependent Cell-mediated Cytotoxicity) @Roxane Jannin

4) Immune memory

Immune memory is the particularity of the immune system to recognize in a fast

specific way an antigen that the body has already met. This recognition triggers a

corresponding immune response called the secondary response. Immunological memory

occurs after a primary immune response against an pathogen. It is specific to an antigen and

it is long-lived, quicker and more effective than the first response.

During the primary response (when the body meets the pathogen for the first time),

the amount of plasma cells secreting antibodies and differentiated T cells increase. We saw

that some B and T cells mature into effector cells but a part of the naïve populations

differentiates into B and T memory cells which can recognize the same antigen (as they

have the same antigen specificities).

“A memory cell is an antigen-specific B or T lymphocyte that does not differentiate into

effector cells during the primary immune response. But, in case of re-exposure to the same

pathogen, they can immediately become effector cells” (Molnar, C., & Gair, J. (n.d.).

Concepts of Biology-1st Canadian Edition). When the body gets through the infection, the effector cells are no longer useful, so they

are subject to apoptosis. In contrast, memory cells persist in the circulation. If the body is

exposed to the same pathogen a second time, the memory cells still circulating freely in the

body differentiate very rapidly into plasma cells and cytotoxic T lymphocytes without the

implication of antigen-presenting cells or helper T cells. That skips the step of activation.

Memory B cells that differentiate into plasma cells secrete a larger number of antibodies

than plasmocytes do during the primary response. Some antibodies generated in the first

response can also linger within the body. The infection is thus neutralized faster.

Figure 11 bis : Concentration of antibody over time

5) Passive immunity and vaccination

Innate and adaptive responses form the active immunity. A different type of

immunity, called passive immunity, occurs when a person is given someone else’s

antibodies. The protection offered by passive immunization is short-lived, usually lasting

only a few weeks or months. There is no delay for the action of passive immunity : its

response to an infectious agent is immediate.

An example of passive immunity is when antibodies of a pregnant woman are passed onto

the fetus via placenta. Transferred antibodies can immediately react to a specific pathogen

which that the baby has never met before. Moreover, when the baby is born, the mother

continues to transfer antibodies to him through breastfeeding. That will protect the baby

during the first months of his life, the time that his immune system becomes functional. This

is called natural passive immunity.

Passive immunization can also be administered to people that have been exposed to a

pathogen for which they cannot synthesize specific antibodies, and thus they can’t fight

against: this is called artificial passive immunity or serotherapy. Antibodies may come from

pooled and purified blood products of people who have the immunity against this pathogen

or from non-human immune animals (breeded for producing antibodies and other types of

treatments).

We have seen so far natural active and passive immunity, artificial passive immunity,

but it remains a type of immunity that we have not treated. Indeed, active immunity can

also be artificially acquired. It can be conferred by the introduction of antigens into the

body, that is to say by immunization. A way to produce active immunity is by vaccination.

The principle of vaccination is to administer an antigenic agent to stimulate the

immune system of a living organism and thus to develop its adaptive immunity against a

specific infectious agent. An antigen is the active substance of a vaccine whose

pathogenicity has been attenuated in order to stimulate the body's natural defenses, but it

does not cause the disease to the organism. The primary immune response allows the

apparition of B and T memory cells so that, in the case of actual contamination, acquired

immunity can trigger faster and stronger thanks to the secondary immune response.

There are four types of vaccines depending on their preparation process : inactivated

infectious agents, live-attenuated agents, subunits of infectious agents and toxoids (eg :

diphtheria and tetanus toxoid).

III. The story of the immunity cells and where to find them : from birth to death

Figure 12 : The organs of the immune system @Public Domain

The cells of the immune system are called leukocytes (or white blood cells) and the organs

of the immune system (also called the lymphoid system) are called lymphoid organs as they

are involved in the growth, development and deployment of lymphocytes (a special class of

leukocytes). In this part we will see the processes of production, differentiation and

maturation of the different leukocytes, as well as the organs involved in these processes.

1) Primary Lymphoid organs and blood

Leukocytes’ birth and growth happens in primary lymphoid tissues, the place of

maturation of the lymphocytes : in thymus for T lymphocytes maturation and in bone

marrow for B lymphocytes maturation and other leukocytes’ growth. For more information

and a quite detailed lineage of the leukocytes, please visit the wonderful LifeMap Discovery

Red Bone marrow : cell donor for hematopoietic system

Figure 13 : Structure of the bone marrow @ Julie Sitolle

Red bone marrow is the place of hematopoiesis, or the production of the immune cells of

from specific stem cells. It can be found in children and adolescent bones. Note that in adult

organisms, red bone marrow slowly turns into yellow bone marrow, which is mainly

composed of fats and cannot assure hematopoiesis.

Furthermore, hematopoiesis only occurs in some bones, like skull, ribs, sternum, vertebral

column, pelvis and proximal ends of femurs.

All begins in red bone marrow, inside the bones. This tissue is composed of hematopoietic

stem cells that differentiate into myeloid progenitor cells or into lymphoid progenitor cells

during hematopoiesis. The first group gives rise to the following blood cells :

- erythrocyte (red blood cells, we will not study them in this chapter)

- monocytes

- megakaryocytes (give the platelets in the blood)

- granulocytes (they used to be called polynuclear cells because some of them,

neutrophilic granulocytes, seem to have several nuclei)

- mast cells (or mastocytes)

The second group (lymphoid progenitor cells) differentiates into immature B, T and Natural

Killer (NK) lymphocytes.

Except for erythrocytes and megakaryocytes, all of these cells belong to the leukocytes class,

the specific cells that perform the different immune responses.

Note that the production of leukocytes is specifically called Leucopoiesis, the production of

lymphocytes is called “lymphopoiesis”, and the production of granulocytes is called

“Granulopoiesis”.

Figure 14: Differentiation tree of the Hematopoietic Stem Cell into leukocytes (and red blood cells)

Licence : CC BY 4.0

a) Genesis of blood cells

Within the bone marrow are created red blood cells (erythrocytes) and

megakaryocytes, the cells producing blood platelets. Platelets have a role in the local

inflammatory response, however we will not talk anymore about them as they are not

considered as a proper component of the immune system. Let’s talk about white blood cells

that come from the differentiation of a myeloid progenitor cell.

Granulocytes

These white blood cells are involved in the innate response. Their differentiation and

acquisition of their functions are mediated by cytokines. For learning about leukocytes

structure and functions, see Table 1 in Part I.

Neutrophilic granulocytes

After maturation, neutrophils leave the bone marrow and travel through blood before dying

4 to 10 hours later. They are never found in tissues unless there is an infection. However,

neutrophils are found in high concentration in blood because they permanently insure their

own replacement.

Eosinophils

This type of granulocyte differentiates in the red bone marrow under the influence of two

main factors : Interleukin-3 and interleukin-5, and GMCSF (Granulocyte Macrophage

Colony Stimulating Factor). Interleukin-5 is produced during a parasite infection or an

allergy. That is why eosinophils are mostly present in responses against parasites, in

allergies and asthma attacks.

Basophils

These granulocytes are exclusively present in blood, even though they represent less than

1% of leukocytes in it. They have a role in the regulation of innate as well as adaptive

response as they can release histamines, proteases and pro-inflammatory molecules.

Basophils, by expressing Immunoglobulin E (IgE) receptors, play a great role in type 1

hypersensitivity reaction, which is a reaction occuring in allergy (see Part IV for learning

more about it).

IgE receptors are high-affinity receptors, meaning that they induce a response even with a

low concentration of IgE. They are produced by plasma cells (mature B cells) in the lymph

nodes.

Mastocytes (or Mast Cells)

We often talk of mastocytes as the tissue equivalent of Basophils. They also play a role in

type 1 hypersensitivity as they can release many chemical mediators such as histamine and

heparin. They express IgE receptors as well.

Monocytes and Macrophages

Monocytes are leukocytes born in the red bone marrow. They respond to an infectious

environment by differentiating into macrophages, into a type of dendritic cells or into

microglial cells (brain immune cells, see Neurons and Synapses). Macrophages and dendritic

cells can perform phagocytosis, and have granules full of cytokines or other chemical

mediators.

Dendritic cells

Dendritic cells (DC) are professional APCs (antigen-presenting cells), meaning that after

having digested a pathogen, they present a small fragment of antigen on their membrane

surface.

There are 4 types of dendritic cells (see Figure 15), depending on their precise function and

place of action. Except for follicular DCs found in follicles, dendritic cells all express MHC

class II on their membrane. Langerhans DCs are found in the skin, lymphoid DCs are

responsible of tolerance in thymus and lymph nodes T cells area (see the cell-mediated

response in Part II), and myeloid DCs catch the antigen and bring it to the secondary

lymphoid organs to induce an immune response.

Figure 15 : Tree of the four types of dendritic cells and their progenitors @Julie Sitolle

b) Lymphocytes genesis

The first category of lymphocytes we are going to review is the Natural Killers cells

(NK). They mature in the bone marrow with the help of several growth factors. They look

like large granular cells.

NK cells , unlike B and T cells, do not express any specific membrane receptors and so do not

have an immune specificity and memory. They only have receptors for MHC class 1 and II.

MHC molecules are found on the surface of antigen-presenting cells (DCs, macrophages and

B cells) as they are the proteins that display the antigen. Here are some examples :

- An infected cell will only present MHC I and antigen parts on its surface, and will be

destroyed by NK cells.

- If a cell presents on its surface the two types of MHC with antigens, it is therefore

recognized as an APC and will have a role in the adaptive system.

- tumoural cells usually present less MHC I on their surface than normal cells. This

abnormal trait is identified by NK cells that forthwith kill tumoural cells.

B and T lymphocytes, however, have specific membrane receptors (B cell receptors “BCR”

are actually antibodies, that can also be found in a free form within the body ). The process

of generating antibodies was the subject of Susumu Tonegawa, Nobel Prize in Physiology or

Medicine in 1987. His paper shows how the huge diversity of BCRs is the consequence of

mutations but most importantly of recombination of genes inside B cells. To shed light on

that, Tonegawa compared non-B cells DNA with B cells DNA in mouse, and proved that

some recombinations have occured. We will see this process in detail with the B cell

maturation.

B Lymphocytes

In the red bone marrow, lymphoid progenitor cells differentiate into immature B

lymphocytes. There, these cells acquire their immunocompetence via a process called

maturation.

Actually, theses cells are supposed to undergo apoptosis unless they release a signal linked

with antigen-receptors normal development. This way, it is easy to avoid abnormal B cells to

survive and harm the organism. Successful synthesis of both heavy and light chains and their

expression on the membrane as well as the assurance the antibodies are not

complementary to the "SELF" are necessary for the survival of B lymphocytes.

Antibodies are composed of two heavy chains (written H or μ) and two light chains (either ᴋ

or λ)(See Figures 16 & 17). They are composed of a constant part (same for all BCRs) and a

variable part which is responsible of the diversity of antibodies and therefore the variety of

B cells and the effectiveness of the humoural response.

Figure 16 : Schema of a B-Cells Receptor or Antibody @Julie Sitolle : Heavy chains (μ) are in green.

Light chains are in pink (𝜅 or 𝜆). A BCR is attached to the B-cell by the end of the constant region of

Heavy chains, while antibodies are found alone in the body.

Let’s take a look at the chains arrangement processes in each B cells.

1) Let’s take the example of a pro-B cell (Fig.17a). It begins with the heavy-chain

rearrangement inside its DNA. A D-JH joining happens in human pro-B cells ‘s

chromosomes 14. Proteins called recombinases bind randomly to one gene on the D

segment and to one gene on the JH segment. (Fig.17b ). The proteins get closer to

each other to form a hairpin separated from the DNA strand, allowing the randomly

chosen genes to be joined together.

Then, a VH-DJ joining happens on one of the chromosome 14, with the same proteins

involved. If the rearrangement fails, the same mechanism occurs on the other

chromosome 14 (although it might fail as well). In the end, if the cell succeeds in

having a productive VDJ exon, the cell becomes a late pro-B cell and expresses heavy

chains called μ, linked to a conventional light chain. At this time is the first

checkpoint : about half of the pro-B cells are killed while the other half passes the

checkpoint.

2) A cell that has passed the first checkpoint is now a pre-B cell. It then induces a

light-chain rearrangement by stopping the rearrangement of heavy chains, and

recruiting the recombinases for light-chains rearrangement. This part begins with a

V-J joining on the chromosome 2, on the allele 𝜅. If the rearrangement is

unproductive, a V-J joining is tried on the other chromosome. If it also fails,

rearrangement is then tried on allele 𝜆 of chromosome 22. Again, it is tried

successively on each chromosome, until one of the rearrangement is productive.

3) At this time is the second checkpoint. It verifies if the pre-B cell shows a complete

μ/𝜅 or μ/𝜆 receptor (a BCR) on its surface. If there is no receptor, the cell dies. If

there is, the cell becomes a immature B-cell and expresses immunoglobulins at its

surface. Its maturation in the bone marrow is finished.

4) The final step, as we get immature B-cells, is for the organism to make sure these

cells will not attack their “SELF”. A negative selection leads to apoptosis immature B

cells that react when presented to the self-antigens. The remaining cells are specific

to one antigen and can’t bind with others. Those B cells may never meet their

specific antigen, as they may die before the antigen comes into the body or because

that form of antigen doesn’t exist. Those are the risks of random antibodies / BCRs

production.

Figure 17 : Gene rearrangement (a) and Maturation steps of a B-Cell (b), from the early pro-B cell to

the functional immature B-cell on both phenotype and genotype scales @Julie Sitolle

H ᴋ λ

V 38-46 30-40 30-40

D 23 0 0

J 6 5 4-5

Number of possible

combinations:

5244-6348 different

H chains

150-200 different ᴋ

chains

120-200 different λ

chains

Table 2 : Estimated number of genes for V, D and J segments, and the corresponding number of

heavy and light chains composition possibilities depending on these numbers. @Julie Sitolle

Adding the probability of joined imprecisions during the recombination (deletion or addition

of nucleotides) and the somatic mutations, the number of possible receptor structures is

huge : about 10¹² possibilities.

T Lymphocytes

Immature T cells migrate through the blood from red bone marrow to thymus, where they

acquire their immunocompetence.

Thymus :

Figure 18 : Schema of the thymus

Thymus is a gland located behind the sternum, on the top of the lungs. It is at its largest

around 4 years old, weighting 30g to 40g. It is very active from prenatal to pre-teenage, and

then reduces to become mostly fats because of the hormones released during adolescence

(around 5g remaining in elderly people). However it still functions during adulthood,

although it reduces ( especially during pregnancy).

Thymus offers a specific micro-environment to lead T cells maturation with cortical and

medullary thymic epithelial cells. It also produces hormones called thymosins involved in

T-cells stimulation (see chapter about Hormones).

In the thymus, only 2% of immature T cells becomes functional. As for B cell, the process of

T cells maturation is long and complex (see Figure 19). First, immature T cells (thymocytes) undergo their receptors (TCR) generating. The genetic

mechanisms are the same as for BCR diversity (see above in section B lymphocytes).

Then in the thymus cortex, thymocytes survive if they succeed in expressing a MHC receptor

on their surface by the first checkpoint (Fig. 19-2) called positive selection. This step

ensures the proper formation of MHC proteins.

Surviving thymocytes migrate to the thymus medulla, and express CD4 and CD8 proteins on

their surface (Fig.19-3). They are then presented to APCs wearing self-antigens (Fig.19-4). If

they bind to self-antigens, they will attack the “SELF” and therefore are killed. This step is

the second checkpoint called negative selection. Finally, the remaining thymocytes (qualified as self-tolerant) finish their maturation by

expressing either CD4 or CD8 proteins.

If the mature T cell expresses the CD8 protein complex, it is a cytotoxic T cell (see in Part II

for its function).

The cells expressing the CD4 protein complex become either helper T cells or a T regulatory

cells. T regulatory cells have a role in maintaining self-tolerance and normal behavior in

helper T cells. (To know more about T Helper cell, see part II of this chapter). Finally, all theses cells are released in the lymphatic system.

Figure 19 : Scheme of maturation process of T cells : Focus on Positive and Negative Selections that

prevent autoimmune attacks from a T cell @Licence : CC BY 4.0

Now that all these cells have matured, they are going to migrate to different tissues and

organs called secondary lymphoid tissues.

2) Secondary lymphoid organs and cells repartition

While granulocytes and mastocytes are heading to blood, lymphocytes begin their work

mainly in secondary lymphoid tissues, which are lymphoid organs where antigens are

trapped.

a) Repartition in blood

First, several immunity cells are going to blood vessels. While neutrophils represent

the main part of white blood cells (60%) of in a healthy human body, monocytes stand for

5-8%, eosinophils for 1-5% (but they are more prevalent in tissues), basophils 1% and finally

dendritic cells only for 0.1%. The remaining 30% divide into the 3 types of lymphocytes :

70% of T cells, 10% to 20% of B cells and the rest as NK cells.

Of course, those proportions may change at a local scale (although that shift might extend

to the whole body) if any infection occurs.

b) B and T Lymphocytes and Secondary Lymphoid Organs

After their development, immature B cells leave the bone marrow and go into the

secondary lymphoid organs. There they will either die, or finish their maturation by binding

to an antigen. (See Part II. 3)“The humoral immune response” for the following of the story

of B lymphocyte maturation) They have a role in adaptive immune response and are part of

the humoral immunity.

T lymphocytes, after maturation, leave the thymus and express a IgD molecule along

with their IgM. Some go to the blood. There we find approximately two Helper T cells (CD4

glycoprotein on the membrane) for one Cytotoxic T cell. The other cells go to the Secondary

Lymphoid Organs, via lymph vessels.

These organs are all over the body, mainly near the main entrances of the organism

(mouth, nose, skin, genital and anal openings). They are supposed to be a place where

antigens that have entered the body can encounter lymphocytes, for acquiring all the tools

essential for an effective immune response. Within secondary lymphoid organs, the primary

follicles are the organized network of dendritic cells and small B cells. This network lies next

to less organized tissues called MALT, that enclose collections of lymphocytes and

macrophages. Here is the list of secondary lymphoid organs :

- Lymph Nodes :

The nodes are linked together by lymph

vessels. The three of these compose the

Lymphatic System. As they are at the

junction of several lymph vessels, lymph

nodes are the organs where the most

antigen are drained out.

Figure 20 : Lymph node structure

- Spleen : Located on the left side of the body, just beneath the diaphragm, the

spleen has many functions, the most important one being to clean blood

from old platelets and red blood cells. Another significant function is the

catch of antigens getting through it (via blood) by lymphocytes and other

white blood cells stored in the spleen (B cells and macrophages).

Fun survival fact : if your spleen has to be removed, other defense organs will

take on most of its task. However, spleen is thought to be the place of

leukocytes genesis in foetus, so it might be an issue for young people.

- Mucosal Associated Lymphoid Tissues (MALT) : These are Lymphatic tissues

in the bowel and other mucous membranes, where most of antigens enter

the body. Some of them are simple (for instance on liver) whereas others

have more complex structures (e.g. Tonsils associated to adenoids and

Peyer’s patches). MALT contain a lot of lymphocytes ready to launch an

immune response whenever they meet an antigen.

IV. Deficiencies, Disabilities and difficulties of the Immune System

1) Autoimmune diseases

Since the end of World War II there has been a significant rise of the number of

autoimmune diseases. According to the AARDA ((American Autoimmune Related Diseases

Association), 50 million americans suffer from various autoimmune diseases.

Most of the time, the autoimmune diseases are caused by a mix of genetic factors,

environmental factors and dysbiosis. The latter is a microbial imbalance (lack or poor

adequation between species) within the body.

Figure 21: Autoimmune diseases factors

a) Genetic predispositions

The wide range of molecules, cells and interactions involved in immunity forms such

a complex system that any tiny change might have huge consequences on it. Let’s take the

example of PTPN22 gene, for which the smallest mutation can have an serious impact on

the protein PTPN22 codes. That protein protein plays a role in several signalisation

pathways, especially as an inhibitor of activation of B and T lymphocytes proliferation. When

mutated, the gene can lead to type 1 diabetes (which is an autoimmune disease) by

triggering an over-activity of certain immune cells.

b) Environmental factors

People use more and more chemical compounds is their everyday lives, even though

some have proved to be hazardous to health. For instance, one autoimmune condition

named “ASIA” is induced by some adjuvants. After the Gulf war, more than 250 000 former

soldiers had health issues, including immune system deficiencies. Several causes may be

involved. The most likely remains the abusive use of chemicals like depleted uranium (used

for tanks ammunitions) or Sarin nerve agent, a toxic gas. Those are the main causes of the

soldiers’ health decline, even though other chemicals might have had an impact. Some

scientists even think war-related stress as a compounding factor for the soldiers’ diseases

development.

c) Microbiota changes

Microbiota changes are tightly linked with environmental factors. For example it

evolves along our eating habits, and our diet has significantly changed over the past 60

years. Even the origin of the food we eat has changed, the meat mostly breeded and very

rarely from wildlife. We also use a lot of pesticides, fungicides, and insecticides.

Human Microbiota is a cornerstone for the immune system, and the way it changes can

have huge impacts on our health. Human gut has a surface of nearly 200 square meters and

contains almost 70% of all the lymphoid tissues in the body. We also can find 10(13)

microorganisms in it (way more than the number of cells that in our body). This microbiota

is very sensitive to the diet and can drastically evolve depending on what we usually eat.

For example, mucins are highly glycosylated proteins that cover the mucosal surfaces,

including bowels. In the colon, these glycoproteins form a physicochemical barrier by

separating the intestinal epithelium from the colonic lumen. This barrier protects epithelial

cells from direct contact with bacteria. One tiny change in this conformation can induce an

infection and accordingly trigger an inflammatory response. So, as we eat more and more

industrial sanitized products, our microbiota becomes weaker and we are more likely to

suffer from an autoimmune disease

2) Immunosuppression

We are going to take the example of HIV-1. It is a lentivirus (a subgroup of retrovirus)

that target the CD4 T cells. For more information on retrovirus, we recommend you check

on the Viruses chapter available on the website.

CD4 or helper T cells are involved in regulations and intermediate reactions. You already

know from Part II that they are responsible for the secretion of interleukin 2 for activating

cell-mediated and humoral responses (Chemical mediation between LB and LT to stimulate

their proliferation). These cells also act in the memory of the immune system as quiescent

cells (sleeping cells)

Figure __ : HIV sketch !!A modifier !! ARN

CD4 T cells that are not quiescent serve as reproduction for the virus (make copies of itself)

and express specific antigen so that CD8 T cells recognise the CD4 as a modified-self and kill

it.

HIV-1 binds to CD4 T cells and merges with it before spreading its genetic material into the

cell. Then the virus RNA is transcribed into DNA thanks to Reverse transcriptase, (an

enzyme also involved in the RT-PCR). Then another enzyme called integrase allow the newly

transcribed viral DNA to integrate within helper T cell’s DNA. This modified DNA is

expressed, resulting in viral proteins production as well as RNA molecules replication (that

will help to virus spread to to other cells).

Infection of a CD4 T cell by the HIV-1

The major advancement of HIV infection is AIDS, and usually occurs in the 10 years following

the infection (without any treatment). It is characterized by the appearance of cancers and

opportunistic infections.

Today, treatments are very effective : one HIV-seropositive person is practically able to live

a normal life if he or she seriously takes prescribed medications. ***

The most commonly used in occidental countries is the HAART (triteraphie). It is the

combination of three drugs, each of them has an effect on a particular step of HIV infection.

We know well how to target the merging part, the retrotranscription part and the integrase

part (sometimes we target other steps but most of the time they are the three main goals).

Still, one major difficulty lingers : HIV has a very poor reparation system and almost never

corrects the mistakes that appears in the replication. That means it is able to mutate very

fast. So, if the patient has a bad observance and forgets his drugs (even 1 or 2 days), the

virus starts to replicate again in presence of semi-active drugs and mutates so the drugs

become ineffective (when the drugs are well taken there is no replication at all). When the

virus has mutated and has become resistant to one drug, patients need to adapt their

treatment very quickly with new drugs. The main issue is that there are not many

possibilities, and doctors might run out of solution. Moreover, the mutated virus can still be

passed on from individuals to others.

The second major difficulty is that some CD4 T infected cells serving as memories cells can

turn into quiescent cells. Today we can’t distinguish an infected quiescent cell from another,

so we can’t entirely wipe out HIV from a body. Almost all of on-going research is focused on

that how can we identify all infected cells to eradicate HIV from an individual.

3) Allergies (overreacting immune response)

Often the result of genetic predispositions, the phenomenon leading to an allergic

response can be divided in two parts : first the “sensitization” part without any symptoms,

and second, the allergic response with symptoms. ***

The sensitization part begins with the first contact between an individual and the allergenic

substance. This substance is recognized as part of non-self by the immune system, usually

by immune defenses close to skin or mucous. Then, dendritic cells present the allergen

antigen on their surface and allow the production of IgE antibodies (see Mastocytes section

in Part III). IgE binds to mast cell and basophils that become very sensitive to this kind of

antigens. From this moment whenever those immune cells meet these allergen antigens,

they will be a lot more quickly activated. That is called “Type 1 Hypersensitivity”.

When activated, mastocytes and basophils produce histamine. Remember in innate

immunity (part I), histamine is a chemical mediator that trigger an inflammatory response.

Some of the possible visibles symptoms of this response are skin-itching, sneezing and runny

nose and lungs bronchoconstriction (produces a lot of mucous). ***

Allergic reaction

4) Transplant case

Transplanting an organ, a tissue or any other biological compound is a effective method for

curing or replacing a missing or deficient one. However, the immune system can be

confused with this new component, and may trigger a response. In that case the transplant

ends in a rejection as the immunity cells don’t recognize the transplanted cells (qualified as

part of the “NON SELF”), and thus lead a massive attack against the new tissues.

The real issue is that rejection is a normal reaction from the body, and so medicine needs

ways to outwit the body’s defenses, without completely disrupting the immune system that

should still be able to fight against any upcoming pathogens.

a) Example of blood transfusion

In the case of blood transfusion, compatibility relies on the ABO blood group system.

Humans can be part of O group (alleles OO), A group (AA or AO), B group (BO or BB), or AB

(AB).

Table 2

Isohemagglutinins are antibodies in plasma that react with the antigens present on the

surface of the red blood cells. A and B antigens are types of isohemagglutinins.

V. Conclusion

Immune system in humans, as in other mammals, is a complex set of structures we

do not completely understand yet. Certain chemical pathways remain unknown, and some

notions need clearer definitions as for instance the limit between SELF and NON-SELF). The

pursuit of research in the field will undoubtedly have a major impact on understanding and

treating numerous conditions (from allergies to cancer). To conclude, please keep in mind

that we could not mention in this chapter every detail known about the immune system.

We encourage you to look on your own if you want to go deeper on that fascinating topic.

For the most curious, here is a cool Khan academy video for learning about how our

immune system knows not to attack our own body :

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