Hypersensitivity (inflammatory) reactions
Six types of hypersensitivity have been described. Types I, II, IImI and
V are mediated by antibody and type IV and VI by cellular mechanisms. In
practice, these reactions may not necessarily occur singly. For example
type II –VI may be involved in producing autoimmune diseases. Type I
reaction (reaginic/anaphylactic/ immediate hypersensitivity) is an
allergic reaction produced within 30 min of exposure to a specific
antigen e.g. house dust,, pollens, animal danders or moulds in certain
genetically predisposed individuals who are said to be atopic. Prausnitz
and Kustner in 1921, showed that the passive transfer of a serum factor
(reagin) from an allergic person to the skin of a normal person could
produce an immediate wheal and flare reaction in the latter in response
to the allergen [25]. The mechanism entails the allergen stimulating
B cells to produce specific IgE, with the aid of T helper cells. This
IgE, which is allergen-specific binds to mast cells via their Fc
receptor . On subsequent exposure, the allergen cross-links the surface
bound IgE on the sensitized mast cell that triggers the mast cell to
degranulate and release inflammatory mediators (histamine,
prostaglandins, slow reacting substance (leukotriene SRS-A)) aimed at
destroying the noxious substance. In Type II reactions ( cytotoxic/
membrane reactions), antibodies (IgG or IgM) are produced against
antigens on the patient’s own cells. These antibodies interacting via
their Fc regions and fixing complement as well as the effector cell can
lead to autoimmune diseases, e.g. autoimmune anaemia. Antibodies can
also ‘block’ a receptor site preventing its normal function e.g.
insulin-resistant diabetes antibodies, or the IgG autoantibodies against
the gastric acid-secretory parietal cells (intrinsic factor antibodies)
found in pernicious anaemia. In Type III reactions ( immune complex
mediated hypersensitivity) there is a hypersensitivity reaction to the
immune complexes when not removed by the reticuloendothelial system but
deposited in the tissues. Complement is activated and results in
inflammatory reactions leading to cellular damage. The soluble complexes
are formed when the antigen is in excess as by injecting large amounts
of heterogenic serum into the circulation causing ‘serum sickness’ or
the precipitation by insoluble complexes when the antibody and antigen
are equivalent or in an excess of antibody causing an ‘arthus reaction’
( a red, oedematous area at site of injection within 4-12h). Complexes
are deposited in the bronchial walls in pulmonary asperigillosis, and in
the vessels in erythema nodosum. Immune complex formation with aself - antigen occurs in the autoimmune disease such as systemic
lupus erythematosus (SLE); Low- grade persistent infection with a weak
antibody response to a microbial antigen occurs with viral hepatitis B
or staphylococcal infective endocarditis and repeated inhalation of an
environmental antigen, e.g. moulds or animal antigen can produce an
extensive allergic alveolitis such as farmer’s lung disease with the
antibodies being IgG. Type IV reactions ( cell- mediated/ delayed
hypersensitivity) reactions) take more than 12 h to develop and can be
produced in several ways. The cell recruitment is initially neutrophil
in nature (within a few hours) and is followed by lymphocytes and
macrophage infiltration (24-48 h). Type IV reactions can be transferred
from one animal to another by certain types of lymphocytes but not by
serum. The reaction is mediated by a) T delayed hypersensitivity cells (
TD ) that have become sensitized to a particular antigen
previously and release lymphokines ( MAF, MIF, Interferon) and
interleukins ( IL-1,-2,-3) ; b) T cytotoxic cells (Tc), which directly
damage infected target cells, e.g. virus- infected cells, allogenic
cells or host cells in graft- versus host disease. Thus, Type IV
reactions are seen in association with viral infections and the
intracellular bacterial infections- tuberculosis, leprosy and
brucellosis and cause severe tissue damage. They are also implicated in
autoimmune diseases such as Hashimoto’s thyroiditis and homograft
rejection. Type V reaction ( stimulating antibody reaction) is an IgG
directed against cell surface antigens that stimulate some cells instead
of killing them. This is seen in the pathogenesis of neonatal
hyperthyroidism as IgG stimulating antibodies directed against thyroid
cells would be capable .of crossing the placenta, or Graves’ disease
(hyperthyroidism) in adults where serum IgG behave like TSH and binds to
the thyroid TSH receptor producing excessive stimulation of thyroid
hormone production. Interestingly, Graves’ disease is associated with
other autoimmune disorders such as pernicious anaemia and myasthenia
gravis ( acetylcholine receptor antibodies at the nicotinic
neuromuscular junction). Interestingly, thymic hyperplasia is found in
70% of myasthenic patients below the age of 40, and a thymic tumour is
found in in 10%. Type VI reaction (antibody-dependent, cell- mediated
cytotoxicity (ADCC) entails killer lymphocytes (K cells) which lyse
target cells coated with antibody. Being activated by antigen-antibody
complexes, the K cells interact with the Fc region of cell-bound
antibody, and destroy the target cells by the release of proteolytic
enzymes. Type VI reactions are also involved in autoimmune diseases,
tumour rejection and defence against helminthic parasites.
Immuno-pharmacology includes the role of anti-inflammatory (e.g.
corticosteroids), immunosuppressive drugs (e.g. corticosteroids,
cyclosporine & tracolimus against T cells) and anti-lymphocytic sera in
dampening these hypersensitivity reactions and the prevention of
transplant/ graft rejection [ 1-4, 26]