Thursday, June 28, 2007

General features of the immune system

Immunity refers to the body’s resistance to invasive
pathogens (viruses, bacteria, fungi, protozoa and multicellular
parasites) or their toxic products, to allergens
(pollen, animal hair, chemicals, etc.) and to unwanted
cells or cell products arising within the body from
cancer or autoimmune diseases. The immune system
comprises (1) cellular defence mechanisms mediated
by several types of leucocytes and (2) humoral defence
mechanisms mediated by soluble proteins, so-called
Background immunology 95
because they are dissolved in the body fl uids rather
than being primarily associated with cells. Any immune
response involves, fi rstly, recognition of the pathogen
or other foreign material and, secondly, elimination
of these invaders. When an immune response occurs
in an exaggerated or inappropriate form, the term
‘hypersensitivity’ is applied. The fundamental concept
underlying the function of the immune system is the
ability to distinguish, at the molecular level, ‘self ’ from
‘non-self ’ (foreign) materials.
All cells of the immune system originate from just
one cell type in the bone marrow of adult mammals,
the haemopoietic stem cell. These pluripotent cells
give rise to two main lineages: (1) the lymphoid lineage
produces lymphocytes and (2) the myeloid lineage
produces mononuclear and polymorphonuclear
phagocytes, megakaryocytes (precursors of platelets)
and mast cells. The precise origin of natural killer cells
and dendritic cells is uncertain, although they do develop
ultimately from haemopoietic stem cells.
With regard to pathogens, the immune response
depends on the site of infection and the nature of the
pathogen. All viruses, some bacteria and some protozoan
parasites replicate inside host cells, whereas
many bacteria and larger parasites replicate in extracellular
spaces and body fl uids. To clear an intracellular
infection, it is necessary to destroy the infected host
cells. Extracellular pathogens are selectively destroyed
and their toxic products neutralized.
Immune responses may be either innate (natural)
or acquired (adaptive). Innate immunity, being genetically
determined, is present from birth and is in
full readiness for an attack by invading pathogens.
The innate defence mechanisms act non-specifi cally
against a wide range of microorganisms and foreign
material and can be mobilized at the site of infection
within hours. The main characteristics and components
of innate immunity occur in the infl ammatory
response. There is no immunological memory; that is,
the response is not dependent upon prior exposure to
a particular infectious agent.
Acquired immunity is not immediately ready to
combat a foreign invader that has never previously
entered the body; it develops over a long period only
after invasion by a novel intruder. However, once an
acquired immune response has occurred, the body acquires
the capacity to recognize and destroy that particular
invader very rapidly the next time it is encountered,
and the individual is now said to be immune to
it. Not only is there an immunological memory, but
the response to the particular invader on subsequent
occasions is much more vigorous and effective than
the response to the fi rst encounter.
It is well documented that a decline in immune function
takes place with advancing age (Walford, 1980).
5.2 Innate immunity
Innate immunity is conferred by the physical barriers
of the skin and mucous membranes and by cellular
and humoral defence mechanisms.
5.2.1 Barriers imposed by the skin and
mucous membranes
Intact skin is a resistant barrier because the outer
horny layer of keratin is impenetrable to most microorganisms.
The skin is further protected by sebaceous
secretions and sweat which contain bactericidal and
fungicidal fatty acids. In the respiratory tract, mucus
containing entrapped particles is constantly being
swept by the action of cilia towards the oropharynx
where it is swallowed. The acidic pH of the stomach
contents destroys most microorganisms.
5.2.2 Cells of the innate immune system
The cell types involved in the innate immune system
include phagocytes, natural killer cells, mast cells and
platelets.
Phagocytes
Phagocytic leucocytes are classifi ed into two main types,
according to the shape of their nuclei. Mononuclear
phagocytes have a simple-shaped nucleus and polymorphonuclear
phagocytes or granulocytes have a bi- or
multi-lobed nucleus. Phagocytes engulf foreign particles
such as bacteria, internalize them and destroy them
in a two-stage process. Firstly, the phagocyte is stimulated
to generate lethal reactive oxidants in a biochemical
process known as the respiratory burst; secondly, the
phagocyte releases a large number of enzymes and other
bioactive molecules from intracellular storage granules
called lysosomes. This release of lysosomal products is
known as degranulation. The lysosomal products are
responsible for digesting the bacteria which have been
killed by the reactive oxidants.
96 Vitamins: their role in the human body
Mononuclear phagocytes
These cell types include macrophages and their precursors,
monocytes. Monocytes circulate in the blood
but in time they migrate to the tissues where they differentiate
into macrophages.
Polymorphonuclear phagocytes
These cell types are subdivided into neutrophils,
basophils and eosinophils on the basis of the affi nity
of their granules for the acidic and basic dyes used in
histology. Neutrophils [commonly referred to in the
literature as PMN (polymorphonuclear leucocytes)]
outnumber by far all other types of phagocyte in
human peripheral blood. Eosinophils are particularly
effective against extracellular parasites. Basophils are
not obviously phagocytic, their main function being
secretion of soluble molecules that mediate infl ammatory
responses.
Macrophages
These cells are able to carry out a remarkable array
of different functions and are an important link
between the innate and acquired immune systems.
In the absence of a stimulus, macrophages remain
relatively quiescent at a particular site and in this
state they are known as resident macrophages. Resident
macrophages line the body cavities and blood
capillaries where they can make early contact with
invading pathogens. They acquire characteristic
morphologies and specialized functions depending
on where they are localized. Examples of resident
macrophages are Kupffer cells (liver), osteoclasts
(bone), microglia (brain), mesangial cells (kidney),
alveolar macrophages (lung) and peritoneal macrophages
(lining the peritoneal cavity). Resident macrophages
possess a variety of cell surface receptors
which allow them to respond to specifi c stimuli very
rapidly. A variety of infl ammatory agents stimulate
the resident macrophages to develop into infl ammatory
macrophages, which express a greater number of
receptors and secrete in copious amounts a variety
of products involved in the infl ammation process.
Among these products are protein components of the
complement system, various coagulation factors and
proteolytic enzymes. Both resident and infl ammatory
macrophages can be stimulated during acquired immune
responses to become activated macrophages,
now with a greatly enhanced ability to destroy certain
pathogens and some types of tumour cells.
Natural killer cells
Found in blood, liver and spleen, these large nonphagocytic
cells kill virally infected host cells and
tumour cells extracellularly by the spontaneous release
of various cytotoxic molecules. Perforins and
cytolysins insert themselves into the plasma membrane
of target cells where they polymerize to form
transmembrane pores. The passage of ions through
these pores disturbs the osmotic equilibrium and
water rapidly enters the cell, causing the cell to swell
and eventually burst. Other molecules enter the target
cell and cause apoptosis by enhanced fragmentation
of its nuclear DNA. Recognition of target cells is
aided by receptors to glycoproteins which appear on
the target cell membrane following viral infection or
oncogenic transformation.
Mast cells
The cytoplasm of these cells is full of membranebound
granules containing a variety of preformed
mediators that produce infl ammation in surrounding
tissues. It is mainly the mast cells that release vasoactive
amines (e.g. histamine and bradykinin) during
acute infl ammation. Mast cells are often situated next
to arterioles, so that the amines can immediately cause
vasodilation when released in response to injury or
infection.
Platelets
These are fragments of megakaryocytes, which pass
from the bone marrow into the bloodstream. Platelets
contribute to the infl ammatory response through the
release of vasoactive amines and various cytokines.
The role of platelets in haemostasis is discussed in
Section 4.4.2.
5.2.3 Phagocytosis
Circulating phagocytes are directed to the site of
infection by chemotaxis and attach to the surface of
the particle to be engulfed. They recognize a particle
as being foreign usually because the particle has been
coated (opsonized) with an opsonin, which binds to
a specifi c receptor on the surface of the phagocyte.
The C3b fragment of the C3 complement protein
is such an opsonin (Section 5.2.6). The edges of the
plasma membrane around the points of attachment
extend outward to engulf the particle, fi nally enclosing
it within a vacuole called the phagosome. The
Background immunology 97
energy required for particle engulfment is derived
from glycolysis (Selvaraj & Sbarra, 1966). Actin and
other contractile fi brils in the cytoplasm surround
the phagosome around its outer edge, pushing it to
the interior. When the phagocyte is activated by any
one of a number of signal molecules, an unusual enzyme,
NADPH oxidase, comes into play. This enzyme,
which is bound to the phagosome membrane and to
the plasma membrane, begins to generate superoxide
– a precursor of several microbicidal oxidants. Almost
simultaneously, the membrane of the phagosome
fuses with the unit membrane of adjacent lysosomes,
the fused membranes rupture, and the lysosomal
contents are discharged into the enlarged vacuole,
now called a phagolysosome. Lysosomal contents also
leak into the extracellular fl uid, with the potential for
damage to local host cells.
The selective discharge of lysosomal enzymes (but
not cytoplasmic enzymes) from human neutrophils
in response to immunological stimuli is regulated by
the opposing actions of intracellular cyclic GMP and
cyclic AMP (Ignarro & George, 1974). Cyclic GMP,
in the presence of calcium, mediates the discharge
of lysosomal enzymes, whereas cyclic AMP inhibits
the discharge. Many cellular functions are similarly
regulated by the opposing effects of these two cyclic
nucleotides. Cellular concentrations of cyclic GMP
and cyclic AMP, and thus cellular functions, can be
infl uenced by hormones and neurotransmitters. For
example, acetylcholine promotes the accumulation
of cyclic GMP and thus enhances lysosomal enzyme
discharge, while adrenaline and histamine promote
the accumulation of cyclic AMP and inhibit enzyme
discharge.

No comments: