How immune complexes form and where they deposit
The development of pathology begins with the meeting of an antigen and an antibody. They can bind directly in the bloodstream or extravascularly (in situ), forming circulating immune complexes (CIC).
The source of the problem is two types of antigens:
- Exogenous: foreign proteins, viruses, or bacteria.
- Endogenous: the body's own tissues against which autoantibodies are mistakenly produced.
The pathological effect of CICs manifests when they deposit in tissues. The walls of blood vessels and filtering systems (e.g., the renal glomerular apparatus) most commonly become targets. Depending on the affected area, diseases are divided into generalized (many organs affected) and local (specific structures affected — joints, kidneys, or skin).
Mechanisms of tissue damage
The deposition of immune complexes beneath the vascular endothelium triggers a powerful cascade of inflammation. The complement system acts as the main driver of destruction:
- The C3b fraction acts as an opsonin, stimulating phagocytosis.
- The C5 factor attracts monocytes and band neutrophils to the focus (chemotaxis).
- Anaphylatoxins (C3a, C5a) cause smooth muscle contraction and increase vascular wall permeability.
- The C5b-9 complex directly destroys cell membranes, causing cytolysis.
Recruited neutrophils bind to CICs via Fc receptors. Attempting to destroy the complexes, leukocytes release lysosomal enzymes, prostaglandins, and reactive oxygen species that literally melt surrounding tissues. Concurrently, Hageman factor is activated and platelet aggregation is triggered. As a result, microthrombosis occurs, the vascular lumen is blocked, and ischemia ensues.
Systemic immune complex diseases
A classic example of a generalized reaction is acute serum sickness, which occurs upon repeated administration of high doses of foreign serum. Its pathogenesis includes three stages: CIC formation in the blood, their deposition in tissues, and subsequent inflammation.
The severity of the process depends on the state of the mononuclear phagocyte system and the size of the complexes themselves. Large CICs (when antibodies are in excess) are rapidly destroyed by macrophages and cause almost no harm. However, small and medium complexes are extremely pathogenic: they circulate in the blood for a long time and easily get stuck in tissues.
The clinical presentation (fever, urticaria, joint pain, proteinuria, and lymphadenopathy) develops approximately 10 days after antigen exposure. Morphologically, this manifests as acute necrotizing vasculitis, arthritis, and glomerulonephritis (endothelial and mesangial cells swell and proliferate in the renal glomeruli, accompanied by monocyte and neutrophil infiltration). If the antigen is constantly present in the blood (antigenemia), the disease becomes chronic.
In some systemic diseases, the antigen is known (e.g., autoantigen persistence in systemic lupus erythematosus). However, in rheumatoid arthritis, polyarteritis nodosa, and membranous nephropathy, the antigen often remains unidentified.
Local reaction: Arthus phenomenon
If immune complexes form and act locally, a local reaction occurs — the Arthus phenomenon. This is an acute immune complex vasculitis that leads to local tissue necrosis.
The reaction develops rapidly: the peak of damage is observed as early as 4–10 hours after injection or contact with the antigen. Macroscopically, this appears as an area of pronounced edema with hemorrhage foci. Under a microscope (light optics), fibrinoid necrosis of the vessel wall is clearly visible. The outcome of such damage is either vascular rupture with local hemorrhage or thrombosis (more common), leading to tissue ischemia.
Briefly: answers to topical questions
Which classes of immunoglobulins form circulating immune complexes in type III hypersensitivity?
Circulating immune complexes in type III hypersensitivity are formed by the following classes of antibodies:
- Immunoglobulin G (IgG) is the main class of antibodies involved in the formation of soluble complexes.
- Immunoglobulin M (IgM) participates in complex formation much less frequently.
- Immunoglobulin A (IgA₁) — polymeric forms of this class may be part of complexes in specific pathologies, such as renal involvement.
Through which pathway is the complement system activated by circulating immune complexes?
Activation of the complement system by circulating immune complexes occurs via two pathways depending on the composition of the complex:
- Classical pathway — the main mechanism initiated by the binding of the C1q component to the Fc fragment of antibodies (IgG or IgM) within the antigen-antibody complex.
- Alternative pathway — activated in specific cases, such as the deposition of complexes containing polymeric IgA₁, as indicated by the absence of C1q and C4 components in tissues.
What factors, besides complex size and macrophage status, influence CIC deposition in tissues?
In addition to complex size and macrophage status, electrical charge influences the deposition of circulating immune complexes in renal tissues. The literature describes the following local factor:
- Charge neutralization — a key mechanism of complex deposition on the basement membrane is the neutralization of the negative electrical charge of the glomerular filter.
Other systemic factors promoting complex deposition in other organs are not described in the sources.
To memorize the main targets of type III hypersensitivity, use the "Three V's" rule: Vessels (vasculitis), Viscera/joints (arthritis), Vascular network of the kidneys (glomerulonephritis).
Class and exam questions
Which immune complexes are most pathogenic and why?
Small and medium complexes formed in slight antibody excess pose the greatest danger. They are not cleared immediately by phagocytes, circulate in the bloodstream for a long time, and deposit in tissues.
What is the dominant morphological sign in systemic immune complex disease?
Acute necrotizing vasculitis is the primary manifestation. Glomerular hypercellularity due to endothelial and mesangial cell proliferation is also observed in the kidneys.
What is the Arthus phenomenon?
This is a local immune complex disease manifested by acute vasculitis and fibrinoid necrosis of tissues. The peak of damage occurs 4–10 hours after antigen exposure.
What else to study on this topic
- The role of the complement system and anaphylatoxins (C3a, C5a) in the development of vascular inflammation.
- Pathogenesis of acute serum sickness: a detailed analysis of the three phases.
- Morphological changes in the renal filter in immune complex glomerulonephritis.
- Differences between systemic lupus erythematosus (SLE) and diseases with an unknown antigen.
- Mechanisms of hemostasis and thrombosis in immune complex vasculitis.
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