1. Compare and contrast hypersensitivity reactions
Introduction
Hypersensitivity reactions are undesirable responses by a normal immune system
that occur in a pre-sensitised individual (i.e. the person must have already been
exposed). There are four main types each with their own characteristics – these are
examined in detail below. Hypersensitivity reactions are closely linked to
autoimmune disease as these can be seen as hypersensitivity to self with loss of
tolerance. Examples of disease caused by each type of hypersensitivity will therefore
be discussed. However, some autoimmune disease are mediated by more than one
type of hypersensitivity reaction
Type 1
Type I hypersensitivity reactions have no known link to autoimmune disease. This
reaction occurs in diseases such as allergic rhinitis and asthma and involves cross-
linking of IgE by an allergen. Allergens are small soluble substances than can cross
mucosal surfaces, such as pollen. IgE comes from plasma cells in locally draining
lymph nodes that secrete the IgE into the blood. Here it binds to mast cells that each
have a different specificity for antibody. If two or more IgE bind to a mast cell and are
subsequently cross-linked by an allergen this causes the mast cell to degranulate. It
then releases mediators such as tryptase and chymase (remodel connective tissue
matrix), heparin and histamine (increase vascular permeability and cause smooth
muscle contraction), IL-4 (recruits Th2 cells), GM-CSF (recruits eosinophils), TNFa
(increases vascular permeability), MIP-1 (acts as chemoattractant) and leukotrienes
(cause smooth muscle contraction and increased vascular permeability). Some of
these mediators are preformed, such as heparin, and others are synthesised de novo,
for example leukotrienes. The end result of this release of mediators is to cause
bronchoconstriction and congestion, expulsion of gastrointestinal tract contents, and
increased vascular permeability resulting in increased lymph flow to lymph nodes.
IL-4 not only induces naïve T cells primed in its presence to become Th2 cells, it also
induces B cell class switching to IgE. IgE also promotes its own binding as when
one IgE has bound to a mast cell it is easier for others to bind. Some individuals have
higher than normal circulating levels of IgE and they are likely to be atopic. Atopy
causes a predisposition to a triad of illnesses – asthma, allergic rhinitis and
eczema. The development of these has also been linked to the hygiene hypothesis,
which states that growing up in a more sterile environment reduces early exposure
(when the immune systems response may be tolerance) to potential allergens and so
increases the chances of atopy (Kremsner et al, 2002).
Type I hypersensitivity reactions usually occur rapidly. Where the allergen enters
directly into the blood stream or is rapidly absorbed, anaphylaxis may result, which
is a life threatening reaction, with severe bronchoconstriction and lymphoedema.
Type II
Type II hypersensitivity reactions are caused by antibody binding directly to cells.
Typical targets are red blood cells (causing haemolytic anaemia) and platelets
(causing autoimmune thrombocytopaenia). The antibody class is IgM, IgG1 or IgG3,
and the antibody coated cells are either phagocytosed or undergo complement
dependent lysis. Type II reactions occur in minutes to hours.

2. Type III
Type III reactions are caused by the deposition of immune complexes, usually
occurring in capillary beds. Autoimmune diseases in which this happens include
SLE (where immune complexes are widely distributed, but particularly in the skin)
and rheumatoid arthritis (where immune complexes are targeted to the joints). The
affinity and size of the immune complex help to determine where it is deposited.
Additionally, the complexes are only formed when there is a similar amount of
antibody and antigen (the antibody is either IgG or IgM). The immune complexes
bind PMN and macrophages, and activate the classical pathway of complement.
In this, antigen antibody complexes lead to the activation of C1, C4 and C2 that act as
a C3 convertase, splitting C3 into C3a and C3b. These then further cleave C5 and
C3a synergises with C5a to recruit neutrophils. C5b forms a membrane attack
complex with C6, 7, 8 and 9 that is responsible for complement mediated lysis. C3b
results in opsonisation. This pathway is regulated by several complement regulatory
proteins such as C1 inhibitor, Factor H and Factor I, which inhibit specific
complement proteins.
An arthrus reaction can occur in which a pre-sensitised individual activates mast
cells leading to the generation of thrombi and tissue necrosis. The type III reaction is
also responsibly for hyper-acute graft rejection, in which the pre-sensitisation is
caused by blood transfusions, a previous graft or multiple pregnancies.
The normal time course of a type II reaction is 3-10 hours.
Type IV
Type IV hypersensitivity is T cell mediated and occurs in diseases such as
rheumatoid arthritis and insulin dependent diabetes. It can be mediated by either
CD4 or CD8 T cells – CD4 T cells secrete IFNg and TNFa, increasing vascular
permeability and leading to a cellular infiltrate, predominantly of leukocytes, but
also macrophages. CD8 T cells are directly cytotoxic and secrete perforin,
granzymes, cathepsins and FasL. Perforin forms an octomer and allows the other
mediators into the target cell. Granzyme A disrupts the mitochondrial membrane
potential causing caspase independent apoptosis, granzyme B activates caspases and
granzyme C works in a similar manner to A. Cathepsin C activates the granzymes
while B protects the T cell from damage. FasL induces caspase dependent apoptosis.
Contact hypersensitivity is a type IV reaction – it has two phases, sensitisation and
effector. The chemical compound binds to an epithelial protein forming a
hapten:peptide complex which is taken up cutaneous antigen presenting cells
leading to the generation of memory cells in the sensitisation stage. In the effector
stage, the memory T cells recognise the complex and they and keratinocytes
together secrete cytokines leading to the characteristic itching, swelling and redness.
Type IV reactions occur over hours to days.
Differences
The time course of each reaction is clearly different, ranging from minutes to days.
Type I is unique as it is the only one not known to be associated with autoimmune

3. disease. Each has a different initiating event leading to the generation of different
cells. As a consequence an individual type of reaction is seen in each
Conclusion
Hypersensitivity reactions are closely linked with autoimmune disease, but also occur
in response to exogenous compounds. Each reaction has a different mechanism but all
result in undesirable immune system activation.