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

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

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

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

Table 3. Delayed hypersensitivity reactions

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

You have learned: