Hypersensitivity diseases:
disorders caused by immune responses
Hypersensitivity
Hypersensitivity
is a term
that is used to identify situations in which some type of substance or
medication triggers an unusually strong and adverse reaction
from the immune
system. In some instances, hypersensitivity reactions can be extremely
uncomfortable, cause permanent damage or even result in death. There are four
commonly accepted types of this condition, with variations of these four
supported by different schools of medical thought.
Allergies are normally classified as Type 1 hypersensitivity. These involve allergic reactions that
produce an almost immediate effect. The individual may begin to have difficulty
breathing, experiencing what amounts to an asthma attack. In more
extreme situations, anaphylaxis
may occur. An antibody-dependent
or cytotoxic reaction defines define Type 2 situations. Within this category,
the hypersensitive reaction manifests with the development of particular
conditions such as Goodpasture’s Syndrome, Myasthenia Gravi or Graves disease.
A Type 2 hypersensitivity type has more long
range implications. Type 3 hypersensitivity is
classified as an immune complex disease. Within this category, conditions such
as Arthus reaction or Serum sickness
occur. Along with Type 2, patients diagnosed with Type 3 often require ongoing
monitoring in order to keep the triggered condition under control. DTH or
delayed type hypersensitivity is known as Type 4.
Within this category, patients may develop various dermatological issues that
are extremely uncomfortable, experience fluctuation in T-cell levels and
possibly develop conditions such as multiple sclerosis. As with other hypersensitivity types, it is important to identify the
substance or medication causing the hypersensitive reaction and prevent any
further ingestion of that substance.
One of the best ways to get an idea of how painful hypersensitivity can be is to consider the momentary
sharp pain that is often experienced when extremely cold beverages come in
contact with a tooth filling. The sudden and intense wave of pain created can
often seem unbearable for a brief moment before leveling off. For people with
hypersensitive reactions to medicine, food or some factor in their environment,
that level of pain does not subside within a moment but can last for an
extended period of time.
Physicians can often identify what is causing the severe
reaction and help the patient learn to avoid the irritant1. This may involve changes of prescription medication,
avoiding certain spices, herbs or foods or altering some aspect of the home or
work environment. While hypersensitivity can be
extremely debilitating and even fatal, it can be managed in most cases.
Immunity
Immunity is a biological term that describes
a state of having sufficient biological defenses to avoid infection, disease or other
unwanted biological invasion. Immunity involves both specific and non-specific
components. The non-specific components act either as barriers or as eliminators
of wide range of pathogens irrespective of antigenic specificity. Other
components of the immune system adapt themselves to each new disease
encountered and are able to generate pathogen-specific immunity.
Innate
immunity or nonspecific immunity is the natural resistance with which a person is born. It
provides resistance through several physical, chemical and cellular approaches.
Microbes first encounter the epithelial layers, physical barriers that line our
skin and mucous membranes. Subsequent general defenses include secreted
chemical signals (cytokines), antimicrobial substances, fever and phagocytic
activity associated with the inflammatory response. The phagocytes express cell
surface receptors that can bind and respond to common molecular patterns
expressed on the surface of invading microbes. Through these approaches, innate
immunity can prevent the colonization, entry and spread of microbes.
Adaptive immunity is often sub-divided
into two major types depending on how the immunity was introduced. Naturally acquired immunity occurs
through contact with a disease causing agent, when the contact was not
deliberate, whereas artificially
acquired immunity develops only through deliberate actions such as
vaccination. Both naturally and artificially acquired immunity can be further
subdivided depending on whether immunity is induced in the host or passively
transferred from an immune host. Passive
immunity is acquired through transfer of antibodies or activated T-cells
from an immune host and is short lived usually lasting only a few months,
whereas active immunity is
induced in the host itself by antigen and lasts much longer, sometimes
life-long. The diagram below summarizes these divisions of immunity-
Figure 1: Divisions of Immunity
A further subdivision of adaptive immunity is characterized
by the cells involved, humoral immunity is the aspect of immunity that is
mediated by secreted antibodies, whereas the protection provided by cell mediated immunity involves
T-lymphocytes alone2.
Humoral immunity is active when the organism generates its own antibodies and
passive when antibodies are transferred between individuals. Similarly, cell
mediated immunity is active when the organisms’ own T-cells are stimulated and
passive when T cells come from another organism.
The
immune system is a network of cells, tissues and organs that work together to
defend the body against attacks by “foreign” invaders. These are primarily microbes—tiny
organisms such as bacteria, parasites and fungi that can cause infections.
Viruses also cause infections but are too primitive to be classified as living
organisms. The human body provides an ideal environment for many microbes. It
is the immune system’s job to keep them out or failing that, to seek out and
destroy them. When the immune system hits the wrong target however, it can
unleash a torrent of disorders, including allergic diseases, arthritis and a
form of diabetes. If the immune system is crippled, other kinds of diseases
result.
The
immune system is amazingly complex. It can recognize and remember millions of
different enemies and it can produce secretions (release of fluids) and cells
to match up with and wipe out nearly all of them. The secret to its success is
an elaborate and dynamic communications network. Millions and millions of
cells, organized into sets and subsets, gather like clouds of bees swarming
around a hive and pass information back and forth in response to an infection.
Once immune cells receive the alarm, they become activated and begin to produce
powerful chemicals. These substances allow the cells to regulate their own
growth and behavior, enlist other immune cells and direct the new recruits to
trouble spots.
Although
scientists have learned much about the immune system, they continue to study
how the body launches attacks that destroy invading microbes, infected cells
and tumors while ignoring healthy tissues. New technologies for identifying
individual immune cells are now allowing scientists to determine quickly which
targets are triggering an immune response. Improvements in microscopy are
permitting the first-ever observations of living B cells, T cells and other
cells as they interact within lymph nodes and other body tissues. In addition,
scientists are rapidly unraveling the genetic blueprints that direct the human
immune response as well as those that dictate the biology of bacteria, viruses
and parasites. The combination of new technology and expanded genetic
information will no doubt reveal even more about how the body protects itself
from disease3.
The
Organs of the Immune System
Bone Marrow
All the cells of the immune
system are initially derived from the bone marrow. They form through a process
called hematopoiesis. During hematopoiesis, bone marrow-derived stem cells
differentiate into either mature cells of the immune system or into precursors
of cells that migrate out of the bone marrow to continue their maturation
elsewhere4. The bone
marrow produces B cells, natural killer cells, granulocytes and immature
thymocytes.
Thymus
The function of the thymus is to
produce mature T cells5.
Immature thymocytes, also known as prothymocytes, leave the bone marrow and
migrate into the thymus. Through a remarkable maturation process sometimes
referred to as thymic education, T cells that are beneficial to the immune
system are spared, while those T cells that might evoke a detrimental
autoimmune response are eliminated. The mature T cells are then released.
Spleen
The spleen is an immunologic filter of the blood. It is made
up of B cells, T cells, macrophages, dendritic cells, natural killer cells and
red blood cells. In addition to capturing foreign materials (antigens) from the
blood that passes through the spleen, migratory macrophages and dendritic cells
bring antigens to the spleen via the bloodstream6. An immune response is initiated when the macrophage
or dendritic cells present the antigen to the appropriate B or T cells. This organ
can be thought of as an immunological conference center. In the spleen, B cells
become activated and produce large amounts of antibody. Also, old red blood
cells are destroyed in the spleen7.
The lymph nodes function as an
immunologic filter for the bodily fluid known as lymph. Lymph nodes are found
throughout the body. Composed mostly of T cells, B cells, dendritic cells and
macrophages, the nodes drain fluid from most of our tissues8. Antigens are filtered out of the lymph in the lymph
node before returning the lymph to the circulation. In a similar fashion as the
spleen, the macrophages and dendritic cells that capture antigens present these
foreign materials to T and B cells, consequently initiating an immune response9.
Figure 3: Organs of
the Immune System
An immune response to foreign antigen requires the presence
of an antigen-presenting cell (APC), (usually either a macrophage or dendritic
cell) in combination with a B cell or T cell. When an APC presents an antigen
on its cell surface to a B cell, the B cell is signalled to proliferate and
produce antibodies that specifically bind to that antigen. If the antibodies
bind to antigens on bacteria or parasites it acts as a signal for macrophages
to engulf (phagocytose) and kill them. Another important function of antibodies
is to initiate the “complement destruction cascade.” When antibodies
bind to cells or bacteria, serum proteins called complement bind to the immobilized
antibodies and destroy the bacteria by creating holes in them. Antibodies can
also signal natural killer cells and macrophages.
If the APC presents the antigen to T cells, the T cells
become activated. Activated T cells proliferate and become secretory in the
case of CD4+ T cells or if they are CD8+ T cells, they become activated to kill
target cells that specifically express the antigen presented by the APC. The
production of antibodies and the activity of CD8+ killer T cells are highly
regulated by the CD4+ helper T cell subset. The CD4+ T cells provide growth
factors or signals to these cells that signal them to proliferate and function
more efficiently. This multitude of interleukins or cytokines that are produced
and secreted by CD4+ T cells are often crucial to ensure the activation of
natural killer cells, macrophages, CD8+ T cells and macrophages.
Figure
4: Immune Response to Self or
Foreign Antigens
Cells of the Immune System
are involved in both in vivo and in vitro immune
responses and have certain functional properties. In the process of
Phagocytosis, macrophages function as effector cells as they recognize engulf
and destroy foreign (antigenic) substances. Macrophages are accessory cells in
the immune response. They are the major antigen-presenting cells of the body
that interact with antigen as a primary step in the induction of an immune
response. B cells can also present antigen10.
Antigen
presentation involved:
1. Binding and uptake of antigen by
the macrophage surface membrane, which creates a tightly bound antigen that is
more immunogenic than free antigen.
2. Processing and later
re-expression of antigen on the antigen-presenting cell surface in association
with MHC (class II)-encoded glycoproteins.
3. Release of soluble mediators,
such as the monokine (macrophage-derived hormone) which stimulate the
maturation and proliferation of T cells (the result of this sequence of events
is the activation of antigen-specific B cells and T cells).
Lymphocytes
are both precursor cells of immunologic function as well as regulators and
effectors of immunity. Smaller lymphocytes (T cells) have a long life span of
months or years, whereas larger lymphocytes (B cells) have a shorter life span
of 5 to 7 days. A general method for detection and quantitation of T cells and
B cells depends on the differential reactivity of the two cell types with
appropriately prepared red blood cells.
These two
types of cells are:
1.T cells accumulate sheep red blood cells (SRBCs) around their surfaces
and form clusters referred to as erythrocyte (E) rosettes.
2.There is no such reaction between B cells and SRBCs, unless the red blood
cells (indicated as E for erythrocytes) are coated with hemolysin-antibody (A)
and special nonhemolytic preparations of guinea pig complement (C), thus called
EAC rosettes.
Surface markers:
CD1, CD3
and CD11 are found on most peripheral blood T cells. CD3 is associated with,
but distinct from the T-cell receptor for antigen; CD11, with the SRBC rosette
receptor. CD4 is present on T helper cells, effector cells for delayed
hypersensitivity and CD2 cell inducers. CD8 is present on cytotoxic and T
suppressor cells. CD10 is present on stem cells, some B cells and activated
peripheral blood T cells.
Subpopulations:
1.Effector T (Te) cell also called TDTH cells are the peripheral
lymphocytic cells responsible for delayed type hypersensitivity (DTH)
reactions.
2.Cytotoxic T (Tc or CTL) cells are induced artificially by immunization
with allogeneic tissue and naturally by tumors and virus. To be induced to the
killer function, the precursor cells must be stimulated by antigen in
association with class II MHC molecules.
3.Memory T (Tm) cells are induced during primary immunization; they
recognize the specific antigen and participate in the anamnestic response.
4.Helper T (Th) cells are lymphocytes that recognize a specific antigen in
association with a homologous class II MHC molecule and collaborate with B
cells and macrophages in the induction of the humoral immune response. Similar
cells collaborate with other T cells to facilitate the production of Te cells.
5.Suppressor T (Ts) cells are lymphocytes that recognize a specific antigen
and interfere with the development of an immune response either directly or via
suppressor factors. These cells may be involved in the prevention of
Autoimmunity. Ts cell precursors are activated by antigens in association with
a particular type of class II MHC molecule
Subpopulations:
B cells
are divided into subpopulations according to the immunoglobulin class they
synthesize: D, M, G, A, and E B-cells respectively.
Surface markers:
Surface
immunoglobulin binds specific antigens and functions as an antigen recognition
site that initiates the differentiation of the B cell, resulting in antibody
synthesis. Contact between the antigen epitope and the immunoglobulin in the
B-cell membrane triggers cell division. As this process continues, the B cell
matures into a plasma cell with abundant rough endoplasmic reticulum, actively
secreting large amounts of the antibody specifically reactive with its
homologous epitope.