Physiology: How the body eliminates immune complexes
In a healthy organism, the formation of antigen-antibody complexes does not lead to their accumulation in the blood or tissues. Erythrocytes are responsible for their safe elimination (destruction). Special CR1 (CD35) receptors are located on the membranes of red blood cells. Using these receptors, erythrocytes bind circulating immune complexes and transport them to liver macrophages, where final engulfment and destruction take place.
Furthermore, when antibodies bind to antigens directly on the surface of foreign cells, a process called opsonization occurs—such "tagged" cells are rapidly recognized and phagocytosed.
Mechanism of pathology and inflammation development
Diseases develop when the elimination system malfunctions. This occurs in cases of phagocyte or complement deficiency, as well as with massive, prolonged antigen exposure or an excess of antibodies.
The key event in type III hypersensitivity is the transition of immune complexes into an insoluble state (often due to antibody excess or complement defects, which normally maintain their solubility) and their deposition on the vascular endothelium and basement membranes.
Tissue damage cascade:
- Complex deposition activates the complement system with the release of anaphylatoxins—small fragments C3a and C5a.
- Anaphylatoxins alter vascular tone and attract monocytes and neutrophils to the site.
- Activated phagocytes begin massive secretion of pro-inflammatory cytokines (IL-1, TNFα, IL-8), aggressive enzymes, and cationic proteins.
- Simultaneously, a membrane attack complex forms, destroying cells.
- If complexes form inside a blood vessel, platelet aggregation occurs, leading to microthrombosis and the release of vasoactive substances.
Arthus phenomenon (local reaction)
The classical experimental model of local immune complex-mediated injury is the Arthus phenomenon. It occurs when an animal (e.g., a rabbit) is repeatedly injected subcutaneously with foreign serum at 5-day intervals.
When a sufficient antibody titer accumulates (usually by the 6th injection), complexes form instantly at the injection site. Severe edema and a focus of hyperergic inflammation develop, culminating in tissue necrosis and vascular thrombosis.
Mast cells and basophils actively participate in this process by degranulating and synthesizing eicosanoids. Neutrophils release bactericidal factors, and the endothelium sharply increases vascular permeability.
Clinical forms: from mild to renal
Immune complex pathology can manifest both locally and systemically.
- Occupational lung diseases (e.g., allergic alveolitis, known as "farmer's lung"). They arise due to the constant inhalation of organic dust (fungal spores, agricultural products).
- Rheumatoid arthritis: an autoimmune disease in which complexes are formed from endogenous IgG and rheumatoid factor (anti-IgG antibodies).
- Experimental glomerulonephritis: renal damage is caused by intermediate-sized complexes that remain soluble. They are small enough to circulate, but too large to pass through the renal filter, thus "trapped" in the glomerular basement membrane.
Serum sickness and systemic lupus erythematosus
Serum sickness occurs when high doses of an antigen (historically, tetanus antitoxin serum) are administered intravenously. Antibodies appear on days 6–7. If the antigen is administered again, complexes form directly within the vascular bed.
Severe clinical manifestations (fever, rash, generalized lymphadenopathy, vasculitis, and arthritis) develop when there is an antigen excess within the immune complex.
The most severe form of systemic type III pathology is systemic lupus erythematosus (SLE). It is driven by the persistent presence of an autoantigen (double-stranded DNA) and a self-sustaining pathological immune response.
Briefly: answers to topical questions
What is the role of mast cells and basophils in the development of the Arthus phenomenon?
- Mast cells and basophils release active molecules via degranulation in response to immune complex binding and the action of anaphylactogens, and also synthesize eicosanoids.
Which immunoglobulin classes participate in complex formation in rheumatoid arthritis?
- IgM is an immunoglobulin class (rheumatoid factor) that acts as anti-IgG antibodies.
- IgA is an immunoglobulin class that participates less frequently in rheumatoid factor formation.
- IgG is an immunoglobulin class that less frequently acts as rheumatoid factor, as well as endogenous IgG to which antibodies bind.
Which blood cells are the first to be recruited to the lesion site by anaphylatoxins C3a and C5a?
- Neutrophils and monocytes are recruited to the lesion site and activated by the action of small complement fragments C3a and C5a.
To remember dangerous complexes in serum sickness: antigen molecules (Ag) are always one more than antibodies (Ab) — $\text{Ag}_2\text{Ab}_1$, $\text{Ag}_3\text{Ab}_2$, $\text{Ag}_4\text{Ab}_3$. Antigen excess is the key to the disease.
Class and exam questions
Why do immune complexes deposit specifically in blood vessels and membranes?
Endothelial cells and basement membranes have a high density of Fc receptors. Circulating insoluble complexes attach to them via their antibodies.
What complex sizes are most dangerous for the development of glomerulonephritis?
Intermediate. They must be small enough to circulate in solution, but large enough to become trapped on the endothelial side of the renal glomerular basement membrane.
How can the Arthus phenomenon be passively reproduced?
One needs to intravenously administer preformed antibodies to a rabbit, wait 4–5 hours (for them to penetrate the skin), and then intradermally inject the antigen. The reaction will be identical to the classical one.
What else to study on this topic
- Function and structure of the CR1 (CD35) receptor on erythrocytes
- Mechanism of generation of C3a and C5a anaphylatoxins
- Role of rheumatoid factor in the development of rheumatoid arthritis
- Pathogenesis of anti-dsDNA antibody production in SLE
- Differences between systemic and local immune complex reactions
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