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the mouse, the amount of LCMV, and the amount of antiviral antibody (Oldstone & Dixon, 1969). Aleutian disease of mink also is characterized by severe glomerulonephritis (Porter et al., 1969). All mink appear to be susceptible to infection by ADV, but those homozygous for the Aleutian gene develop a more severe form of the disease, characterized by heavy deposition of virus, antibody, and complement in the glomeruli. However, relatively mild glomeru- lar lesions are seen in mice infected with LDV. In humans, circulating Australia antigen can exist in the form of antigen—antibody complexes (Zucker- man, 1971). One case of immune-complex nephritis with deposition of Australia antigen, IgG, and complement in the glomeruli has been reported, and in 4 cases of hepatitis autopsy disclosed the presence of Australia antigen, IgG, IgM, and comple- ment in glomerular capillaries.

There is generally little evidence that vasculitis can be caused by virus—antibody complexes, but vascular lesions suggestive of polyarteritis nodosa and containing immunoglobulins have been reported late in the course of infection with ADV and EIAV. Recently, polyarteritis nodosa has been described in patients with circulating Australia antigen (Gocke et al., 1971); in one such case, Australia antigen, immunoglobulin, and complement were detected in the arterial wall (Gocke et al., op. cit.). In 5 cases of fatal hepatitis, Australia antigen, immuno- globulin, and complement were found in the intima of arterioles exhibiting changes typical of periarte- ritis. It has also been suggested that immune com- plexes may be causally involved in the urticaria and arthritis (Alpert et al., 1971) sometimes associated with hepatitis.

producing virus-induced immune-complex disease. Whether the causal factor is the size of the complex, the nature of the viral antigen, the amount or type of antibody, the attachment of accessory factors such as complement (Winchester et al., 1971) or rheumatoid factor (Notkins, 1971; Winchester et al., 1971; Ziegenfuss et al., 1971), or the rate at which the antigen and antibody turn over (in the glomeru- lar lesions) remains to be determined.

To date, virus-induced immune-complex disease has been attributed to the deposition of virus— antibody complexes during persistent virus infections (Oldstone & Dixon, 1971b). Conceivably, immune- complex disease also could occur from the repeated deposition of such complexes during various acute and recurrent virus infections. It should be empha- sized that, in addition to virion—antibody complexes, antibody bound to virus-induced membrane anti- gens, soluble viral antigens, and viral nucleoproteins might contribute to the pool of circulating immune complexes.

The mechanism of tissue injury associated with deposition of virus—antibody complexes is presu- mably similar to that involved in the deposition of nonviral antigen—antibody complexes. It is known that activation of the complement sequence by immune complexes can effect the release of sub- stances that have the capacity to increase vascular permeability, contract smooth muscle, and attract polymorphonuclear and mononuclear leucocytes. These factors would seem to play a role in the tissue injury associated with immune-complex disease. In addition, it has been postulated that immune complexes might activate components of the clotting system and thereby cause the deposition of fibrin.

Although deposition of circulating immune com- plexes appears to be the most likely explanation of these findings, the possibility has not been excluded that viral antibody might attach to viral antigens released locally from infected cells or to virus-induced antigens on the surface of infected cells (see section entitled " Antibody-mediated immunopathological injury "). In several autopsy studies of patients with various forms of hepatitis, intracellular and extracellular deposits of Australia antigen, immuno- globulins and complement were reportedly found in liver parenchymal and Kupffer cells (Nowos- lawski et al., 1972). In these cases, immunoglobulins directed specifically against Australia antigen were eluted from the Ever with 2.5 m thiocyanate. At present, however, there is very little information available to pinpoint the factors responsible for


(1) The presence of immune complexes in the kidney, arterial walls, or other tissues should be confirmed by demonstrating viral antigens, specific antiviral antibody, and complement in the lesions by immunolluorescence. If, however, the antigen cannot be detected because antigenic sites have been saturated by antiviral antibody, the antibody should if possible be dissociated by standard tech- niques (e.g., acid buffer, pH 2.0-3.0). The eluted antigen or antibody may be characterized by im- munodiffusion, complement fixation, virus neutrali- zation, or other techniques.

(2)Attempts should be made to recover and iden- tify infectious virus from the kidney, extrarenal

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