Immune complex diseases

Immune complexes are formed when antibody meets antigen, and generally they are removed effectively by the liver and spleen via processes involving complement, mononuclear phagocytes and erythrocytes.

Immune complexes may persist and eventually deposit in a range of tissues and organs. The complement and effector cell-mediated damage that follows is known as a type III hypersensitivity reaction or immune complex disease.

The sites of immune complex deposition are partly determined by the localization of the antigen in the tissues and partly by how circulating complexes become deposited.

Immune complex formation can result from:

Fig. 25.1 Three categories of immune complex disease

This table indicates the source of the antigen and the organs most frequently affected.

Type II and type III hypersensitivity reactions are similar in concept and action and are not mutually exclusive. Both types of reactions may be seen in autoimmune rheumatic disorders such as systemic lupus erythematosus where autoimmune haemolytic anaemia and immune thrombocytopenic purpura may occur.

Persistent infection with a weak antibody response can lead to immune complex disease

The combined effects of a low-grade persistent infection and a weak antibody response lead to chronic immune complex formation, and eventual deposition of complexes in the tissues (Fig. 25.2). Diseases with this etiology include:

• leprosy;

• malaria;

• dengue hemorrhagic fever;

• viral hepatitis; and

• staphylococcal infective endocarditis.

Fig. 25.2 Immunofluorescence study of immune complexes in infectious disease

These serial sections of the renal artery of a patient with chronic hepatitis B infection are stained with fluoresceinated anti-hepatitis B antigen (1) and rhodaminated anti-IgM (2). The presence of both antigen and antibody in the intima and media of the arterial wall indicates the deposition of complexes at this site. IgG and C3 deposits are also detectable with the same distribution.

(Courtesy of Dr A Nowoslawski.)

Immune complexes can be formed with inhaled antigens

Immune complexes may be formed at body surfaces following exposure to extrinsic antigens.

Such reactions are seen in the lungs following repeated inhalation of antigenic materials from molds, plants, or animals. This is exemplified in:

• farmer’s lung, where there are circulating antibodies to actinomycete fungi (found in moldy hay); and

• pigeon fancier’s lung, where there are circulating antibodies to pigeon antigens.

Both diseases are forms of extrinsic allergic alveolitis, and occur only after repeated exposure to the antigen. Note that the antibodies induced by these antigens are primarily IgG, rather than the IgE seen in type I hypersensitivity reactions. When antigen again enters the body by inhalation, local immune complexes are formed in the alveoli leading to inflammation and fibrosis (Fig. 25.3).

Fig. 25.3 Extrinsic allergic alveolitis

The histological appearance of the lung in extrinsic allergic alveolitis (1) shows consolidated areas due to cell accumulation. When fungal antigen is inhaled into the lung of a sensitized individual, immune complexes are formed in the alveoli (2). Complement fixation leads to cell accumulation, inflammation, and fibrosis. Precipitin antibody (P) present in the serum of a patient with pigeon fancier’s lung (3) is directed against the fungal antigen Micropolyspora faeni. Normal serum (N) lacks antibodies to this fungus.

Precipitating antibodies to actinomycete antigens are found in the sera of 90% of patients with farmer’s lung. However, they are also found in some people with no disease, and are absent from some patients, so it seems that other factors are also involved in the disease process, including type IV hypersensitivity reactions.

Immune complex disease occurs in autoimmune rheumatic disorders

Immune complex disease is common in autoimmune disease, where the continued production of autoantibody to a self antigen leads to prolonged immune complex formation. As the number of complexes in the blood increases, the systems responsible for the removal of complexes (mononuclear phagocyte, erythrocyte, and complement) become overloaded, and complexes are deposited in the tissues (see Fig. 25.16). Systemic lupus erythematosus (SLE) is the classic disease characterized by immune complex deposition and others include Henoch-Schönlein purpura and primary Sjögren’s syndrome.

Fig. 25.16 Immunofluorescence study of immune complexes in autoimmune disease

These renal sections compare the effect of systemic lupus erythematosus (type III hypersensitivity) (1) and Goodpasture’s syndrome (type II hypersensitivity) (2). In each case the antibody is detected with fluorescent anti-IgG. Complexes, formed in the blood and deposited in the kidney, form characteristic ‘lumpy bumpy’ deposits (1). The anti-basement membrane antibody in Goodpasture’s syndrome forms an even layer on the glomerular basement membrane (2).

(Courtesy of Dr S Thiru.)

Cryoglobulins precipitate at low temperature

Cryoglobulins are immunoglobulins that precipitate reversibly at low temperature. They may be divided into three classes:

• type I consists of a single monoclonal immunoglobulin and is typically found in association with lymphoproliferatve diseases;

• type II is monoclonal IgM with rheumatoid factor activity, i.e. it binds to IgG;

• type III consists of polyclonal IgM rheumatoid factors.

Types II and III, also referred to as mixed cryoglobulins, are found in association with infectious, immunological, and neoplastic diseases. Mixed cryoglobulinemic vasculitis is a major extra-hepatic manifestation of chronic hepatitis C virus infection. Clinical features include arthralgia, cutaneous purpuric vasculitis, glomerulonephritis and peripheral neuropathy. Hepatitis C virus associated mixed cryoglobulinemia is characterized by a clonal expansion of B cells secreting IgM-RF which may be found in the liver, bone marrow and in the peripheral blood mononuclear cells of hepatitis C virus infected patients.

Immune complexes and inflammation

Immune complexes are capable of triggering a wide variety of inflammatory processes:

Fig. 25.4 Immune complexes as a trigger for increasing vascular permeability

Immune complexes normally bind complement and are removed to the liver and spleen after binding to CR1 on erythrocytes. In inflammation, immune complexes act on basophils and platelets (in humans) to produce vasoactive amine release. The amines released (e.g. histamine, 5-hydroxytryptamine) cause endothelial cell retraction and thus increase vascular permeability.

Studies with knockout mice indicate that complement has a less proinflammatory role than previously thought, whereas cells bearing Fc receptors for IgG and IgE appear to be critical for developing inflammation, with complement having a protective effect.

The vasoactive amines released by platelets, basophils, and mast cells cause endothelial cell retraction and thus increase vascular permeability, allowing the deposition of immune complexes on the blood vessel wall (Fig. 25.5). The deposited complexes continue to generate C3a and C5a.

Fig. 25.5 Deposition of immune complexes in blood vessel walls

Increased vascular permeability allows immune complexes to be deposited in the blood vessel wall. This induces platelet aggregation and complement activation. The aggregated platelets form microthrombi on the exposed collagen of the basement membrane of the endothelium. Neutrophils are attracted to the site by complement products, but cannot ingest the complexes. They therefore exocytose their lysosomal enzymes, causing further damage to the vessel wall.

Platelets also aggregate on the exposed collagen of the vessel basement membrane to form microthrombi.

The aggregated platelets continue to produce vasoactive amines and to stimulate the production of C3a and C5a. Platelets are also a rich source of growth factors – these may be involved in the cellular proliferation seen in immune complex diseases such as glomerulonephritis.

Polymorphs are chemotactically attracted to the site by C5a. They attempt to engulf the deposited immune complexes, but are unable to do so because the complexes are bound to the vessel wall. Therefore they exocytose their lysosomal enzymes onto the site of deposition (see Fig. 25.5). If simply released into the blood or tissue fluids these lysosomal enzymes are unlikely to cause much inflammation, because they are rapidly neutralized by serum enzyme inhibitors. But if the phagocyte applies itself closely to the tissue-trapped complexes through Fc binding, then serum inhibitors are excluded and the enzymes may damage the underlying tissue.

Experimental models of immune complex diseases

Experimental models are available for the main types of immune complex disease described above:

Care must be taken when interpreting animal experiments because the erythrocytes of rodents and rabbits lack the receptor for C3b (known as CR1), which readily binds immune complexes that have fixed complement. This receptor is present on primate erythrocytes.

Serum sickness can be induced with large injections of foreign antigen

In serum sickness, circulating immune complexes deposit in the blood vessel walls and tissues, leading to increased vascular permeability and thus to inflammatory diseases such as glomerulonephritis and arthritis.

Serum sickness is now commonly studied in rabbits by giving them an intravenous injection of a foreign soluble protein such as bovine serum albumin (BSA). After about 1 week antibodies are formed, which enter the circulation and complex with antigen. Because the reaction occurs in antigen excess, the immune complexes are small (Fig. 25.w1). These small complexes are removed only slowly by the mononuclear phagocyte system and therefore persist in the circulation.

Fig. 25.w1 Time course of experimental serum sickness

Following an injection of xenogeneic serum there is a lag period of approximately 5 days, in which only free antigen is detectable in serum. After this time, antibodies are produced to the foreign proteins and immune complexes are formed in serum; it is during this period that the symptoms of nephritis and arteritis appear. To begin with, small soluble complexes are found in antigen excess; with increasing antibody titers, larger complexes are formed, which are deposited and subsequently cleared. At this stage the symptoms disappear.

Q. Suggest two reasons why small immune complexes would be cleared more slowly than large complexes

A. Small complexes activate complement less effectively than large complexes because C1 must bind to several Fc regions before it is activated. The avidity of complexes for binding to phagocytes will also be increased when several Fc regions are available to bind to the Fc receptors on a phagocyte. If this were not so, monomeric antibody would block binding of complexes to Fc receptors.

The formation of complexes is followed by an abrupt fall in total hemolytic complement.

The clinical signs of serum sickness that develop are due to granular deposits of antigen–antibody and C3 forming along the glomerular basement membrane (GBM) and in small vessels elsewhere. As more antibody is formed and the reaction moves into antibody excess, the size of the complexes increases and they are cleared more efficiently, so the animals recover. Chronic disease is induced by daily administration of antigen.

Q. Why would immune complexes deposit in the glomerulus when the complexes are formed outside the kidney?

A. The glomerulus has fenestrated endothelium and is a site of filtration for large volumes of plasma under high pressure.

Autoimmunity causes immune complex disease in the NZB/NZW mouse

The F₁ hybrid NZB/NZW mouse produces a range of autoantibodies (including anti-erythrocyte, anti-nuclear, anti-DNA, and anti-Sm) and suffers from an immune complex disease similar in many ways to SLE in humans. A NZB/NZW mouse is born clinically normal, but within 2–3 months shows sign of hemolytic anemia. Tests for anti-erythrocyte antibody (the Coombs’ test), anti-nuclear antibodies, lupus cells, and circulating immune complexes are all positive, and there are deposits in the glomeruli and choroid plexus of the brain. The disease is much more marked in the females, who die within a few months of developing symptoms (Fig. 25.w2).

Fig. 25.w2 Autoimmune disease in NZB/NZW mice

The graph shows the onset of autoimmune disease in female NZB/NZW mice with advancing age. Incidence refers to the percentage of mice with the features identified. Immune complexes were detected by immunofluorescent staining of a kidney section. Anti-nuclear antibodies were detected in serum by indirect immunofluorescence. Proteinuria reflects kidney damage. Autoantibodies to erythrocytes develop later in the disease and so are less likely to relate to kidney pathology. Onset of autoimmune disease is delayed in male mice by approximately 3 months.

The role of Fc receptors in the ‘treatment’ of immune complex disease

Buy Membership for Allergy and Immunology Category to continue reading. Learn more here