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Chapter 10 : Immune Complex Reactions

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Abstract:

Immune complex reactions are caused by immunoglobulin antibody reacting directly with tissue antigens (usually basement membrane antigens) or by antibody reacting with soluble antigen in the blood to form soluble antigen-antibody complexes that deposit in tissues. The Arthus reaction is a dermal inflammatory response caused by the reaction of precipitating antibody with antigen placed in the skin. The lesions of serum sickness directly correlate with the presence of soluble immune complexes. Human and experimental glomerulonephritis may also be initiated by antibodies to glomerular basement membrane (anti-GBM) or to antigens on epithelial cells. The experimental model is known as experimental autoimmune glomerulonephritis; the human diseases caused by anti-GBM are poststreptococcal glomerulonephritis, Goodpasture's disease, and anti-GBM nephritis associated with vasculitis. The major pathologic features of rheumatic fever are widespread inflammation and scarring in connective tissue in the heart, joints, lungs, pleura, subcutaneous tissue, and skin. The diffuse connective tissue diseases include rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, polymyositis (dermatomyositis), and progressive systemic sclerosis (scleroderma). The major pathologic changes of systemic lupus erythematosus (SLE) most frequently involve the kidney and skin, but systemic vasculitis may lead to symptoms relating to any organ of the body. In addition to the renal glomerulus, other organs of the body also contain capillary basement membrane exposed to circulating blood: the lung, synovial capillaries, the choroid plexus of the brain, and the uveal tract of the eye. These organs are susceptible to anti-basement membrane antibody attack and deposition of immune complexes.

Citation: Sell S. 2001. Immune Complex Reactions, p 302-358. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch10
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Figures

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Figure 10.1

Immune complex reactions. Antibody (usually IgG) reacts with soluble antigens to produce soluble circulating immune complexes or with basement membranes (such as renal glomerular basement membrane). Antibody-antigen complexes cause activation of complement with formation of inflammatory (phlogistic) complement fragments. Fragments C3a, C4a, and C5a (anaphylatoxin) cause constriction of vascular endothelium (increased vascular permeability). C5a is also chemotactic for polymorphonuclear leukocytes, and C3b enhances phagocytosis. Released lysosomal polymorphonuclear enzymes digest tissues, producing “fibrinoid” necrosis. Fibrinoid means “fibrinlike” and refers to the histologic appearance of the acellular amorphous areas produced by “digestion” of tissue by lysosomal enzymes that resemble the appearance of fibrin in clotted blood.

Citation: Sell S. 2001. Immune Complex Reactions, p 302-358. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch10
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Image of Figure 10.2
Figure 10.2

Comparison of double diffusion in agar precipitin reaction and Arthus reaction. When antibody and antigen are allowed to diffuse toward each other in agar, a precipitin band forms when the antigen and antibody concentration in the agar are in equivalence. Similarly, if antigen is injected into the skin, it will diffuse toward the vessels. The major precipitin reaction occurs in the walls of small vessels, usually arterioles, where antibody in the circulation diffuses out to meet antigen diffusing in from the tissue.

Citation: Sell S. 2001. Immune Complex Reactions, p 302-358. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch10
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Image of Figure 10.3
Figure 10.3

Steps in the Arthus reaction. (1) Injection of antigen into the dermis. (2) Diffusion of antigen in tissue to vessels. (3) Reaction of antigen with circulating antibody in the wall of small arterioles. (4) Formation of antibody-antigen complexes, aggregation of Fc of antibody, and activation of complement. (5) Contraction and separation of endothelial cells by C3a, C5a (anaphylatoxin), and attraction of neutrophils by C5a and C5a des-Arg chemotactic factors. (6) Activation of neutrophils in vessel wall with release of lysosomal enzymes. (7) Digestion of vascular wall producing fibrinoid necrosis. (8) Resolution or scarring, depending on severity of reaction.

Citation: Sell S. 2001. Immune Complex Reactions, p 302-358. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch10
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Image of Figure 10.4
Figure 10.4

Steps in serum sickness. (1) Formation of soluble antibody-antigen complexes in circulation. Such complexes do not fix complement because Fcs are not aggregated. (2) Soluble complexes pass through open endothelial spaces in glomeruli and deposit on the epithelial side of the basement membrane or in walls of small arteries. Accumulation of complexes results in formation of aggregates of immunoglobulin, activating complement. (3) Neutrophils are attracted, pass into basement membrane or vessel wall, and release lysosomal enzymes, causing destruction of basement membranes.

Citation: Sell S. 2001. Immune Complex Reactions, p 302-358. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch10
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Figure 10.5

Comparison of antigen elimination, precipitin reaction, and serum complement levels during experimental serum sickness. Immune elimination of antigen follows production of antibody that binds to antigen in the circulation. When antibody first appears, there is an excess of antigen so that soluble immune complexes in antigen excess are formed. These complexes lodge in arteries and, in particular, in glomeruli, where aggregates of immunoglobulin fix complement. This results in lesions of serum sickness and a fall in serum complement. As more antibody is produced, complexes in equivalence and then antibody excess are found. Since these complexes contain aggregated Fc regions of immunoglobulin, they will be cleared from the circulation by the reticuloendothelial system because of receptors on macrophages for aggregated Fc and C3b.

Citation: Sell S. 2001. Immune Complex Reactions, p 302-358. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch10
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Figure 10.6

Pathogenesis of glomerulonephritis. Depicted is part of a glomerulus. The mesangial cells are located in the center and support the endothelial cells (END), which line the inside of the basement membrane. There are gaps in the cytoplasm of the endothelial cells, which expose the basement membrane to blood components. The upper left part of the figure illustrates deposition of antiglomerular basement membrane (anti-GBM) antibody as a linear deposit of immunoglobulin on the endothelial side of the basement membrane. The upper right depicts deposition of soluble immune complexes on exposed basement membrane after contraction of endothelial cells by vasoactive amines or activation of anaphylatoxin. The lower left segment illustrates that the complexes may deposit as large clumps, distorting the foot processes of the endothelial cells. Dissolution of the basement membrane by release of lysosomal enzymes from polymorphonuclear leukocytes (POLYS) activated by complement or alterations in the electrostatic properties of the basement membrane by anti-GBM or immune complex deposition leads to leakage of proteins into the urine (proteinuria) (upper right). If more extensive destruction of the basement membranes occurs, cellular elements of the blood, as well as basement membrane fragments, may be detected in the urine. Prolonged accumulation of immune reactants leads to thickening of the basement membrane and fusion of the foot processes of epithelial cells (EPI). Clinically, this is expressed as a loss of the filtering capacity of the kidney and retention of toxic metabolites (uremia).

Citation: Sell S. 2001. Immune Complex Reactions, p 302-358. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch10
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Image of Figure 10.7
Figure 10.7

Effect of charge on immune complex localization in glomeruli. Cationic immune complexes (positively charged) preferentially localize in the glomerular basement membrane (A). Subepithelial localization may be explained by a higher density of anions on the epithelial side of the basement membrane. Cationic free antigen may deposit in the basement membrane (B), and subsequent reaction with antibody leads to formation of immune complexes within the basement membrane. Anionic complexes tend to be taken up by the mesangial cells (C) and are less pathogenic but may also localize on the endothelial side of the basement membrane (D).

Citation: Sell S. 2001. Immune Complex Reactions, p 302-358. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch10
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Image of Figure 10.8
Figure 10.8

Schematic localization of Goodpasture antigen α3 chain of type IV collagen in glomerular basement membrane. The endothelial and epithelial surface of the glomerular basement membrane is lined with laminin, the membrane itself is composed of a scaffold of two subtypes of type IV collagen molecules (building blocks). Subtype A (classical) contains α1 and α2 chains; subtype B contains the α3 chain (Goodpasture antigen). The endothelial surface has a net negative charge; it repels negatively charged antibodies, but cationic antibodies pass into the membrane to react with Goodpasture antigen. Serum of patients with poststreptococcal glomerulonephritis may bind with any of the major components of the basement membrane. (Modified from B. G. Hudson, J. Wieslander, B. J. Wisdom, Jr., and M. E. Noelken, Lab. Investig. 61:256–269, 1989.)

Citation: Sell S. 2001. Immune Complex Reactions, p 302-358. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch10
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Image of Figure 10.9
Figure 10.9

Glomerulonephritis: clinical-pathologic correlations. The mechanisms of glomerulonephritis illustrated may produce a varied clinical and pathologic picture. (I) Anti-glomerular basement membrane antibody reacts with antigens on the lumenal side of the glomerular basement membrane and produces a linear deposition when examined by immunofluorescence. (II) Soluble immune complexes formed elsewhere pass through the glomerular basement membrane and lodge on the epithelial side, producing lumpy-bumpy deposits, or lodge within or on the endothelial side of the basement membrane as granular deposits. Granular deposit disease may also be produced from endothelial cell surface antigen- antibody complexes shed into the basement membrane. (III) Complement in the absence of immunoglobulin may be detected as a granular deposit. Hypocomplementemic glomerulonephritis may be caused by a preceding immunoglobulin deposit or by the action of properdin, both of which may activate complement. No single mechanism produces a particular type of clinical picture or pathologic lesion, although hypocomplementemic glomerulonephritis is usually of the chronic variety. A capillary lumen, basement membrane endothelial cell foot plates, and an epithelial cell are illustrated. (Modified from an illustration by C. Wilson, Scripps Clinic and Research Foundation, La Jolla, Calif.)

Citation: Sell S. 2001. Immune Complex Reactions, p 302-358. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch10
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Image of Figure 10.10
Figure 10.10

The immune response to streptococcal group A antigens and rheumatic fever. Antibodies produced to streptococcal antigens cross-react with host tissue antigens. These “autoantibodies,” as well as soluble immune complexes, are responsible for the lesions of rheumatic fever (myocarditis, endocarditis, arthritis, vasculitis, and glomerulonephritis).

Citation: Sell S. 2001. Immune Complex Reactions, p 302-358. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch10
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Image of Figure 10.11
Figure 10.11

Pathologic features of connective tissue diseases. The relative frequency of the lesions associated with connective tissue diseases (bottom) is indicated by the thickness of the boxes (top). Serum sickness is included because its characteristic lesions (vasculitis, glomerulonephritis, myocarditis, and arthritis) are also found in the connective tissue diseases. This suggests a primary role for immune complex mechanisms in connective tissue disease.

Citation: Sell S. 2001. Immune Complex Reactions, p 302-358. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch10
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Image of Figure 10.12
Figure 10.12

Current concepts of the pathogenesis of rheumatoid arthritis postulate that an as yet unidentified antigen (infectious agent, host autoantigen) present in the joint cavity stimulates the production of an antibody. Antigen-antibody complexes that produce an alteration in the tertiary structure of the antibody, revealing new or buried antigenic determinants, are formed. These determinants in turn stimulate the production of another antibody, RF (IgM or IgG), which can react with IgG. Complexes form in the synovial fluid and activate complement components which attract PMNs. A proliferation of lymphocytes and plasma cells in the synovial lining tissue converts the synovium into a lymphoid organ, which produces RF that is released locally into the synovial fluid. TDTH lymphocytes in the synovium are activated to produce lymphokines that attract and activate macrophages. Activated macrophages and lymphocytes secrete cytokines that upregulate expression of cell adhesion molecules on endothelial cells and synovial fibroblasts. Macrophages also produce osteoclast activating factor and other activation factors that lead to destruction of adjacent bone. Hyperplasia of granulation tissue and inflammatory cells occurs and extends as a mass (pannus) over the articular cartilage. The pannus produces collagenase and elastase that destroys the joint cartilage. This pannus may progress to form a scar in the joint that leads to immobilization.

Citation: Sell S. 2001. Immune Complex Reactions, p 302-358. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch10
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Image of Figure 10.13
Figure 10.13

Formation of LE cells. LE cells are PMNs that have phagocytosed the nuclei of lymphocytes by coating the nuclei with antibody. This takes place at 37°C upon incubation of the whole blood of a patient with SLE who has antibody to nucleoprotein or other nuclear antigens. Lymphocytes break up, and lymphocyte nuclei become coated with antibody (LE factor), swell, and are phagocytosed by PMNs. LE cells may also be formed by phagocytosis of the nuclei of cells other than lymphocytes.

Citation: Sell S. 2001. Immune Complex Reactions, p 302-358. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch10
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References

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Tables

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Table 10.1

Classification of immune complex glomerular disease

Citation: Sell S. 2001. Immune Complex Reactions, p 302-358. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch10
Generic image for table
Table 10.2

Some forms of glomerulonephritis of humans a

Citation: Sell S. 2001. Immune Complex Reactions, p 302-358. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch10
Generic image for table
Table 10.3

Pathologic overlap in selected vasculitis syndromes a

Citation: Sell S. 2001. Immune Complex Reactions, p 302-358. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch10
Generic image for table
Table 10.4

Revised criteria for the diagnosis of rheumatic fever (updated 1992) a

Citation: Sell S. 2001. Immune Complex Reactions, p 302-358. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch10
Generic image for table
Table 10.5

The 1987 revised criteria for the classification of rheumatoid arthritis (traditional format) a

Citation: Sell S. 2001. Immune Complex Reactions, p 302-358. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch10
Generic image for table
Table 10.6

Spondyloarthropathies associated with HLA-B27 a

Citation: Sell S. 2001. Immune Complex Reactions, p 302-358. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch10
Generic image for table
Table 10.7

The 1982 revised criteria for classification of systemic lupus erythematosus a

Citation: Sell S. 2001. Immune Complex Reactions, p 302-358. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch10
Generic image for table
Table 10.8

Some reactivities of antinuclear antibodies a

Citation: Sell S. 2001. Immune Complex Reactions, p 302-358. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch10
Generic image for table
Table 10.9

Nuclear staining patterns observed in patients with connective tissue diseases

Citation: Sell S. 2001. Immune Complex Reactions, p 302-358. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch10
Generic image for table
Table 10.10

Autoantibodies in SLE and other connective tissue diseases a

Citation: Sell S. 2001. Immune Complex Reactions, p 302-358. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch10
Generic image for table
Table 10.11

Genetic features of SLE

Citation: Sell S. 2001. Immune Complex Reactions, p 302-358. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch10
Generic image for table
Table 10.12

Characteristics of inflammatory myopathies a

Citation: Sell S. 2001. Immune Complex Reactions, p 302-358. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch10
Generic image for table
Table 10.13

Symptoms and lesions of PSS

Citation: Sell S. 2001. Immune Complex Reactions, p 302-358. In Immunology, Immunopathology, and Immunity, Sixth Edition. ASM Press, Washington, DC. doi: 10.1128/9781555818012.ch10

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