Introduction to Immunology
The challenge of infection and the constitution of the immune system
 Infections are a major cause of morbidity and mortality worldwide.

The body fights infection through the functions of its immune system, whose
power has been harnessed by the development of vaccination (immunisation).
A major success of vaccination has been the worldwide eradication of
smallpox.

There are many types of infective agents. Within the main categories of
viruses, bacteria, fungi, protozoa and parasitic worms there are many
different species each of which poses a different threat to the body.
Furthermore, the differences in nature, mode of entry into the body, and
mechanisms of replication and spread in the body of different infective agents
mean that a range of defensive mechanisms is necessary. Thus, a variety of
cellular and molecular components constitute the immune system.

The cellular constituents of the immune system include the white blood cells
(leucocytes), as well as cells in specialised tissues and cells scattered
throughout most tissues of the body. They can be categorised according to
their developmental origin from stem cells in the bone marrow (myeloid and
lymphoid), or their morphology (the polymorphonuclear leucocytes known as
granulocytes, and mononuclear cells).

There are a large number of secreted molecular mediators of immunity.
Some have anti-microbial activities, whereas others have regulatory or
inflammatory effects.

The constituents of the immune system are spread throughout the body. This
is particularly illustrated by the lymphocytes. They are produced and develop
in the primary lymphoid organs (bone marrow and thymus) and then
recirculate around the body in the blood. They congregate in specialised
lymphoid tissues that include the spleen, lymph nodes and mucosa-associated
lymphoid tissues (MALT).

Lymphocytes enter the spleen from the blood and then return directly to the
blood stream. Most lymphocytes that enter lymph nodes do so directly from
the blood, but some diffuse into other tissues and drain to lymph nodes via
the afferent lymphatics. Lymphocytes return to the blood stream from lymph
nodes via the efferent lymphatics, with most entering the blood at the
thoracic duct.
The nature of immunity
 The major functions of the immune system are the recognition of infective
agents by interacting with microbes and their components, and defence of the
body by the elimination of microbes and their components.

Immune recognition and defence are achieved in two ways: by components of
the immune system that generate innate immunity, and others that generate
adaptive immunity.

The main features of innate immunity are that it is quickly activated when
infection occurs; it remains the same on repeated exposure to the same
microbe and is moderately efficient. Innate immunity provides a general
response to categories of microbes (eg. viruses or bacteria), and is triggered
by the recognition of chemical structures that are characteristic of microbes –
these are often termed pathogen-associated molecular patterns (PAMPs), eg.
bacterial lipopolysaccharide and viral double-stranded RNA. These PAMPs
interact with pattern recognition receptors expressed on cell surfaces (eg.
toll-like receptors).

The main features of adaptive (also known as acquired) immunity are that it
is more slowly activated than innate immunity, but its efficacy improves upon
repeated exposure to the same microbe. Once activated, adaptive immunity
is highly efficient and provides specific responses tailored to each individual
type of microbe. This is because adaptive immunity involves recognition of
antigens specific to each type of microbe that are recognised by antigenreceptors that are clonally expressed by lymphocytes. Thus, lymphocytes are
the cell type responsible for the properties of adaptive immunity.

The first infection by a particular microbe generates a primary immune
response. This normally requires microbes to penetrate surface epithelial
barriers of the body, eg. the epidermis of the skin. An immediate local innate
response in the infected tissues is generated by components of the immune
system resident in those tissues (eg. macrophages and complement
proteins). This also generates inflammatory mediators (augmented by the
activation of mast cells) that attract further leucocytes and serum proteins
into the infected tissues from the blood stream.

While the above innate response is being generated, antigens are carried
from the site of infection to nearby lymphoid tissues (eg. lymph nodes) in
order to generate an adaptive immune response. Some antigens are carried
free in the lymph, and some are captured by specialised cells, present in most
tissues of the body, called dendritic cells: these migrate to the lymphoid
tissues carrying the antigens with them. In the lymphoid tissues the antigens
activate lymphocytes that specifically recognise them (which will be only a
few of all the lymphocytes in these tissues). The specifically activated
lymphocytes and antibodies (produced by the B lymphocytes) can then
recirculate back to the site of infection.

If re-infection with the same type of microbe occurs soon after the response
above, then pre-formed antibodies and effector lymphocytes will be available
immediately. A later re-infection will generate a secondary immune response
by memory lymphocytes formed during the primary response: these give a
faster and bigger response than occurred in the primary response, hence the
term adaptive immunity.

Different types of defensive strategy are required to deal with microbes that
occupy different tissue compartments when they infect the body. Microbes
that remain outside cells (extra-cellular) are available for being coated
(opsonised) by antibodies and complement proteins, and can be engulfed and
digested by phagocytes. Some microbes that have been phagocytosed by
macrophages are resistant to digestion and can survive and replicate in intracellular vesicles, in which case the macrophages require activation signals
from helper T lymphocytes to increase their digestive capacity. Other
microbes deliberately infect cells: this applies to all viruses that use the
metabolic machinery of the cells they infect to bring about their replication.
Interferon proteins can block the replication of viruses in infected cells, and
killer cells (natural killer cells and cytotoxic T cells) kill infected cells thereby
preventing replication of the intra-cellular microbes.
Immunopathology
 Refers to those diseases in which the immune system is involved in the
pathophysiology. This may involve defects in, or inappropriate activity of, the
immune system.

Immunodeficiency disorders are those in which particular components of the
immune system are missing or defective. Primary immunodeficiencies are
genetic disorders, eg. severe combined immunodeficiency, in which
lymphocytes are not produced. Secondary immunodeficiencies are acquired
during life, eg. acquired immunodeficiency syndrome (AIDS) due to infection
with human immunodeficiency virus (HIV) that infects and kills helper T
lymphocytes.

Allergies are due to inappropriate adaptive immunity against non-infective
environmental materials (termed allergens) that leads to inflammatory tissue
damage. Examples include allergic rhinitis (eg. hayfever caused by plant
pollens), asthma (that may be caused by house dust mite proteins), and
eczema. Anaphylaxis is a very dangerous systemic form of allergic response.
All the above are examples of atopic allergies: a different type of allergic
response is seen in contact dermatitis (eg. nickel allergy). Allergies affect up
to 30% of the UK population.

In autoimmune diseases, adaptive immunity is generated directly against
certain of the body’s own components (referred to as autoantigens).
Examples include autoimmune thyroiditis, rheumatoid arthritis and systemic
lupus erythematosus (SLE). About 5% of the UK population are affected by
autoimmune diseases.

The rejection of transplanted tissue grafts is a man-made form of
immunological tissue damage caused by antigenic differences in tissue
components between donor and recipient that generate an adaptive anti-graft
immune response by the recipient.

Lymphoproliferative diseases occur when there is malignant transformation of
cells of the immune system: they include lymphomas, leukaemias and
myelomas.
Recommended reading:
Todd I, Spickett G (2005) Lecture Notes: Immunology. 5th edition. Blackwell
Publishing. Chapter 1. OR
Todd I, Spickett G (April 2010) Lecture Notes: Immunology. 6th edition.
Wiley/Blackwell. Chapter 1.