The Immune System

I- Primary and secondary Lymphoid organs

1- Primary Lymphoid organs: Bone marrow and thymus

2- Secondary Lymphoid organs: Spleen and lymph nodes (lymphatic ganglia)

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1- Primary Lymphoid organs: Bone marrow and thymus
2- Secondary Lymphoid organs: Spleen and lymph nodes (lymphatic ganglia)
Phagocytosis and formation of APC antigen presenting cell:
APC antigen presenting cells: Macrophages, dendritic cells, B-lymphocytes.
T and B-lymphocytes (TLs and BLs)
They are specific white blood cells that recognize specific antigens using their cell receptors. The TLs
express T cell receptors (TCR) and CD molecules. The BLs express B cell receptors (BCR) called also
fixed antibodies (Abs) or immunoglobulins (Igs).

TCR and BCR

Variable regions of the TCRs and BCRs
The variable regions of TCRs and BCRs are made up of amino acid chains that are coded by specific
mini-genes (V, J, D, & C mini-genes) that are recombined (change their position in the DNA) to form
millions of different types of cell receptors.
Types of human antibodies (Ab) or immunoglobulins (Ig):
There are five types of Igs: IgM, IgA, IgG, IgD, & IgE. These types are represented in the following figure:
Double recognition of the T cell receptor TCR
1- The TCR’s edges recognize the edges of the MHC molecule
2- The TCR’s center recognizes the foreign peptide or the mutated peptide

Maturation of BLs and TLs:

1- Maturation of BLs: BLs’ production and maturation takes place in the bone marrow.
2- Maturation of TLs: TLs’ production takes place in the bone marrow while TLs’
maturation takes place in the thymus.
Specificity of BCR and TCR: B cells and T cells antigen recognition

Immune complex:
Many antibodies combine with one antigen that expresses different antigenic determinants (epitopes) to
form an immune complex:
Immune complex:
Many antibodies combine with many identical antigens expressing one type of epitopes to form an
immune complex:

MHC class I and class II molecules:

1. a- MHC class I expresses self-peptides get from the degradation of self-polypeptides/proteins
synthesized inside normal (non-infected) body cells under the control of human normal genes.
MHC class I that holds self-peptide forms a complex molecule called Immunological self.
Immunological self = self-MHC I + self-peptides.

b- MHC class I expresses mutated peptides get from the degradation of mutated
polypeptides/proteins synthesized inside the mutated body cells under the control of mutated genes
of the mutated human cells such as the cancerous cells.

c- MHC class I expresses non-self-peptides get from the degradation of foreign non-self-
polypeptides/proteins synthesized inside the infected human cells under the control of foreign genes
of the invader (viruses & bacteria).

MHC class I that holds mutated or non-self-peptides forms a complex molecule called Modified self.
Modified self = self-MHC I + non-self /or mutated peptides.
2. MHC class II expresses only non-self-peptides get from the degradation of foreign invaders
processed inside the normal human body cells (macrophages, dendritic cells, & B lymphocytes) after
phagocytosis.

MHC class II that holds non-self-peptides forms a complex molecule called Modified self. Modified
self = self-MHC II + non-self-peptides.
Activation of a T helper (TH, also known as T4 cells) by an APC
The T helper, that succeeds in recognizing the modified self (made up of self-MHC II + non-self peptide)
expressed on the surface of an APC (e.g. a macrophage), makes double recognition of modified self-complex
using its TCR. Additionally, it uses a molecule called CD4 expressed on its surface to recognize the basic
part of the self- MHC II molecule. These constitute the first signal needed to activate this T helper (TH)
cell. Signal 1 constitutes of two sub-signals:

-Signal 1a: The TCR of TH recognizes the modified self-antigen made up of self MHC II + non-self peptide.

-Signal 1b: The CD4 of TH recognizes the basic part of self MHC II

The second signal constitutes of IL 1/or 12 (interleukin 1/or 12) molecules secreted by the APC and received
by this TH using specific receptors (R).
Activation of a T killer (TK, also known as T cytotoxic or T8 cells) by an infected cell and a
T helper
The T killer, that succeeds in recognizing the modified self (made up of self-MHC I + non-self /or mutated
peptide) expressed on the surface of an infected or a mutated body cell, makes double recognition of
modified self-complex using its TCR. Additionally, it uses a molecule called CD8 expressed on its surface
to recognize the basic part of the self- MHC I molecule. These constitute the first signal needed to activate
this T killer (TK) cell. Signal 1 constitutes of two sub-signals:

-Signal 1a: The TCR of TK recognizes the modified self-antigen made up of self MHC I + non-self /or
mutated peptide.

-Signal 1b: The CD8 of TK recognizes the basic part of self MHC I.

The second signal constitutes of IL 2 (interleukin 2) molecules secreted by the effector (active) TH and
received by this TK using specific receptors (R).
Activation of a B lymphocyte (BL) by a naked antigen and a T helper
The B lymphocyte expresses on its surface a B cell receptor (BCR) called a fixed antibody. BCR recognizes
a naked antigen (Ag) which is not hold on MHC molecules. This forms the first signal for activating the
BL. The second signal constitutes of IL 4 (interleukin 4) secreted by T helper and received by this BL using
specific receptors (R).
The clonal selection

• Each T and B lymphocyte newly produced in the bone marrow express a unique antigen-binding cell
receptor (unique TCR for a TL and unique BCR for a BL).
• Only those that recognized an antigen (Ag) become active TLs or BLs.
• Selection: Active TLs or BLs now selected to induce an immune response (fight) against the intruder (Ag).
• Clonal expansion: The selected TLs or BLs go from the site where they had recognized the Ag to the
secondary lymphoid organs (spleen or lymph nodes) where they proliferate (divide by mitosis) to form a
clone of TLs or BLs.
• Each clone constitutes of many identical cells, which all have the same antigenic specificity. This means
that the BLs of a clone express the same type of BCR that recognize only one type of epitopes of a naked
antigen. Moreover, the TLs of a clone express the same type of TCR that recognize only one type of
modified self-antigen (non-self-peptide hold on MHC molecule).
• The cells of a clone then start to differentiate. Few of them do not complete there differentiation, they are
said to be partially differentiated Memory cells. Other cells continue their differentiation to become
Effector cells.
• Memory cells that have the same type of antigen-binding cell receptors remain inactive and may survive
for a long time waiting for the second encounter with the same intruder (Ag). Upon the second encounter,
memory cells will become active again and selected to proliferate to form new clone of memory cells and
effector cells.
• Effector cells (THs, TKs, & BLs) create immune responses (fights) against specific intruder (Ag);
therefore, these responses called specific immune responses. Effector cells fight for 24 hours then they die
due to exhaustion (overtiredness).
• Effector THs secrete interleukin (IL) molecules. Depending on the type of Ag recognized, effector THs
produce either IL- 4 to activate BLs, or IL- 2 to activate TKs, or both of them.
• Effector TKs recognize (become in contact with) the body cells infected by the same intruder and kill
them by secreting perforin and granzymes molecules onto the infected cells.
• Effector BLs (also called plasmocytes or plasma cells) secrete antibodies (Abs)/ immunoglobulins (Igs)
into the body’s fluids in order to capture the intruder and neutralize it (stop its action in the body).
The primary immune response:
During the first encounter with an intruder (Ag), few BLs succeed in recognizing the foreign Ag. These BLs
activated and selected to multiply by mitosis to form a clone of identical BLs showing the same type of BCRs
that recognize the same Ag. Among the clone, some cells become memory cells while others become effector
plasmocytes (plasma cells) that secrete antibodies to capture the intruders (Ag) of the same type recognized before
by the selected BLs.

The secondary immune response:

During the second encounter with the same intruder (Ag), memory cells produced during the first encounter
with this intruder recognize it. They proliferate to form a clone of memory and effector cells. The secondary
immune response is more efficient, more amplified, and faster than the primary immune response.

-More efficient because it protects the body from the intruder for a longer time (sometimes for the life span).

-More amplified because much more antibodies produced to neutralize the Ags.

-Faster because the intruder can be eliminated in about 18 hours while in the first immune response elimination
takes from 5 to about 14 days.
Activation of T-helper by a Macrophage or by an activated dendritic cell DC (APCs):
Inflammatory reaction

It is a protective response done by a body against microbes. It is a critical innate (non-specific) immune defense
against intruders; it eliminates more than 95% of microbes that cross the first line of defense of a body. Four
signs characterize inflammatory reaction: Redness, Hotness, Edema (swelling), and Pain.

Injured skin (as shown in the images bellow) allow microbes to enter to a body, then macrophages (or dendritic
cells) phagocyte these microbes and start to produce Cytokines (such as Kinins). Moreover, body cells damaged
by the microbial secretions (such as toxins) start to release cytokines (such as prostaglandins) in order to inform
the immune system (WBCs) and the nervous system about the damage. Cytokines secreted by macrophages and
mast cells (histamines cytokines) target the endothelial cells (white muscle cells that cover the blood capillary)
of the local blood capillaries. As a result the endothelial cells will shrink (contract slightly) causing the dilation
of the blood capillary and the formation of tinny openings in the wall of the blood capillary. These openings
allow the flow of blood plasma out of the capillary into the inflamed area; consequently, swelling (Edema)
occurs in this area.
The dilation of the blood capillary increases the blood flow in this area; consequently, more warm blood will
reach this area which results in increasing its temperature more than the neighboring areas (hotness). Moreover,
the increase in the volume of blood that reaches this area turns it more red (redness) due to the increase in the
number of red blood cells flowing in the blood.

Prostaglandins secreted by damaged body cells combine with specific receptors located on the surface of pain
sensory nerve cells (Nociceptors). As a result, these nerve cells will be excited; they create nervous messages
and transmit them to the cerebrum. When pain message reach the cerebrum you start feeling pain, and you can
consciously perceive the intensity of the damage, its location, and so on, which helps you in dealing with this
problem.
Specific Immune Response (SIR)

There are two types of specific immune responses: Cell-mediated and Humoral Immune Responses. They both
promoted by Helper T cells.

The cell-mediated IR is an IR created by T Killers, which kill the infected body cells throughout a direct contact
between them and the infected cells.

The Humoral IR is an IR created by Plasmocytes (active B-lymphocytes), which release antibodies in the
body’s fluids (plasma of blood and lymph/or serum). Free antibodies neutralize the microbes and help in their
elimination from the body by facilitating phagocytosis and activating complement enzymes.

Mode of action of Antibodies (Humoral Immune Response)

Viral and bacterial infection of cells can be blocked by neutralizing antibodies. Antibodies intervene in three
main processes of microbes’ elimination: a) Neutralization; b) Opsonization; and c) Complement activation.
Neutralization: The variable regions of an antibody block (cover) the active site of the microbial’ antigens or
free antigens (toxic proteins); consequently, their harmful action in a body will be stopped (neutralized).
Opsonization: A pathogen marked by antibodies is phagocytized by phagocytes (such as DCs, Macrophages,
and Neutrophils). Using its variable regions, the antibody captures and marks the pathogen. Meanwhile, using
its constant region, it combines with membrane receptors located on phagocytes. This combination between the
marked pathogen and phagocytes facilitates phagocytosis and pathogens’ elimination.
Complement activation: The complements are mainly enzymes (also called class III molecules). They are
components of the non-specific immune response that complement the action of a specific immune response
(antibodies). Among dozens, scientists distinguish nine main complement enzymes, which are known as C1,
C2,….C9.

The Complement Cascade:

First, C1 binds to the constant regions of several neighboring Abs that adhere to a pathogen (Ag). Then it
becomes active and splits C2 and C4 into two pieces each: C2a & C2b, and C4a & C4b. C2a and C4b combine
and split C3 into C3a & C3b. C2a & C4b combine with C3b and split C5 into C5a & C5b. Both C3a and C5a
molecules attract T, B cells and phagocytes to the marked pathogens/inflamed area by chemotaxis. C5b
combines with C6, C7, and C8 and activate C9 enzymes, which will immerse themselves in the membrane of
the pathogen causing the formation of pores (perforation) in its membrane and leakage of cytoplasm out of it;
consequently, the pathogen will be destroyed. Since, each activated complement enzyme activates another one;
this chain activation of the complement proteins is called the complement cascade.
Phagocytosis is a non-specific immune response that induces specific-immune responses by activating T
Helpers. Moreover, specific Humoral immune response (using antibodies secreted by B-lymphocytes)
promotes non-specific immune responses such as Opsonization (phagocytosis of pathogens marked by
antibodies) and complement cascade.
Medical Tests

Vaccination and Serotherapy

I- Vaccination: Is the process of administration of a weakened whole pathogen, one of its components (its
antigens), or a toxoid (weakened toxin), to a body. It aims at immunizing this body against this pathogen.

Importance of immunological memory:

Vaccination is a clinical application of immunization designed to artificially help the body to defend itself.
A vaccine against infection is a modified form of a natural antigen, which may be either the whole pathogen,
one of its components, or a toxin. A vaccine does not cause disease when administered but induces the healthy
host (the vaccinee) to mount a primary immune response against epitopes of the modified (weakened) antigen
and to generate large numbers of memory B and T cells.
In an unvaccinated individual (Fig. below left panel), naïve B and T cells capable of combatting an infecting
pathogen are present in relatively low numbers when the pathogen is first encountered. A primary immune
response is all that can be mounted so that, in many cases, the individual becomes sick until antibodies and/or
effector T cells can act to clear the invader. In a vaccinated individual (Fig. below, right panel), a collection of
circulating antibodies and an expanded army of pathogen-specific memory B and T cells have already been
generated prior to a first exposure to the natural pathogen. When the natural pathogen attacks, the circulating
antibodies provide a degree of immediate protection from the invader. In addition, the memory B and T cells are
quickly activated, and a secondary immune response is mounted that rapidly clears the infection before it can
cause serious illness.
The characteristics of Vaccination:

Vaccination is a preventive, active, and durable method of immunization:

It is preventive because the vaccinated person becomes immunized against a pathogen. He is able to induce
secondary immune response using memory B and T cells. Therefore, he will not be affected by the pathogen
and hence will not manifest any symptoms of the disease.

It is active because the vaccine activates the vaccinated person’s specific immunity and hence he/she will
produce his/her own antibodies and effector T cells to eliminate the intruder.
It is durable because an immunized body, which has encountered the pathogen, produces Long-Lived Plasma
Cells (LLPCs) that are able to produce antibodies against this pathogen approximately in a continuous manner;
so the immunized body will be protected from this pathogen almost for his life-span.

The effect of mass vaccination of a population on the spreading of a disease among them:
II- Serotherapy (Serum therapy): It is the treatment of an infectious disease by injection of serum containing
antibodies specific to one pathogen into a body infected by this pathogen. The injected readymade antibodies
can spread in the patient’s body and capture this pathogen; this will facilitate its neutralization and elimination
from this body.

This serum with specific antibodies can be either extracted from an immunized animal against this disease or
made in the laboratories by using new biotechnological techniques.

The characteristics of Serotherapy:

Serotherapy is a curative, passive, and not-durable method of immunization:

It is curative because it is used to treat a person which is already infected by a pathogen. In some cases, it can be
used as a protective method (prophylaxis).

It is passive because the antibodies used to eliminate the intruder were not made by the infected person himself
(they were made by other organisms). Injection of readymade antibodies does not lead to the activation of
specific immunity against the pathogen.

It is not durable because the readymade antibodies injected in a body have short life-span (about three months);
so they will protect the body for a short time.

Example on Serotherapy that might be used to treat patients infected by Corona virus or to protect
healthcare workers from COVID-19
Vaccination versus Serotherapy

Immunodeficiencies
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Autoimmune diseases

1- Autoimmunity
2-Mechanisms involved in autoimmune diseases