IMMUNOLOGY - Roitt I. - Mir 2000

Chapter 25. Hypersensitivity - Type III

TISSUE DEPOSITION OF COMPLEXES

Immune complexes can remain in the Circulation for extended periods. However, their persistence here is usually harmless in itself; problems arise only when these complexes become deposited in Tissues.

This raises two key questions:

✵ what triggers the deposition of complexes, and

✵ why do complexes in different diseases exhibit an affinity for specific tissues?

Increased vascular permeability appears to be the most critical factor in the tissue deposition of immune complexes

Animal experiments demonstrate that inert substances, such as colloidal carbon, become deposited in vessel walls following the administration of vasoactive compounds (e.g., histamine or serotonin). Similarly, circulating immune complexes are deposited when agents that induce the release of vasoactive amines (including histamine) from mast Cells are administered. Pretreatment with antihistamines effectively blocks this effect.

Investigations into experimental immune complex disease in rabbits have shown that prolonged administration of vasoactive amine antagonists, such as chlorpheniramine and methysergide, significantly reduces immune complex deposition (Fig. 25.17). Of even greater prophylactic significance is the finding that young NZB/NZW mice treated with methysergide developed less severe renal damage compared with control animals (Fig. 25.18).

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Fig. 25.17. Serum sickness was induced in rabbits via a single injection of bovine serum albumin. The experiments were conducted on three groups of animals: 1) controls, 2) animals with depleted platelets, and 3) animals receiving drugs that block the action of vasoactive amines. The incidence of Heart and lung lesions characteristic of serum sickness was recorded. Drug administration significantly mitigated disease severity by decreasing vascular permeability and, consequently, reducing immune complex deposition.

Fig. 25.18. Renal damage (assessed by the degree of proteinuria) was monitored in NZB/NZW mice over a 5-month period. Untreated animals developed severe proteinuria, whereas mice treated with methysergide did not. Methysergide blocks The production of the vasoactive amine 5-hydroxytryptamine (serotonin), thereby inhibiting various inflammatory reactions, such as complex deposition, neutrophil infiltration of vessel walls, and endothelial Cell proliferation, which drive glomerular pathology.

Increased vascular permeability can lead to numerous consequences, The Significance of which depends on The Nature of the disease and the animal species. This complicates the interpretation of individual data obtained from experimental models. Overall, however, Complement, mast cells, basophils, and platelets can all be considered potential sources of vasoactive amines.

Immune complex deposition is most likely in anatomical structures characterized by high Blood pressure and turbulent blood flow

Many macromolecules are deposited in the glomerular capillaries of the Kidneys, where blood pressure is approximately four times higher than in other capillary beds (Fig. 25.19). If glomerular pressure is reduced in rabbits through partial renal artery constriction or ureteral ligation, macromolecule deposition is likewise diminished. Conversely, if glomerular pressure is elevated via the induction of experimental Hypertension, immune complex deposition within the glomeruli increases, as demonstrated in the serum sickness model. The most severe damage occurs in regions subject to turbulent blood flow, such as arterial bends and bifurcations, as well as in "vascular filters" like the choroid plexus and the ciliary body of the eye.

Fig. 25.19. Factors influencing complex deposition include filtration and high blood pressure, both of which operate during ultrafiltrate formation in the renal glomeruli (1). Turbulent blood flow at arterial bends or bifurcations (2) also promotes immune complex deposition.

Complex deposition in specific tissues may be linked to the intrinsic antigen affinity for those sites

While localized high blood pressure explains the frequent deposition of immune complexes in certain Organs, it does not account for why complexes target different organs in various diseases. In systemic lupus erythematosus (SLE), the kidneys are the primary target organ, whereas in rheumatoid Arthritis—despite the presence of circulating complexes—the kidneys are usually spared, and the joints become the main target.

It is possible that organ-specific pathology is determined by the antigen moiety within the complex, an hypothesis supported by a compelling experimental model. The administration of endotoxin to mice causes cellular damage and the release of DNA, which binds to the basement membrane of capillaries in intact glomeruli. This triggers polyclonal B-cell activation and the production of anti-DNA Antibodies, which interact with the tissue-fixed DNA, leading to the local formation of immune complexes (Fig. 25.20). The production of rheumatoid factor—IgM antibodies directed against IgG—facilitates the further formation of immune complexes in situ. It is quite likely that Antigens with specific organ affinities will also be identified in other diseases.

Fig. 25.20. Endotoxin administered to mice increases vascular permeability and damages cells, leading to the release of DNA, which is subsequently deposited (1) onto the Collagen of the glomerular capillary basement membrane (GCBM). Endotoxin can also induce polyclonal B-cell activation, prompting some cells to produce autoantibodies, such as anti-DNA and anti-IgG (the latter known as rheumatoid factors, RF). Anti-DNA antibodies bind to the deposited DNA, forming local immune complexes (2). While RF exhibits low affinity for monomeric IgG, it binds with high avidity to the pre-formed DNA/anti-DNA complex (3). Consequently, further immune complex formation proceeds in situ.

The electrical charge of both the antigen and the antibody can also play a critical role in certain cases. For instance, positively charged antigens and antibodies are more likely to be deposited on the negatively charged glomerular basement membrane. Furthermore, The Fate of complexes containing glycoprotein antigens is influenced by their degree of glycosylation, as certain clearance mechanisms (such as those involving mannan-binding lectin) are triggered by interactions with sugar residues.

In A number of diseases, both antibodies and antigens are produced locally within the target organ. This is most prominent in rheumatoid arthritis, where the rheumatoid factor—an IgG anti-IgG antibody—is produced by plasma cells in the synovial membrane; these antibodies then interact with one another (autoassociation), thereby triggering an inflammatory response.

The site of immune complex deposition depends in part on their size

The kidneys provide a classic example of this phenomenon. Small immune complexes can pass through the glomerular capillary basement membrane and reach its epithelial side, whereas the membrane is impermeable to large complexes, which typically accumulate between the endothelium and the basement membrane or within the mesangium (Fig. 25.21). The size of immune complexes is determined by the valency of the antigen, as well as the titer and affinity of the antibodies.

Fig. 25.21. The site of immune complex deposition in the kidneys depends on the size of the complexes circulating in the blood. Large complexes are deposited on the glomerular capillary basement membrane (GCBM), whereas small complexes pass through it to the epithelial side.

Immune complex deposition is influenced by the class of constituent IMMUNOGLOBULINS

There are notable AGE AND SEX differences regarding the classes and subclasses of anti-DNA antibodies produced in SLE. For instance, as NZB/NZW mice age, There is a switch from predominantly IgM synthesis to the production of IgG2a. In females, this switch occurs earlier than in males and coincides with the onset of renal disease, highlighting Structure/19.html">The Importance of antibody isotype in tissue deposition of complexes (Fig. 25.22).

Fig. 25.22. In NZB/NZW mice, immune complex disease develops spontaneously, following an early-life switch in antibody class from IgM to IgG2a. The graph shows The ratio of IgM and IgG2a anti-DNA antibody isotypes in females and males. Both the class switch and fatal renal disease occur earlier in female mice of this strain.