Chapter 1

Overview of the immune system.

The protection conferred by the immune system can be divided into two linked activities: recognition
and reaction. Innate immunity includes molecular and cellular mechanisms that are set up before an
infection and whose purpose is to prevent or eliminate it. Adaptive immunity is established in
response to infections and adapts to recognize, eliminate and later remember the invading pathogen.
Adaptive immunity has four characteristic attributes:
■ Antigenic specificity
■ Diversity
■ Immune memory
■ Recognition of the own and the strange

An effective immune reaction includes two main

groups of cells: T lymphocytes and antigen-
presenting cells. The two main populations of
lymphocytes: B cells and T cells.

B cells
B cells or B lymphocytes mature within the bone
marrow; when they leave it, each expresses a unique
antigen-binding receptor on its membrane. This
antigen-binding receptor or B cell receptor is a
membrane-bound
antibody
molecule. When a
virgin or naïve B
cell (which has
not encountered
any antigen
before) first
encounters the
antigen
corresponding to
its membrane-
bound antibody,
the binding of the
antigen to the
antibody causes
the cell to divide
rapidly and its progeny to become differentiate into memory B cells and effector B cells called plasma
cells. Memory B cells have a longer lifespan than naïve cells and express the same membrane-bound
antibody as the original B cell. Plasma cells produce the antibody in a form that can be secreted and
have little or no membrane-bound antibody. Secreted antibodies are the main effector molecules of
humoral immunity.

T cells
T cells are also generated in the bone marrow. Unlike B cells, T cells migrate to the thymus gland to
mature. Maturing T cells express on their membrane a unique antigen-binding molecule, called the T
cell receptor (TCR). There are two well-defined subpopulations of T cells: T helper cells (TH) and
cytotoxic T cells (TC). T cells that display CD4 usually function as TH cells, while those that display
CD8 almost always function as TC cells. Unlike membrane-bound antibodies on B cells, which
recognize free antigens, most T cell receptors can only identify antigens bound to cell membrane
proteins called major histocompatibility complex (MHC) molecules. There are two main types of MHC
molecules: MHC class I molecules, which almost all nucleated cells of vertebrate species express,
and MHC class II molecules, which only antigen-presenting cells (APCs) express. When a naïve T
cell encounters antigen associated with an MHC molecule on a cell, it proliferates and differentiates
into memory T cells and various effector T cells. Once the TH cell recognizes and interacts with a
complex of antigen
and MHC class II
molecule, it becomes
activated: it
undergoes a
metabolic
transformation and
begins to secrete
various cytokines.
Secreted cytokines
play an important role
in the activation of B
cells, TC cells,
macrophages, and
several other cell
types involved in the
immunoreaction.

Antigen-presenting
cells interact with T cells
Activation of the humoral and cell-mediated branches of the immune system requires cytokines
produced by TH lymphocytes. These specialized cells, which include macrophages, B lymphocytes
and dendritic cells, are distinguished by two properties: a) they express MHC class II molecules on
their membranes and b) they are capable of producing cytokines that cause the activation of TH cells.
Antigen-presenting cells first internalize antigen, either by phagocytosis or endocytosis, and then
display a portion of said antigen on their membrane bound to an MHC class II molecule. The TH
lymphocyte interacts with the complex of antigen and MHC class II molecule on the membrane of the
antigen-presenting cell. This cell then produces an additional signal that leads to the activation of the
TH cell.
Episode 2
Cells and Organs of the immune system.

CD* comes from “group of differentiation”, (from the English cluster of differentiation ).

B lymphocytes
The B designation of lymphocytes comes from the bursa of Fabricius, the site where these cells
mature in birds; The name was appropriate since the bone marrow is also its main site of maturation
in several mammalian species. Mature B cells are definitively distinguished from other lymphocytes
and all other cells by their synthesis and display of membrane-bound immunoglobulin (antibody)
molecules, which serve as receptors for antigen.

T lymphocytes
T lymphocytes derive their name from their site of maturation in the thymus. During this process, the
T cell gains the ability to express on its membrane a unique antigen-binding molecule called the T cell
receptor. Regulatory T cells are identified by the presence of both CD4 and CD25 on their
membranes. However, unlike T helper cells that carry CD4, Treg cells suppress immunoreactions:
they are negative regulators of the immune system. Like TH and TC cells, members of the Treg
subpopulation of T cells can be progenitors of memory cells.

Natural killer cells

The body contains a small population of large granular lymphocytes called natural killer cells that
have cytotoxic activity against a wide range of tumor cells and against cells infected by certain
viruses. They have the ability to recognize tumor or virus-infected cells even though they lack
antigen-specific receptors. Natural killer cells are part of the innate immune system, and most are
devoid of T cell receptors or immunoglobulin incorporated into their plasma membranes; in other
words, they do not express the membrane molecules and receptors that distinguish the B and T cell
lineages.
Chapter 3
Innate immunity.

Innate immunity consists of defenses against infection that are ready to be activated immediately
even before the attack of a pathogen. The innate immune system includes physical, chemical, and
cellular barriers. The main physical barriers are skin and mucous membranes. Chemical barriers
include the acidity of
stomach contents and
specialized soluble
molecules with
antimicrobial activity.
There is a second
system, called
adaptive immunity,
which is induced by
exposure to
microorganisms and
combats infection with
a specific response
tailored to the
attacking pathogen in
the form of a large population of B and T lymphocytes that specifically recognize the invader. .

Anatomical barriers

Connections between innate and adaptive immunity

The immune system reacts to invasion with two critical functions: it detects the invader through
sensors, and it attacks it with an elaborate response mechanism. These molecular sensors recognize
specific general molecular patterns, such molecules are called pattern recognition receptors (PRRs),
and when such patterns are detected in pathogens, they are called pathogen-related molecular
patterns (PAMPs). Soluble mediators (soluble mediators recognize PAMPs) include initiators of the
complement system, such as mannose-binding lectin (MBL) and C-reactive protein. If any PAMP
interacts with these mediators, the complement system will be activated.
Immature dendritic cells and macrophages of the invaded tissue have various receptors, including the
most important group of innate receptors discovered to date: Toll-like receptors (TLR), which detect
microbial products. Signals initiated in the TLRs of macrophages stimulate phagocytic activity and the
production of chemical agents that are toxic to the phagocytosed microorganisms. Activated
macrophages also secrete a class of molecules known as cytosines, which modify the behavior and
physiology of cells and tissues that are targets of attack. For example, activated macrophages
secrete IL-1, IL-6 and TNF that promote inflammation.

Inflammation
Inflammation combats the early phases of an infection and sets in motion processes that lead to the
repair of damaged tissue. There is vasodilation, edema and extravasation of leukocytes that release
chemicals that act as chemoattractants. However, not all chemoattractants are chemokines.
 The binding of chemokines
or other chemoattractants
to receptors on the
membrane of neutrophilic
cells triggers an activating
signal that induces a
conformational change in a
neutrophil membrane
molecule called integrin,
which increases its affinity
for intercellular adhesion
molecules (ICAM) present.
in the endothelium. An
important function of cells
attracted to the inflamed
site is phagocytosis of
invading microorganisms.

Neutrophil extravasation
can be divided into four
steps: a) rolling, b) activation by chemoattractant stimulus, c) arrest and adhesion and d)
transendothelial migration.

Soluble molecules and membrane-related

receptors
These include antimicrobial peptides such
as defensins and cathelicidins as well as
interferons, an important group of
cytokines with antiviral action.

Innate immunity uses

various receptors to
detect infection
Macrophages, Toll-like
receptors, MBL, C-
reactive protein,
neutrophils, dendritic
cells, lipopolysaccharide
binding protein (LBP),
NOD proteins (nucleotide
oligomerization and
binding domain, recognize
products derived from
bacterial peptidoglycans).
Cell types of innate
immunity
NK cells
Natural killer (NK) cells are a first line of defense against many different viral infections. They detect
and destroy infected cells. NK cell-mediated lysis effectively eliminates the infection or keeps it under
control for days, until the adaptive immune system attacks the infection with cytotoxic T lymphocytes
and virus-specific antibodies. However, some viral infections are probably completely eliminated by
innate mechanisms such as NK cells. Activated natural killer cells are also potent producers of
various cytokines that regulate other cells of the immune system, thereby shaping and modifying
defenses against the pathogen. It is notable that NK cells produce interferon γ and TNF-α. Both can
stimulate the maturation of dendritic cells, the key coordinators of innate and adaptive immunity.
Interferon γ is also a potent mediator of macrophage activation and an important regulator of TH cell
development, establishing a direct link between NK cells and the adaptive system.

dendritic cells
They interact with both TH cells and TC cells. Mature dendritic cells are capable of activating both
types of lymphocytes because they have the capacity to present exogenous antigens at both MHC I
and MHC II and send intense costimulatory signals to T cells. These versatile cells also mount direct
attacks against the pathogens they detect. Some produce IL-12 which has to do with the activation of
T cells.
Chapter 4
Antigens and antibodies.

The molecules of the adaptive immune system are the antibody and the T cell receptor. Antibody and
T cell receptor molecules exhibit a higher degree of specificity, recognizing antigenic determinants or
specific epitopes. Secreted antibodies circulate in the blood, where they act as effectors of humoral
immunity by seeking out antigens and marking them for elimination. Antigens are specifically defined
as molecules that interact with the B cell immunoglobulin receptor (or the T cell receptor when
complexed with MHC). Immunogenicity is the ability to induce a humoral or cell-mediated immune
response. Antigenicity is the ability to specifically combine with the end products of previous
responses (i.e., secreted antibodies, surface receptors on T cells). Haptens are antigenic but
incapable of inducing a specific immune reaction by themselves. Immunogenicity depends in part on
four properties of the immunogen: alterity, molecular size, chemical composition and complexity, and
ability to be processed and presented with an MHC molecule on the surface of an antigen-presenting
cell or an altered self-cell.

Adjuvants
Adjuvants are substances that, when mixed and injected with an antigen, increase the
immunogenicity of said antigen. Adjuvants are frequently used to boost the immune reaction when an
antigen has low immunogenicity or only small amounts of it are available. In general, adjuvants
appear to exert one or more of the following effects:
■ Prolongation of antigen persistence
■ Intensification of costimulatory signals
■ Increased local inflammation
■ Stimulation of nonspecific proliferation of lymphocytes

This infiltration of cells at the site of injection of the adjuvant results in the formation of a mass of
cells, dense and rich in macrophages, called granuloma.

Epitopes
They are those specific places that interact with immune cells, therefore, an antigenic molecule can
have several epitopes.

Antibodies are heterodimers

Antibody molecules have a common structure of four peptide chains, two light and two heavy. The
variable region – light chains and the constant region – heavy chains.
Antibody-mediated effector functions
 Antibody promotes opsonization
Opsonization, which is the promotion of phagocytosis of antigens by macrophages and
neutrophils, is an important factor in antibacterial defenses. On the surfaces of macrophages
and neutrophils, as well as other cells that are not involved in phagocytosis, are protein
molecules called Fc receptors (FcR), which can bind the constant region of immunoglobulin
(Ig) molecules.
 Antibodies activate complement
IgM and IgG can activate the complement system.
 Antibody-dependent cell-mediated cytotoxicity (ADCC) destroys other cells
The antibody acts as a newly acquired receptor that allows the attacking cell to recognize and
destroy the target cell.
 Some antibodies can cross epithelial layers by transcytosis
IgA is the main antibody species that carries out this transcytosis, although IgM can also be
transported to mucosal surfaces. They also transfer considerable amounts of IgG from the
mother to the fetus. The antibody must be transported through the placental tissue that
separates the mother and fetus. It occurs in the third trimester. It is a passive immunization.

Antibody classes and biological activities

Immunoglobulin G (IgG)
IgG, the most abundant class in serum, constitutes about 80% of total serum
immunoglobulins.
■ IgG1, IgG3 and IgG4 easily cross the placenta and play an important role in
protecting the developing fetus.
■ IgG3 is the most effective complement activator, followed by IgG1; IgG2 is
less efficient and IgG4 is not able to activate complement at all.
■ IgG1 and IgG3 bind with high affinity
to Fc receptors on phagocytic cells and
therefore mediate opsonization. IgG4
has intermediate affinity for Fc
receptors, and IgG2 has extremely low
affinity.

Immunoglobulin M (IgM)
IgM represents 5 to 10% of total serum immunoglobulin.
Monomeric IgM is expressed as an antibody bound to B cells.
Plasma cells secrete pentameric IgM. IgM is the first class of
immunoglobulin that is produced in a primary response to
antigen and is also the first immunoglobulin synthesized by the
newborn. IgM is also more efficient than IgG at activating
complement.