IMMUNOLOGY - Roitt I. - Mir 2000

Chapter 25. Hypersensitivity - Type III

EXPERIMENTAL MODELS OF IMMUNE COMPLEX DISEASES

Experimental models exist for all three TYPES OF IMMUNE complex-mediated diseases described above.

✵ The effects of chronic infection are mimicked by serum sickness induced by the injection of foreign antigen.

✵ Autoimmune processes develop spontaneously in NZB/NZW mice.

✵ The Arthus reaction serves as a model for localized tissue injury caused by exogenous antigen.

The Structure/127.html">Interpretation of Results obtained from experimental models requires caution, given that rodent and rabbit erythrocytes lack C3b receptors (known as CR1), which readily bind immune complexes following Complement fixation. In contrast, primate erythrocytes possess these receptors.

Serum sickness can be reproduced by the administration of large amounts of foreign antigen

In serum sickness, circulating immune complexes deposit in Blood vessel walls and Tissues, leading to increased vascular permeability and subsequent inflammation, much like the pathology seen in Glomerulonephritis and Arthritis.

Before the advent of Antibiotics, serum sickness was a frequent complication in the Treatment of conditions such as diphtheria, which required the administration of massive doses of therapeutic Antibodies. Horse anti-diphtheria serum was commonly used, leading some patients to develop antibodies against equine Proteins.

Today, serum sickness is typically studied in rabbits by the intravenous injection of a soluble foreign protein, such as bovine serum albumin (BSA). After approximately 1 week, the rabbit mounts an antibody response, and circulating antibodies bind to the antigen. Because this reaction takes place in antigen excess, the resulting immune complexes are small in size (Fig. 25.7). These small complexes are cleared slowly—exclusively by the mononuclear phagocyte system—and therefore persist in the bloodstream for extended periods. Following complex formation, There is a sharp drop in total complement levels; the clinical signs of serum sickness are driven by granular deposits of antigen-antibody complexes and the deposition of C3 along the basement membranes of renal glomerular capillaries and other small vessels. As increasing amounts of antibody are produced and the equivalence point shifts toward antibody excess, the complexes grow larger and are cleared more rapidly, leading to the animal's recovery. Daily administration of the antigen converts the condition into a chronic disease.

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Fig. 25.7. Following the administration of xenogeneic serum, there is a latent period lasting approximately 5 days, during which the antigen circulates only in free form. Antibodies to the foreign proteins then develop, and immune complexes appear in the serum; it is precisely at this stage that the symptoms of nephritis and arteritis manifest. Initially, under conditions of antigen excess, only small, soluble immune complexes are formed. As antibody titers rise, larger complexes are assembled and deposited in tissues, but they are also cleared rapidly. At this stage, the clinical symptoms resolve.

Autoimmune reactions in NZB/NZW mice are accompanied by immune complex disease

F₁ hybrid mice (NZBxNZW) produce a variety of autoantibodies (including those directed against erythrocytes, Cell nuclei, DNA, and Sm) and develop an immune complex disease that closely resembles human systemic lupus erythematosus (SLE). NZB/NZW mice are born clinically normal and healthy, but by 2–3 months of age, they begin to show signs of hemolytic anemia. Tests for anti-erythrocyte antibodies (Coombs test), antinuclear antibodies, lupus erythematosus Cells, and circulating immune complexes yield positive results, while complex deposits can be detected in the renal glomeruli and choroid plexus. The disease is significantly more severe in females, who typically die within a few months after the onset of symptoms (Fig. 25.8).

Fig. 25.8. The graph illustrates the age-dependent onset of various autoimmune manifestations in female NZB/NZW mice. The ordinate represents the "incidence"—the proportion of mice of a given age exhibiting the specified traits. Immune complexes were detected by immunofluorescence staining of Kidney sections, and serum antinuclear antibodies by indirect immunofluorescence. Proteinuria served as an indicator of renal involvement. Autoantibodies to erythrocytes appear later in the course of the disease and are therefore likely less directly linked to the initiation of renal pathology. In male mice, the disease manifests approximately 3 months later.

Intradermal antigen administration in previously sensitized animals elicits the Arthus reaction

The Arthus reaction develops locally, within and around the walls of small Blood Vessels, and is most commonly demonstrated in the Skin.

The animal is repeatedly immunized until serum antibody levels (predominantly IgG) reach a detectable titer. Subsequent subcutaneous or intradermal injection of the antigen triggers a local inflammatory response, sometimes accompanied by marked edema and Hemorrhage (depending on the dose of antigen administered). The reaction peaks within 4–10 hours, gradually subsides, and by 48 hours usually leaves only minimal residual signs (Fig. 25.9). Immunofluorescence studies reveal that the deposition of antigen, antibody, and complement in vessel walls is followed by neutrophilic infiltration, while platelets aggregate within the vessel lumen (Fig. 25.10). All of these events can lead to vascular occlusion and, in severe cases, tissue necrosis. By 24–48 hours, neutrophils are replaced by mononuclear cells, and eventually a small number of plasma cells appear.

Fig. 25.9. Illustration of three primary skin tests. Type I hypersensitivity (1) is characterized by the appearance, within roughly 15 minutes, of a well-demarcated wheal 5–7 mm in diameter. In Type III hypersensitivity (2), the Arthus reaction develops over 5–12 hours, covering a larger area (50 mm or more) with less distinct borders. Type IV (delayed-type) hypersensitivity (3) manifests at 24–48 hours as an area of erythema and induration approximately 5 mm in diameter.

Fig. 25.10. Intradermally injected antigen binds to specific antibodies diffusing from the blood, resulting in The formation of immune complexes. These complexes activate complement and interact with platelets, which release vasoactive amines. Immune complexes also stimulate macrophages to release TNF and IL-1 (not shown). The complement fragments C3a and C5a trigger mast cell degranulation and recruit neutrophils into the tissue. Mast cell mediators, including histamine and Leukotrienes, enhance blood flow and capillary permeability. The inflammatory response is further amplified by lysosomal Enzymes released from polymorphonuclear cells. In addition, C3b deposited on the complexes opsonizes them, promoting phagocytosis. The Arthus reaction occurs in individuals whose blood contains precipitating antibodies, such as agricultural workers suffering from extrinsic allergic alveolitis ("farmer's lung").

Complement activation via the classical or alternative pathway is crucial for The Development of the Arthus reaction. In the absence of complement, neutrophils are not recruited to the reaction site, and the response is limited to mild edema.

The cytokine TNFα enhances cell-mediated immune responses through multiple pathways (see Chapter 10). Administration of anti-TNFα antibodies attenuates the Arthus reaction. There are also reports regarding the efficacy of anti-TNF antibodies in rheumatoid arthritis.

The severity of the reaction is directly dependent on the antibody-to-antigen ratio. Complexes formed in the presence of either antigen or antibody excess are significantly less toxic than those formed when these factors are in balance.