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type 3 hypersensitivity

Tuesday 10 March 2009

Antigen-antibody complexes produce tissue damage mainly by eliciting inflammation at the sites of deposition. The toxic reaction is initiated when antigen combines with antibody within the circulation (circulating immune complexes) and these are deposited, typically in vessel walls, or the complexes are formed at extravascular sites where antigen may have been deposited previously (in situ immune complexes).

Some forms of glomerulonephritis in which immune complexes are formed in situ after initial implantation of the antigen on the glomerular basement membrane can be observed.

The mere formation of antigen-antibody complexes in the circulation does not imply the presence of disease; immune complexes are formed during many immune responses and represent a normal mechanism of antigen removal.

The factors that determine whether the immune complexes formed in circulation will be pathogenic are not fully understood, but some possible influences are discussed later.

Two general types of antigens cause immune complex-mediated injury: (1) The antigen may be exogenous, such as a foreign protein, a bacterium, or a virus; or (2) Under some circumstances, the individual can produce antibody against self-components-endogenous antigens. The latter can be circulating antigens present in the blood or, more commonly, antigenic components of one’s own cells and tissues.

Immune complex-mediated diseases can be generalized, if immune complexes are formed in the circulation and are deposited in many organs, or localized to particular organs, such as the kidney (glomerulonephritis), joints (arthritis), or the small blood vessels of the skin if the complexes are formed and deposited locally. These two patterns are considered separately.

Systemic immune complex disease

Acute serum sickness is the prototype of a systemic immune complex disease; it was at one time a frequent sequela to the administration of large amounts of foreign serum (e.g., immune serum from horses used for passive immunization.) The occurrence of diseases caused by immune complexes was suspected in the early 1900s by a physician named Clemens von Pirquet.

Patients with diphtheria infection were being treated with serum from horses immunized with the diphtheria toxin. Von Pirquet noted that some of these patients developed arthritis, skin rash, and fever, and the symptoms appeared more rapidly with repeated injection of the serum.

Von Pirquet concluded that the treated patients made antibodies to horse serum proteins, these antibodies formed complexes with the injected proteins, and the disease was due to the antibodies or immune complexes.

He called this disease "serum disease"; it is now known as serum sickness. In modern times the disease is infrequent, but it is an informative model that has taught us a great deal about systemic immune complex disorders.

The pathogenesis of systemic immune complex disease can be divided into three phases:

- (1) formation of antigen-antibody complexes in the circulation;
- (2) deposition of the immune complexes in various tissues, thus initiating;
- (3) an inflammatory reaction at the sites of immune complex deposition.

The first phase is initiated by the introduction of antigen, usually a protein, and its interaction with immunocompetent cells, resulting in the formation of antibodies approximately a week after the injection of the protein. These antibodies are secreted into the blood, where they react with the antigen still present in the circulation to form antigen-antibody complexes.

In the second phase, the circulating antigen-antibody complexes are deposited in various tissues.

The factors that determine whether immune complex formation will lead to tissue deposition and disease are not fully understood, but two possible influences are the size of the immune complexes and the functional status of the mononuclear phagocyte system.

Large complexes formed in great antibody excess are rapidly removed from the circulation by the mononuclear phagocyte system and are therefore relatively harmless. The most pathogenic complexes are of small or intermediate size (formed in slight antigen excess), which bind less avidly to phagocytic cells and therefore circulate longer.

Because the mononuclear phagocyte system normally filters out the circulating immune complexes, its overload or intrinsic dysfunction increases the probability of persistence of immune complexes in circulation and tissue deposition.

In addition, several other factors, such as charge of the immune complexes (anionic versus cationic), valency of the antigen, avidity of the antibody, affinity of the antigen to various tissue components, three-dimensional (lattice) structure of the complexes, and hemodynamic factors, influence the tissue deposition of complexes.

In addition to the renal glomeruli, the favored sites of immune complex deposition are joints, skin, heart, serosal surfaces, and small blood vessels. For complexes to leave the microcirculation and deposit in the vessel wall, an increase in vascular permeability must occur.

This is believed to occur when immune complexes bind to inflammatory cells through their Fc or C3b receptors and trigger release of vasoactive mediators as well as permeability-enhancing cytokines. Mast cells may also be involved in this phase of the reaction.

Once complexes are deposited in the tissues, they initiate an acute inflammatory reaction (third phase). During this phase (approximately 10 days after antigen administration), clinical features such as fever, urticaria, arthralgias, lymph node enlargement, and proteinuria appear.

Wherever complexes deposit, the tissue damage is similar. Two mechanisms are believed to cause inflammation at the sites of deposition: (1) activation of the complement cascade, and (2) activation of neutrophils and macrophages through their Fc receptors.

Complement activation promotes inflammation mainly by production of chemotactic factors, which direct the migration of polymorphonuclear leukocytes and monocytes (mainly C5a) and by release of anaphylatoxins (C3a and C5a), which increase vascular permeability.

The leukocytes that are drawn in by the chemotactic factors are activated by engagement of their C3b and Fc receptors by the immune complexes.

This results in the release or generation of a variety of pro-inflammatory substances, including prostaglandins, vasodilator peptides, and chemotactic substances, as well as several lysosomal enzymes, including proteases capable of digesting basement membrane, collagen, elastin, and cartilage. Tissue damage is also mediated by oxygen free radicals produced by activated neutrophils.

Immune complexes have several other effects, including aggregation of platelets and activation of Hageman factor; both of these reactions augment the inflammatory process and initiate the formation of microthrombi. The resultant inflammatory lesion is termed vasculitis if it occurs in blood vessels, glomerulonephritis if it occurs in renal glomeruli, arthritis if it occurs in the joints, and so on.

It is clear from the foregoing that complement-fixing antibodies (i.e., IgG and IgM) and antibodies that bind to leukocyte Fc receptors (some subclasses of IgG) induce the pathologic lesions of immune complex disorders.

Because IgA can activate complement by the alternative pathway, IgA-containing complexes may also induce tissue injury. The important role of complement in the pathogenesis of the tissue injury is supported by the observations that during the active phase of the disease, consumption of complement decreases the serum levels, and experimental depletion of complement greatly reduces the severity of the lesions.

If the disease results from a single large exposure to antigen (e.g., acute serum sickness and perhaps acute poststreptococcal glomerulonephritis), the lesions tend to resolve, owing to catabolism of the immune complexes. A chronic form of serum sickness results from repeated or prolonged exposure to an antigen.

Continuous antigenemia is necessary for the development of chronic immune complex disease because, as stated earlier, complexes in antigen excess are the ones most likely to be deposited in vascular beds.

This occurs in several human diseases, such as systemic lupus erythematosus (SLE), which is associated with persistent antibody responses to autoantigens.

In many diseases, however, the morphologic changes and other findings suggest immune complex deposition but the inciting antigens are unknown. Included in this category are membranous glomerulonephritis, many cases of polyarteritis nodosa, and several other vasculitides.


The morphologic consequences of immune complex injury are dominated by acute necrotizing vasculitis, with necrosis of the vessel wall and intense neutrophilic infiltration.

The necrotic tissue and deposits of immune complexes, complement, and plasma protein produce a smudgy eosinophilic deposit that obscures the underlying cellular detail, an appearance termed fibrinoid necrosis.

When complexes are deposited in kidney glomeruli, the affected glomeruli are hypercellular because of swelling and proliferation of endothelial and mesangial cells, accompanied by neutrophilic and monocytic infiltration.

The complexes can be seen on immunofluorescence microscopy as granular lumpy deposits of immunoglobulin and complement and on electron microscopy as electron-dense deposits along the glomerular basement membrane.

Local Immune Complex Disease (Arthus Reaction)

The Arthus reaction is a localized area of tissue necrosis resulting from acute immune complex vasculitis, usually elicited in the skin. The reaction can be produced experimentally by intracutaneous injection of antigen in an immune animal having circulating antibodies against the antigen.

As the antigen diffuses into the vascular wall, it binds the preformed antibody, and large immune complexes are formed locally, which precipitate in the vessel walls and trigger an inflammatory reaction.

In contrast to IgE-mediated type I reactions, which appear immediately, the Arthus lesion develops over a few hours and reaches a peak 4 to 10 hours after injection, when it can be seen as an area of visible edema with severe hemorrhage followed occasionally by ulceration.

Immunofluorescent stains reveal complement, immunoglobulins, and fibrinogen deposited in the vessel walls, usually the venules, and histologically the vessels show fibrinoid necrosis and inflammation. Thrombi are formed in the vessels, resulting in local ischemic injury.