Hypersensitivity reactions

 

Abdul Ghaffar (Phone: 733-3279; e-mail: ghaffar@uscmed.sc.edu)

 

MBIM 650/720 Medical Microbiology - Fall 1998 Lectures: 19-20

 

TEACHING OBJECTIVES:

1. Classification of hypersensitivity reactions

2. Diseases associated with hypersensitivity reactions

3. Mechanisms of damage in hypersensitivity reactions

4. Diagnosis and treatment of conditions due to hypersensitivity

 

 

READING:

 

Roitt, Brostoff and Male: Immunology, 4th Ed., Chapters 23-26.

Hypersensitivity refers to 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

 

It is also known as immediate or anaphylactic hypersensitivity. The reaction may involve skin (urticaria and eczema), eye (conjunctivitis), nasopharynx (rhinorrhea, rhinitis), bronchopulmonary tissues (asthma) and gastrointestinal tract (gastroenteritis). The reaction may cause from minor inconvenience to death. The reaction takes 15-30 minutes from the time of exposure to the antigen. The reaction may, sometime, have a delayed onset (10-12 hours). Immediate hypersensitivity is mediated by IgE. The primary cellular component in this hypersensitivity is 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 receptors 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 that deplete cytoplasmic Ca++ suppress degranulation.

 

 

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.). The agents released from mast cells and their effects are listed in Table 1.

 

 

Table 1. Pharmacologic Mediators of Immediate Hypersensitivity

 

 

mediator

 

 

preformed mediators in granules

histamine

tryptase

kininogenase

ECF-A

(tetrapeptides)

broncho-constriction, mucus secretion, vaso-dilation, vascular permeability

proteolysis, C3 activation

kinins and vaso-dilation, vascular permeability, edema

Attract eosinophil and neutrophils

 

newly formed mediators

leukotriene B4

leukotriene C4, D4

prostaglandins D2

PAF

basophil attractant

same as histamine but 1000x more potent

edema and pain

platelet deaggregation and haparin release: micro-thrombi

 

 

The reaction is amplified by the attraction of platelets (due to PAF), which release histamine and vaso-active 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. Eosinophil may also control the local reaction by releasing arylsulphatase, histaminase, phospholipase-D and prostaglandin-E, although this role of eosinophil is now in question.

 

Cyclic nucleotides appear to play a major role in the modulation of immediate hypersensitivity reaction, although their exact function is still 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 and are used therapeutically (Table 2). Conversely, agents which decrease cAMP or stimulate cGMP, aggravate allergic conditions.

 

Table 2: Relationship between allergic symptoms and cyclic-neucleotides

 

 

lowering of cyclic-AMP

elevation of cyclic-AMP

stimulation of a-adrenergic receptor

(nor-epinephrin, phenyl-epinephrin)

or

blocking of b-adrenergic receptor

(propanolol)

stimulation of b-adrenergic receptor

(epinephrine, isoproterenol)

blocking of a-adrenergic receptor

(phenoxybenzamine)

elevation of cyclic-GMP

inhibition of phosphodiesterase

(theophylline)

stimulation of g-cholinergic receptor

(acetyl choline, carbacol)

binding of histamine-2 or PGE to their receptors

WORSENING OF SYMPTOMS

IMPROVEMENT OF SYMPTOMS

 

 

Diagnostic tests for immediate hypersensitivity include skin (Prick and intradermal) tests, measurement of total IgE and IgE antibodies against specific antigens. Total IgE and specific IgE antibodies are measured by a modification of RIA (RAST, RIST, PRIST). Increased IgE levels are indicative of atopic condition, although IgE may be elevated in some non atopic diseases (e.g., myeloma, helminthic infection, etc.).

Prausnitz Kustner (P-K) test has been used in vivo for diagnosis of allergy and passive cutaneous anaphylaxis (PCA) is its animal equivalent.

Symptomatic treatment is achieved with antihistamines which block histamine receptors. Chromolyn sodium inhibits mast cell degranulation, probably, by inhibiting Ca++ influx. There appears to be a genetic predisposition for atopic diseases and there is evidence for HLA (A2) association.

Hypo-sensitization (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. 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

It is also known as cytotoxic hypersensitivity. Various organs and tissues may be involved. The reaction time is minutes to hours. It is primarily mediated by antibodies of IgM or IgG class (rarely IgA) and complement (Figure 2). Phagocytes and K cells may also play a role (ADCC).

The lesion contains antibody, complement and neutrophils. Diagnostic tests include tests for circulating antibody and the presence of antibody and complement in the lesion by immunofluorescence. The staining pattern is normally smooth and linear.

 

 

 

Type III Hypersensitivity

It 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., 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.

The reaction may take 3-10 hours after exposure to antigen (as in Arthus reaction). It is mediated by soluble immune complexes. They are mostly of IgG class, although IgM and rarely IgA may also be involved. The antigen may be exogenous (chronic bacterial, viral or parasitic infections), or endogenous (non-organ specific autoimmunity). 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 done by platelets and neutrophils (Figure 3). The lesion primarily contains neutrophils; 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). Presence of immune complexes in serum and depletion in complement level are also diagnostic. Polyethylene glycol mediated turbidity (nephelometry), binding of C1q and Raji cell tests are utilized to detect immune complexes. Treatment includes anti-inflammatory agents.

 

 

Type IV Hypersensitivity

 

It is also known as cell mediated or delayed type hypersensitivity. The classical example of this hypersensitivity is tuberculin (Montoux) reaction 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 various 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, chemicals, heavy metals, etc.) in which the lesions are more papular. Type IV hypersensitivity can be classified into four categories depending on the time of onset and clinical and histological appearance (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 cells (TH1) secrete lymphokines (IL-2, IFN-g, TNF-b) which recruit and activate monocytes and macrophages, that cause the bulk of damage (Figure 4). The delayed hypersensitivity lesions contain mainly monocytes and few T cells.

 

Major lymphokines involved in delayed hypersensitivity reaction include monocyte chemotactic factor, migration inhibition factor, macrophage activation factor, interleukin-II, TNF a/b, interferons, etc.

 

Diagnostic tests in vivo include delayed cutaneous reaction (e.g., Montoux test) and patch test (for contact dermatitis). In vitro tests for delayed hypersensitivity include mitogenic response, lympho-cytotoxicity, migration inhibition and IL-2 production.

 

Corticosteroids and other immunosuppressive agents are used in treatment.

 

 

Table 5. Comparison of Different Types of hypersensitivity

 

characteristics

type-I

(anaphylactic)

type-II

(cytotoxic)

type-III

(immune complex

type-IV

(delayed type)

antibody

antigen

response time

appearance

 

histology

 

transferred with

examples

IgE

exogenous

15-30 minutes

weal & flare

 

basophils and eosinophil

antibody

atopic asthma, hay fever

IgG, IgM

cell surface

minutes-hours

necrosis and lysis

 

antibody and complement

antibody

erythroblastosis

fatales, Goodpasture nephritis

IgG, IgM

soluble

3-8 hours

erythema and

edema

complement and neutrophils

antibody

Farmer=s lung,

SLE

None

tissues & organs

48-72 hours

erythema and induration

monocytes and lymphocytes

T-cells

tuberculin test, poison ivy, granuloma

 

 

 

You have learned:

 

Distinctions between different types of hypersensitivity.

Mechanisms of immune-mediated damages.

Examples of different types of hypersensitivity and overlap among them.

Diagnostic test for hypersensitivity diseases and treatments.

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