Etiology and nature of antigens
The main trigger for launching type III allergic reactions is soluble proteins. Pathology develops if these protein structures enter the body in excess amounts, act repeatedly, or are continuously formed within the body itself.
Depending on their origin, antigens are divided into two large groups:
- Exogenous (external) antigens. Enter the body from the environment. These include foreign sera and blood plasma used for therapeutic purposes, as well as vaccine solutions. In addition, the source can be insect bites, inhalation of protein-containing substances, and infection with various microorganisms or fungi.
- Endogenous (internal) antigens. Formed directly in the patient's tissues. This occurs against the background of prolonged infectious processes, parasitic infestations (e.g., trypanosomiasis or helminthiasis), as well as tumor growth and paraproteinemias.
Pathogenesis: from antigen encounter to inflammation
The development process of precipitin reactions represents a strict five-stage sequence.
1. Immunological stage Begins with the recognition of the soluble protein by macrophages. This is followed by complex cellular cooperation: the macrophage transmits information to the T lymphocyte, which activates the B lymphocyte. Activated B lymphocytes transform into plasma cells and begin active synthesis of specialized antibodies — IgM and IgG.
2. Formation of immune complexes (ICs) Upon re-exposure to the same antigen, molecular binding occurs. The main feature of the synthesized immunoglobulins is their pronounced ability to precipitate (form a precipitate) upon contact with the antigen. The resulting structures are called immune complexes.
3. Sensitization stage (fate of the complexes) The formed precipitates circulate with the bloodstream and lymph throughout the body and then fix (deposit) in various tissues and organs. This leads to general sensitization of the body.
4. Pathochemical stage Fixation of ICs and activation of reactions for their removal lead to the appearance of allergy mediators in the blood and tissues. The complement factor is actively involved in this process.
5. Pathophysiological stage (damage) Mediators and the deposited complexes themselves have a destructive effect on target tissues. Direct damage to cells and non-cellular structures occurs. The permeability of vascular walls and basement membranes increases sharply. Pronounced immune inflammation is triggered, and the blood clotting process is activated, leading to microthromboses.
Clinical manifestations
Diseases developing via the type III mechanism are conventionally called immune complex diseases. Their clinical picture depends on the exact location where the precipitates have fixed.
If complexes form in the systemic circulation or lymph and are then distributed to organs, a systemic (generalized) form occurs. A classic example of such a course is serum sickness.
The main pathologies based on the immune complex mechanism include:
- Serum sickness;
- Arthus reaction (proceeds as a local reaction);
- Membranous glomerulonephritis;
- Allergic forms of vasculitis;
- Polyarteritis nodosa;
- Allergic alveolitis;
- Allergic forms of pancytopenia.
Briefly: answers to topical questions
Which specific inflammatory mediators are released during the pathochemical stage of type III allergic reactions?
In the pathochemical (pathobiochemical) stage of type III allergy, mediators appear in the blood and tissues due to the fixation of immune complexes and activation of reactions for their removal. The sources mention the following for these reactions:
- leukotrienes and prostaglandins (PGs);
- chemoattractants and chemotactic substances;
- vasoactive agents and vasodilator proteins;
- procoagulants;
- lysosomal enzymes of phagocytes/neutrophils;
- reactive oxygen species (ROS), free oxygen radicals;
- complement components: C3a, C3b, C5a, as well as C4b, C2a, C5, C5b, C6, C7, and C5b-9 membrane attack complexes;
- histamine, serotonin, kinins, TNF-α, factor XII (Hageman factor), thromboxane A2.
Their effects indicated in the sources: damage to cells and non-cellular structures, induction of inflammation, increased permeability of vascular walls and basement membranes, activation of thrombus formation.
Through which pathway is the complement system activated upon fixation of immune complexes?
Upon fixation of immune complexes, complement system activation occurs via the classical (antibody-dependent) pathway.
- Initiation — recognition of the antigen-antibody complex occurs.
- Binding — the C1q molecule interacts with the Fc fragment of the antibody (IgM or IgG) within the complex.
- Formation of the active complex — attachment of C1r and C1s subunits leads to the formation of the C1qrs enzymatic complex.
Subsequently, this triggers a cascade of C4 and C2 component cleavage reactions, culminating in the formation of the classical pathway C3 convertase and subsequent lysis of targets.
Which chemotactic factors are formed upon complement activation in type III reactions?
Upon complement activation in immune complex reactions, the sources list the following as chemotactic factors or chemotaxis-related components:
- C5 — chemotactic factor; associated with the migration of band neutrophils and monocytes.
- C5a — ligand for the C5aR receptor on neutrophils, monocytes, basophils, and eosinophils; the function of this receptor is mediator release and chemotaxis.
- C3a — ligand for the C3aR receptor on mast cells, basophils, monocytes/macrophages, and neutrophils; the function of this receptor is mediator release and chemotaxis.
These components participate in the recruitment of polymorphonuclear leukocytes to immune precipitates and their accumulation in vessel walls and perivascularly.
It is easy to remember the main participants of the damaging complex by the abbreviation AAC: Antigen + Antibody + Complement. It is this triad that precipitates and triggers immune inflammation.
Class and exam questions
Which immunoglobulins are involved in type III reactions?
Precipitating antibodies of the IgG and IgM classes play the main role. Their key feature is the ability to form a precipitate upon contact with a soluble antigen.
What is the difference between local and systemic forms of the reaction?
The systemic form (e.g., serum sickness) develops when immune complexes circulate in the blood and deposit in various organs. The local form (Arthus phenomenon) occurs with local formation and fixation of precipitates.
What happens at the pathophysiological stage?
Immune inflammation develops: cells are damaged, the permeability of vessels and basement membranes increases, and microthrombosis is activated.
What else to study on this topic
- Mechanisms of cellular cooperation (macrophage → T lymphocyte → B lymphocyte) at the immunological stage
- The role of the complement system in the formation and fixation of immune complexes
- Serum sickness as a classic model of generalized immune complex reaction
- Arthus phenomenon: features of the development of local immune inflammation
- Pathogenesis of membranous glomerulonephritis and polyarteritis nodosa in type III allergy
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