Tissue damage mechanism (pathogenesis)
Normally, immune complexes are utilized by the body, but in cases of antigen excess or complement system deficiency, their clearance is impaired. As a result, soluble complexes deposit in vascular walls, on basement membranes, and on structures with Fc receptors.
The inflammatory reaction cascade develops in stages:
- Cell activation. Platelets and basophils are immediately involved in the process.
- Mediator release. Cells release pro-inflammatory cytokines (including TNF-α), chemokines, and vasoactive amines (primarily histamine), which sharply increase vascular permeability.
- Vascular disorders. Platelet aggregation occurs, leading to the formation of multiple microthrombi in capillaries.
- Cellular infiltration and necrosis. Complement components (anaphylatoxins C3a, C4a, C5a) act as chemoattractants. Driven by C5a, neutrophils rush into the lesion. They release aggressive lysosomal enzymes that directly destroy tissue and cause necrosis.
- Late stage. Macrophages join the process in the final stages of inflammation.
Classification and clinical manifestations
Inflammation triggers can be both exogenous antigens (pathogens of chronic bacterial, viral, fungal, and protozoal infections) and endogenous autoantigens.
General (systemic) forms Characterized by the circulation of immune complexes throughout the body. Their deposition causes systemic vasculitis (vascular damage), arthritis (joints), and nephritis (kidneys). A classic example is serum sickness. It occurs upon administration of high doses of foreign protein, such as therapeutic horse tetanus antitoxin. The pathology has a latent period of 6–7 days—the time required for the immune system to generate a sufficient antibody titer.
Organ-specific (local) forms The reaction is localized in a specific tissue. In systemic lupus erythematosus (SLE), the skin is affected, and lupus nephritis damages the kidneys. An important clinical phenomenon is the Arthus reaction. It develops upon repeated intradermal injection of an antigen due to the local formation of complexes with pre-existing antibodies. 3–10 hours after injection, pronounced edema, hemorrhagic inflammation, and tissue necrosis occur at the injection site.
Laboratory diagnostics
To confirm Type III hypersensitivity, it is necessary to visualize immune deposits or assess their concentration in the bloodstream:
- Tissue analysis (biopsy specimens). The gold standard is the indirect immunofluorescence assay (IFA). This method allows for the detection of specific fluorescence of immunoglobulin and complement component deposits directly in affected structures.
- Blood test. The method of precipitating circulating immune complexes using polyethylene glycol is applied. After precipitation, the laboratory technician determines the concentration of IgG in the resulting precipitate.
Briefly: answers to topical questions
What human diseases develop via the Type III hypersensitivity mechanism?
Systemic and organ-specific diseases caused by the deposition of immune complexes develop via the Type III hypersensitivity mechanism. These include:
- Serum sickness — a systemic reaction to the administration of high doses of a foreign antigen.
- Systemic lupus erythematosus — a systemic disease with the formation of autoantibodies to nuclear antigens.
- Arthus reaction — local hemorrhagic inflammation and tissue necrosis.
- Glomerulonephritides — including lupus and immune complex glomerulonephritis.
- Polyarteritis nodosa — systemic vascular damage.
- Systemic vasculitides and arthritides.
How is normal clearance of immune complexes from the bloodstream carried out?
Normal clearance of immune complexes from the bloodstream is carried out with the participation of complement components and cellular receptors. This process involves the CR1 receptor (CD35) expressed on erythrocytes, monocytes, and macrophages; it binds C3b, iC3b, C4b, and C3d and participates in immune complex clearance. Complement system deficiency disrupts immune complex clearance and promotes their deposition in tissues. Deficiencies in C1q and DNase-1 are associated with impaired clearance of nuclear material.
The rule of three "C's": Complexes, Complement, Capillaries. The essence of the pathology: soluble immune Complexes bind Complement and deposit on Capillary basement membranes, causing their destruction.
Class and exam questions
Why are immune complexes not cleared from the bloodstream, but instead deposit in tissues?
The main risk factors are antigen excess and complement system deficiency. This leads to impaired natural clearance of the blood from the formed structures.
What role do neutrophils play in Type III hypersensitivity?
Neutrophils are attracted to the lesion by the anaphylatoxin C5a. There, they release lysosomal enzymes that damage surrounding tissues and lead to necrosis.
What is the difference between the Arthus reaction and serum sickness?
The Arthus reaction is local inflammation (edema, necrosis) developing within 3–10 hours upon intradermal antigen administration. Serum sickness is a systemic pathology with a latent period of 6–7 days, occurring in response to the administration of high doses of foreign protein.
What else to study on this topic
- The role of anaphylatoxins (C3a, C4a, C5a) in the activation of the cellular link of inflammation
- The mechanism of precipitation of circulating immune complexes with polyethylene glycol
- The pathophysiology of microthrombosis development in immune complex reactions
- Autoantigens as triggers for the development of systemic lupus erythematosus
- The principle of the immunofluorescence assay (IFA) method in biopsy specimens
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