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MICROBIOLOGY AND IMMUNOLOGY MOBILE - IMMUNOLOGY CHAPTER SEVENTEEN
HYPERSENSITIVITY REACTIONS
Hypersensitivity refers to excessive, undesirable (damaging,
discomfort-producing and sometimes fatal) reactions produced by the normal
immune system. Hypersensitivity reactions require a pre-sensitized (immune)
state of the host. Hypersensitivity reactions can be divided into four types:
type I, type II, type III and type IV, based on the mechanisms involved and time
taken for the reaction. Frequently, a particular clinical condition (disease)
may involve more than one type of reaction.
Type I Hypersensitivity
Type I hypersensitivity is also known as immediate or anaphylactic hypersensitivity. The reaction may involve skin (urticaria and eczema), eyes (conjunctivitis), nasopharynx (rhinorrhea, rhinitis), bronchopulmonary tissues (asthma) and gastrointestinal tract (gastroenteritis). The reaction may cause a range of symptoms from minor inconvenience to death. The reaction usually takes 15 - 30 minutes from the time of exposure to the antigen, although sometimes it may have a delayed onset (10 - 12 hours).
Immediate hypersensitivity is mediated by IgE. The primary cellular component
in this hypersensitivity is the mast cell or basophil. The reaction is amplified
and/or modified by platelets, neutrophils and eosinophils. A biopsy of the
reaction site demonstrates mainly mast cells and eosinophils.
The mechanism of reaction involves preferential production of IgE, in response
to certain antigens (allergens). IgE has very high affinity for its receptor on
mast cells and basophils. A subsequent exposure to the same allergen cross links
the cell-bound IgE and triggers the release of various pharmacologically active
substances (figure 1). Cross-linking of IgE Fc-receptor is important in mast
cell triggering. Mast cell degranulation is preceded by increased Ca++ influx,
which is a crucial process; ionophores which increase cytoplasmic Ca++ also
promote degranulation, whereas, agents which deplete cytoplasmic Ca++ suppress
degranulation.
The agents released from mast cells and their effects are listed in Table 1.
Mast cells may be triggered by other stimuli such as exercise, emotional stress,
chemicals (e.g., photographic developing medium, calcium ionophores, codeine,
etc.), anaphylotoxins (e.g., C4a, C3a, C5a, etc.). These reactions, mediated by
agents without IgE-allergen interaction, are not hypersensitivity reactions
although they produce the same symptoms.
Table 1. Pharmacologic Mediators of Immediate Hypersensitivity |
|
MEDIATOR |
|
Preformed mediators in granules |
|
histamine |
bronchoconstriction, mucus secretion, vasodilatation, vascular permeability |
tryptase |
proteolysis |
kininogenase |
kinins and vasodilatation, vascular permeability, edema |
ECF-A |
attract eosinophil and neutrophils
|
Newly formed mediators |
|
leukotriene B4 |
basophil attractant |
leukotriene C4, D4 |
same as histamine but 1000x more potent |
prostaglandins D2 |
edema and pain |
PAF |
platelet aggregation and heparin release: microthrombi |
The reaction is amplified by PAF (platelet activation factor) which causes platelet aggregation and release of histamine, heparin and vasoactive amines. Eosinophil chemotactic factor of anaphylaxis (ECF-A) and neutrophil chemotactic factors attract eosinophils and neutrophils, respectively, which release various hydrolytic enzymes that cause necrosis. Eosinophils may also control the local reaction by releasing arylsulphatase, histaminase, phospholipase-D and prostaglandin-E, although this role of eosinophils is now in question.
Cyclic nucleotides appear to play a significant role in the modulation of immediate hypersensitivity reaction, although their exact function is ill understood. Substances which alter cAMP and cGMP levels significantly alter the allergic symptoms. Thus, substances that increase intracellular cAMP seem to relieve allergic symptoms, particularly broncho-pulmonary ones, and are used therapeutically (Table 2). Conversely, agents which decrease cAMP or stimulate cGMP aggravate these allergic conditions.
Table 2 - Relationship between allergic symptoms and cyclic-nucleotides |
|
Lowering of cyclic-AMP |
elevation of cyclic-AMP |
stimulation of α-adrenergic
receptor or blocking of β-adrenergic
receptor |
stimulation of β-adrenergic
receptor blocking of α-adrenergic
receptor inhibition of
phosphodiesterase binding of histamine-2 or PGE to their receptors |
elevation of cyclic-GMP |
|
stimulation of γ-cholinergic
receptor |
|
WORSENING OF SYMPTOMS |
IMPROVEMENT OF SYMPTOMS |
Diagnostic tests for immediate hypersensitivity include skin
(prick and intradermal) tests (fig. 1A), measurement of total IgE and specific
IgE antibodies against the suspected allergens. Total IgE and specific IgE
antibodies are measured by a modification of enzyme immunoassay (ELISA).
Increased IgE levels are indicative of an atopic condition, although IgE may be
elevated in some non-atopic diseases (e.g., myelomas, helminthic infection,
etc.).
There appears to be a genetic predisposition for atopic diseases and there is
evidence for HLA (A2) association.
Symptomatic treatment is achieved with antihistamines which
block histamine receptors. Chromolyn sodium inhibits mast cell degranulation,
probably, by inhibiting Ca++ influx. Late onset allergic symptoms, particularly
bronchoconstriction which is mediated by leukotrienes, are treated with
leukotriene receptor blockers (Singulair, Accolate) or inhibitors of the
cyclooxygenase pathway (Zileutoin). Symptomatic, although short term, relief
from bronchoconstriction is provided by bronchodilators (inhalants) such as
isoproterenol derivatives (Terbutaline, Albuterol). Thophylline elevates cAMP by
inhibiting cAMP-phosphodiesterase and inhibits intracellular Ca++ release is
also used to relieve bronchopulmonary symptoms.
The use of IgG antibodies against the Fc portions of IgE that binds to mast
cells has been approved for treatment of certain allergies, as it can block mast
cell sensitization.
Hyposensitization (immunotherapy or desensitization) is another
treatment modality which is successful in a number of allergies, particularly to
insect venoms and, to some extent, pollens. The mechanism is not clear, but
there is a correlation between appearance of IgG (blocking) antibodies and
relief from symptoms. Suppressor T cells that specifically inhibit IgE
antibodies may play a role.
Type II Hypersensitivity
Type II hypersensitivity is also known as cytotoxic hypersensitivity and may affect a variety of organs and tissues. The antigens are normally endogenous, although exogenous chemicals (haptens) which can attach to cell membranes can also lead to type II hypersensitivity. Drug-induced hemolytic anemia, granulocytopenia and thrombocytopenia are such examples. The reaction time is minutes to hours. Type II hypersensitivity is primarily mediated by antibodies of the IgM or IgG classes and complement (Figure 2). Phagocytes and K cells may also play a role (ADCC).
The lesion contains antibody, complement and neutrophils. Diagnostic tests
include detection of circulating antibody against the tissues involved and the
presence of antibody and complement in the lesion (biopsy) by
immunofluorescence. The staining pattern is normally smooth and linear, such as
that seen in Goodpasture's nephritis (renal and lung basement membrane) (figure
3A) and pemphigus (skin intercellular protein, desmosome) (figure 3B).
Treatment involves anti-inflammatory and immunosuppressive agents.
Type III Hypersensitivity
Type III hypersensitivity is also known as immune complex hypersensitivity. The reaction may be general (e.g., serum sickness) or may involve individual organs including skin (e.g., systemic lupus erythematosus, Arthus reaction), kidneys (e.g., lupus nephritis), lungs (e.g., aspergillosis), blood vessels (e.g., polyarteritis), joints (e.g., rheumatoid arthritis) or other organs. This reaction may be the pathogenic mechanism of diseases caused by many microorganisms.
The reaction may take 3 - 10 hours after exposure to the antigen (as in Arthus reaction). It is mediated by soluble immune complexes. They are mostly of the IgG class, although IgM may also be involved. The antigen may be exogenous (chronic bacterial, viral or parasitic infections), or endogenous (non-organ specific autoimmunity: e.g., systemic lupus erythematosus, SLE). The antigen is soluble and not attached to the organ involved. Primary components are soluble immune complexes and complement (C3a, 4a and 5a). The damage is caused by platelets and neutrophils (Figure 4). The lesion contains primarily neutrophils and deposits of immune complexes and complement. Macrophages infiltrating in later stages may be involved in the healing process.
The affinity of antibody and size of immune complexes are important in production of disease and determining the tissue involved. Diagnosis involves examination of tissue biopsies for deposits of Ig and complement by immunofluorescence. The immunofluorescent staining in type III hypersensitivity is granular (as opposed to linear in type II such as seen in Goodpasture's syndrome). The presence of immune complexes in serum and depletion in the level of complement are also diagnostic. Polyethylene glycol-mediated turbidity (nephelometry), binding of C1q and Raji cell test are utilized to detect immune complexes. Treatment includes anti-inflammatory agents.
Type IV Hypersensitivity
Type IV hypersensitivity is also known as cell mediated or
delayed type hypersensitivity. The classical example of this hypersensitivity is
tuberculin (Montoux) reaction (figure 5) which peaks 48 hours after the
injection of antigen (PPD or old tuberculin). The lesion is characterized by
induration and erythema.
Table 3 - Delayed hypersensitivity reactions |
||||
Type |
Reaction time |
Clinical appearance |
Histology |
Antigen and site |
contact |
48-72 hr |
eczema |
lymphocytes, followed by macrophages; edema of epidermis |
epidermal ( organic chemicals, poison ivy, heavy metals, etc.) |
tuberculin |
48-72 hr |
local induration |
lymphocytes, monocytes, macrophages |
intradermal (tuberculin, lepromin, etc.) |
granuloma |
21-28 days |
hardening |
macrophages, epitheloid and giant cells, fibrosis |
persistent antigen or foreign body presence (tuberculosis, leprosy, etc.) |
Type IV hypersensitivity is involved in the pathogenesis of many autoimmune and infectious diseases (tuberculosis, leprosy, blastomycosis, histoplasmosis, toxoplasmosis, leishmaniasis, etc.) and granulomas due to infections and foreign antigens. Another form of delayed hypersensitivity is contact dermatitis (poison ivy (figure 6), chemicals, heavy metals, etc.) in which the lesions are more papular. Type IV hypersensitivity can be classified into three categories depending on the time of onset and clinical and histological presentation (Table 3).
Mechanisms of damage in delayed hypersensitivity include T lymphocytes and monocytes and/or macrophages. Cytotoxic T cells (Tc) cause direct damage whereas helper T (TH1) cells secrete cytokines which activate cytotoxic T cells and recruit and activate monocytes and macrophages, which cause the bulk of the damage (figure 4). The delayed hypersensitivity lesions mainly contain monocytes and a few T cells.
Major lymphokines involved in delayed hypersensitivity reaction
include monocyte chemotactic factor, interleukin-2, interferon-gamma, TNF
alpha/beta, etc.
Diagnostic tests in vivo include delayed cutaneous reaction (e.g. Montoux test
(figure 5)) and patch test (for contact dermatitis). In vitro tests for delayed
hypersensitivity include mitogenic response, lympho-cytotoxicity and IL-2
production.
Corticosteroids and other immunosuppressive agents are used in
treatment.
Table 5 - Comparison of Different Types of hypersensitivity |
||||
characteristics |
type-I |
type-II |
type-III |
type-IV |
antibody |
IgE |
IgG, IgM |
IgG, IgM |
None |
antigen |
exogenous |
cell surface |
soluble |
tissues & organs |
response time |
15-30 minutes |
minutes-hours |
3-8 hours |
48-72 hours |
appearance |
weal & flare |
lysis and necrosis |
erythema and edema, necrosis |
erythema and induration |
histology |
basophils and eosinophil |
antibody and complement |
complement and neutrophils |
monocytes and lymphocytes |
transferred with |
antibody |
antibody |
antibody |
T-cells |
examples |
allergic asthma, hay fever |
erythroblastosis fetalis, Goodpasture's nephritis |
SLE, farmer's lung disease
|
tuberculin test, poison ivy, granuloma |
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