Allergy: Mechanisms and Stages of Development
Allergy is a specific excessive secondary immune reaction to allergen (antigen) followed by tissue damage and organ dysfunction.
The specifity of the Ist type of allergic reactions is maintained by production of anti-allergen antibodies named as “reagins” or “cytophilic antibodies” due to their ability to interact with different cell lines.
These antibodies arise after primary antigen challenge, and their concentration increases during subsequent contacts. Clinical manifestations of allergy emerge only after the secondary antigenic challenge.
Time period between the primary interaction of allergen with immune system and their secondary contact with allergy development is termed as sensitization period. It lasts from several days to several months, years and even decades from primary antigenic stimulation.
At this latent period allergen-specific T- and B cells populations proliferate and differentiate with memory cell formation. Th2 cell subpopulation activates B cells by direct contact and by secretion of IL-4, 5, 9, 13, and 15. Activated B lymphocytes switch the production of allergen-specific antibodies to IgE class capable of stimulating mast cells and basophils. This is next followed by basophil/mast cell degranulation resulting in allergy manifestations.
Secretion of gamma interferon, IL-1, or IL-12 by Th1 and macrophages inhibits allergic reactions.
There are several consecutive stages in progression of allergic reactions:
– sensitization stage (period);
– immunological stage;
– pathochemical stage;
– pathophysiological stage;
– stage of clinical manifestations.
In sensitization period allergen-specific antibodies of IgE class and some subclasses of IgG (e.g., IgG4) arise after antigen priming. These antibodies eventually fix to specific membrane Fcε-receptors on basophils and mast cells.
In immunological stage as the result of secondary contact the allergen binds to IgE-antibodies on basophils and mast cells. This interaction promotes basophil/mast cell activation. It occurs due to the cross-linkage of two membrane IgE-receptors that is followed by membrane signal transmission into the cells. Cellular src-thyrosine kinases phosphorylate the number of regulatory proteins, resulting in basophil degranulation. It is noteworthy that after the degranulation basophils retain their viability.
Pathochemical stage begins from the moment of granules release. Pre-existing primary allergy mediators are liberated immediately. There are histamine, serotonin, platelet-activating factor (PAF), specific proteases of mast cells – tryptase and chymase.
At the same time the other mediators of allergy begin to synthesize de novo. The major ones are arachidonic acid metabolites.
They are formed by the cyclooxygenase and lipoxygenase pathways due to phospholipase A2 action. The first pathway results in production of prostaglandins and thromboxanes. Most active are prostaglandin F2α, D2 and thromboxane А2. By contrast, prostaglandin E2 inhibits allergic reactions.
The second lipoxygenase pathway is slower. It provides the synthesis and liberation of the most powerful allergy mediators – leukotriens B4, C4, D4.
Usually allergy mediators decrease intracellular concentration of cyclic AMP.
At the same time different cytokines and chemoattractants are produced (IL-4, 5, 6, 8, eosynophil and neutrophil chemotactic factors). Eosynophils, neutrophils, macrophages and other cells become accumulated in allergy area (late phase of reaction). They produce other secondary messengers (bradykinin, heparin, complement factors and many others). Interaction of mediators with vessel endotheliocytes accelerates cells extravasation.
Mediator action provokes significant local or systemic hypersensitivity response resulting in pathophysiological stage of allergic reaction. Tissue inflammation, skin rashes, glandular hypersecretion, bronchial obstruction, arterial hypotension with collapse are developed.
The last phase is the stage of clinical manifestations. The symptoms of various allergic diseases (anaphylactic shock, bronchial asthma attack, urticaria, pollinose, angioneurotic edema or Quincke’s disease, food and drug allergy, allergic rhynitis and others) develop in this stage.