Download Hypersensitivity (allergy).

Dental Microbiology #211
IMMUNOLOGY
Lecture 6
Thursday September 29, 2005
Adverse Immune responses and Immune deficiencies.
Not all immune responses are beneficial. The immune system can react to foreign
antigens in a way that is deleterious to the host, thus leading to allergies or
hypersensitivity states, or can even mistakenly recognize self antigens as foreign and
give rise to autoimmune diseases.
Hypersensitivity (allergy).
Definition:
Altered capacity of the body to react to a foreign substance
The hypersensitivity states or allergies can be divided into four categories:
Type I (IgE antibody-mediated)
Type II (IgG and IgM-mediated)
Type III (Immune complex-mediated)
Type IV (T cell-mediated)
Type I (IgE-mediated hypersensitivity reactions)
There are certain antigens and routes of Ag exposure that favour IgE Ab production
Antigens that evoke IgE responses are collectively called allergens. The symptomatology
is different depending on whether the Ag is injected, inhaled or ingested i.e. depending
on the target tissue (Fig. 1) .
Over 30% of individuals in the western hemisphere have the tendency to develop
IgE-mediated reactions. They are called atopic individuals The atopic state is influenced
by both genetic and environmental factors. The prevalence of atopic allergy and asthma
increases in economically developed regions due to air pollution. There also seems to be
some connection between exposure to infectious diseases that affect the respiratory tract
and increase in incidence of bronchial asthma.
Despite its low concentration in the plasma (<50 nannograms/ml) IgE (Fig 2) has
a very potent biological effect. The Fc segment of IgE binds with extremely high affinity
to an Fc receptor called FcRI, on the membrane of mast cells and basophils. IgE has a
half life of only two days in the plasma but over 30 days when bound to a basophil or
mast cell surface.
The biologcal effector mechanism of IgE is triggered when mast cell- (or
basophil)- bound IgE molecules are cross-linked by multivalent Ag .The cross-linking
induces membrane modifications resulting in the release to the cell exterior of granules
containing powerful pharmacologic mediators such as histamine, and serotonin. The
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process is called degranulation (Fig.3.). Basophils are circulating polymorphonuclear
leukocytes while mast cells reside in tissues
IgE Ab binds with high affinity to Fcreceptors on mast cell membrane, via its Fc
segment. Specific antigen (allergen) in multivalent form, cross-links two or more IgE
molecules via their Fab portions. This process signals the release of pharmacological
mediators of allergy from intracellular deposits. The process is called degranulation.
Most allergens are relatively small molecular weight soluble proteins carried on
desiccated particles (pollen, dander, dried animal saliva, house mite faeces (Fig 4),
etc) which become released from the particles, and penetrate either the respiratory tract or
the gastro-intestinal mucosa, depending on whether they are air-borne or ingested.
The release of pharmacologic mediators from mast cells and basophils has two
major pathological consequences: contraction of smooth muscles and increase in
capillary vassel permeability. All symptoms of IgE-mediated allergic reactions can
be explained based on these two effects. Release of pharmacologic mediators from mast
cells and basophils has different effects on different tissues: in the gastrointestinal (g.i.)
tract: diarrhoea, and vomiting; in the airways: bronchial constriction, decreased airway
diameter leading to the development of bronchial asthma. Increase in vascular
permeability leading to edema and mucus discharge (hay fever, allergic rhinitis); in
blood vessels: edema and erythema (redness) (Fig. 5 ) (see also Fig. 1).
In the oral cavity a specific condition called Oral Allergy Syndrome appears when an
allergen (from foods or drugs) makes contact with the oral cavity in sensitive patients.
This syndrome is characterized by a rapid swelling of the lips, tongue, gums, palate and
pharynx.
An IgE-mediated allergic reaction is divided into an immediate response
(seconds to minutes) and a late-phase response (8-10 hr). Because of the rapidity of the
reaction, IgE-mediated reactions have also been termed Immediate-type
hypersensitivity reactions.
The intradermal injection of a minute amount of allergen into an allergic (atopic)
individual gives rise to a local reaction called cutaneous anaphylaxis, characterized by
the immediate appearance of a blister containing histamine called a wheal and redness
around it called erythema or flare (Fig.6).
If the allergen is given in higher doses, or reaches the circulation, the sudden
release of large quantities of mediators by the basophils in the circulation, will cause a
generalized or systemic reaction called systemic anaphylaxis or anaphylactic shock.
These reactions can be fatal, such as reactions to insect venoms, to drugs (antibiotics and
sulphonamides) or even to foods which can readily gain access to the general circulation.
Note: anaphylactic shock to local anaesthetics such as lidocaine or novocaine
although rare, have been reported and should be of concern in dental practice.
Treatment
Allergy can be treated: a) by inhibiting IgE production through immune deviation, called
also desensitization therapy or b) by interfering with the release of mediators or with
their pharmacologic effects, such as administration of anti-histamines and topical steroids
such as Fluticasone propionate (Flonase), or of drugs that prevent mast cell/basophil
degranulation such as cromolyn sodium. Epinephrine should be administered
immediately when an anaphylactic shock is suspected.
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Type II hypersensitivity:
IgG antibodies directed against red blood cells activate the complement cascade which in
turn induces hemolysis and a syndrome called autoimmune hemolytic anemia. IgG
antibodies against glomerular basement membrane antigens induce
glomerulonephritis.
Type III hypersensitivity:
Soluble Antigen reacting with soluble Ab in the circulation activate the complement
cascade leading to powerful inflammatory reactions due to the release of anaphylatoxins
(see notes for lecture 4 on Complement). When deposited into the joints, these immune
complexes give rise to arthritis, when deposited in the kidneys they lead to the
development of glomerulonephritis.
Type IV hypersensitivity.
Is due to the activation of Th-1 cells. The prototypic type-IV reaction is demonstrated
after the intradermal administration of a small dose of an antigen recognized mainly by
Ag-specific memory CD4+ Th-1 cells. This results in a local cutaneous reaction called
delayed-type hypersensitivity (DTH). It is called “delayed” because, unlike the IgEmediated reactions, DTH reactions take 12-24 hr to appear. The aspect of the lesion is
also different from the wheal and flare reaction. Typical examples of DTH reactions are
cutaneous reactions to tuberculin in individuals that were in previous contact with
tubercle bacilli (Mycobacterium tuberculosis),(see also notes for lecture 5) and reactions
to poison ivy (Fig. 7).
Autoimmune diseases.
Chronic inflammatory conditions that arise as a result of either Ab- or T cell-mediated
responses to self-antigens (auto-antigens).
Typical examples:
Juvenile Diabetes: Target tissue: Beta islets of the pancreas
Multiple Sclerosis. Target tissue: CNS white matter (Myelin)
Systemic Lupus Erythematosus (SLE): Target tissue: Kidney, Joints, Leukocytes
Graves disease. Target tissue: Thyroid gland.
Rheumatoid arthritis. Target tissue (joints).
Immune deficiencies.
Occur when one or more components of the immune system is defective. Immune defects
can be inherited or acquired. In each category, immune defects can involve the T cell,
the B cell or both compartments of the immune system.
Inherited defects:
Genetic defects can occur in almost any molecule involved in the immune response.
T cell defects:
DiGeorge syndrome: Failure of the thymus to be formed (thymic aplasia).
Patients suffer from general susceptibility to infections since the absence of T
lymphocytes impacts also on the ability of B cells to synthesize antibodies
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Inherited B cell defects:
X-linked agammaglobulinemia: X-chromosome-linked inability to produce B
lymphocytes, leads to absence of Ig. Patients suffer mainly from infectious diseases with
bacteria and viruses that cannot be cleared by T cell-mediated immune responses alone.
Inherited mixed T and B cell defects: Severe combined immune deficiencies (SCID).
Patients suffer from total susceptibility to infections since no T or B cells are generated.
Defects of innate immunity:
Inherited defects of phagocytic function.
Inherited defects of complement: Loss of specific complement components. Inability to
form the MAC and/or to produce anaphylatoxins.
Acquired immune deficiencies.
Acquired immune deficiency syndrome (AIDS). The immune response becomes
defective as a result of exposure to the Human Immunodeficiency Virus (HIV).
The HIV infects selectively CD4+ T cells and macrophages. The disease is usually lethal
due to loss of CD4+ T cells.
B cell and T cell tumours (myelomas and lymphomas).
The uncontrolled growth either B or T lymphocyte tumours encroaches on the ability of
normal T and B cells to divide and perform their function.
Consequences of immunodeficiencies in dental patients.
Oral problems usually arise in immunocompromized patients. These include:
Increased incidence of infections in the oral cavity, even with organisms that are
usually non-pathogenic such as Candida species (candidiasis) in AIDS patients
Ulcerations in patients undergoing cancer chemotherapy, immune ablation in
preparation for bone marrow transplantation, and in AIDS
Xerostomia
Sialadenitis
Osteomyelitis
Papillary atrophy of the tongue
Herpes virus infections
Periodontal disease
Increased plaque formation.
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