Introduction

The immune system is composed of cells, tissues and
molecules that fight against the foreign pathogens. It is divided into innate
(non-specific) immune system, which is composed of epithelial barriers,
phagocytic cells, plasma proteins (complements, cytokines); it is the first
line of defense and adaptive (specific) immune system, which is composed of T
and B lymphocytes; it is the second line of defense. If the innate immunity
fails, the adaptive immunity comes into action to fight against the invading
pathogen.

Entry
of pathogen

Bacteria, virus, fungi, parasites are the main
pathogens invading the body. These pathogens encounter epithelial barriers in
different sites. Some enter through skin, respiratory tract like streptococcal
bacteria, gastrointestinal mucosa, urinary tract and conjunctival epithelium.
Most of the cases, pathogens enter through traumatic areas.

Recognition
of pathogen by phagocytes

Once the pathogen enter, the immune system express
several types of cell surface and soluble proteins (cytokines) that quickly
recognize the pathogen-associated molecular patterns (PAMPs), which are foreign structures that characterize the groups
of pathogens. For example, lipopolysaccharides of gram-negative bacteria.
Phagocytes (neutrophils, macrophages and dendritic cells) naturally express a
variety of receptors (scavenger, mannose, complement, toll like and fc
receptors); collectively referred to pattern recognition receptors (PRRs) that recognize
pathogen-associated molecular patterns (PAMPs) specifically.

Phagocytosis
and killing of a pathogen

Soluble pattern recognition receptors and effector
molecules of the innate immune system, including complements and lectins
opsonize the pathogen by binding the pathogen and phagocytes express receptors
for these opsonins. Once a pathogen binds to receptors on phagocyte, the plasma
membrane of the binding site redistributes and engulfs the pathogen. The formed
vesicle around the pathogen pinches off. This vesicle referred to as phagosome.
The cell surface receptors also deliver signals that stimulate the microbicidal
activities of phagocytes.

Phagosome fuses with lysosomes to form a
phagolysosome. Activated neutrophils and macrophages produce proteolytic enzymes
(elastase and cathepsin G) that destroy microbes. Activated phagocytes convert
molecular oxygen into reactive oxygen species (ROS), which are highly oxidizing agents that destroy microbes.
Phagocyte oxidase system is the primary free generating system, stimulated and
activated by INF-y and signals from TLRs. Phagocyte oxidase reduce molecular
oxygen into superoxide radicals. Superoxide is converted into hydrogen peroxide,
used by myeloperoxidase enzyme to convert unreactive halide ions into reactive
hypohalous acids that are toxic to bacteria.

In addition to ROS, macrophages produce reactive
nitric oxide (NO), by the action of
inducible nitric oxide synthase (iNOS). NO combine with hydrogen peroxide or
superoxide to produce highly reactive peroxynitrite radicals that kill
microbes.

Induction
of inflammation

Macrophages release cytokines and chemokines in
response to bacterial constituents to initiate inflammation. Inflammation is referred
to swelling, color, rubor and dolor of which reflect the effects of cytokines
and chemokines on the local blood vessels. The blood vessels dilate and become
permeable, leading to increased local blood flow and the leakage of fluids into
surrounding tissues. Adhesion of cytokines and complement fragments on
endothelium, attracting leukocytes to attach to endothelial cells of the blood
vessel wall and migrate to the site of infection by the action of chemokines.
The migration of cells into the tissue and their actions causing pain.
Neutrophils and macrophages are the main inflammatory cells. Lymphocytes also
involve in inflammatory response.

Attraction
of cells to the site of infection

Neutrophils and monocytes are attracted to the site of
infection by sticking to adhesion molecules on endothelial cells by cytokines
and chemokines produced in response to infection. Their attraction occurs
through the following steps:

1.      Selectin-mediated
rolling of leukocytes on endothelium: In response to cytokines, (TNF, IL-1),
endothelial cells at the site infection quickly increase surface expression of
selectins proteins (P-selectin, E-selectin).Selectin mediate the attachment of
T cells and neutrophils to endothelial venules at the site of inflammation.
Leukocyte detach and bind again thus roll along the endothelial surface.

2.      Chemokine-mediated
increase in affinity of integrin: Chemokines stick to specific receptor on the
surface of the rolling leukocytes. Leukocytes express integrins adhesion
molecules. Chemokines increase the affinity of leukocyte integrins for their
ligands, and increase the avidity of integrin-mediated attachment of leukocytes
to the endothelial surface.

3.     
Stable integrin-mediated adhesion of
leukocytes to endothelium: TNF and IL-1 enhance endothelial expression of
integrin ligands (VCM-1, the ligand for VLA-4 and ICAM-1, the ligand for LFA-1
and Mac-1 integrins), resulting in the attachment of leukocytes tightly to
endothelium.

4.     
Migration of leukocytes through the
endothelium: Chemokines act on the leukocytes attached to the endothelium to
migrate through the spaces between endothelium along the chemical concentration
gradient, toward the site of infection. The leukocytes produce the enzymes that
enable them to pass the vessel wall, and then accumulate in the extravascular
tissue around invading pathogens.

Pathogen
elimination and/ or adaptive immunity activation

Normally, phagocytes ingest and kill microbes. If
microbes develop the mechanisms that enable them to survive inside the
phagocytes, the innate immunity is incapable to eliminate the microbes. T cells
recognize protein antigens of intracellular pathogens as peptides bound to
major histocompatibility complex (MHC) molecules. These molecules are class II
MHC-associated antigen of phagocytized microbe, mediating the effect of CD4+
Th1 cells. Th1 cells produce cytokines (IFN-y) that activate the phagocytes to
kill the pathogens. Activated macrophages remove dead tissues and induce the
repairing of tissue by secreting growth factors that stimulate the
proliferation of fibroblast, transforming growth factor-? (TGF-?) and the
formation of new blood vessel.

CTLs killer cells recognize class I MHC-associated
peptide antigen residing in the cytoplasm of phagocytes. CTLs bind and react to
the target cell through coreceptor (CD8) and leukocyte function-associated-1
(LFA-1) integrin. CTL-target cell contact results quickly in the formation of
an immunological synapse. This immunological synapse generate the signal that
activate the CTL killer cell. Once CD8+ T cells have differentiated
into functional CTLs, they release cytotoxic proteins to the target cell,
thereby inducing apoptosis of infected cell.