(5) An autoimmune response may be produced if the virus (a) releases host-cell antigens, (b) alters host-cell antigens and act as a " helper determinant ", or (c) depresses the host genome, thus increasing the production of embryonic or other antigens.
In addition, the genetic makeup of the host, while not a mechanism of producing immunopathological damage, can influence the nature and severity of injury incurred during virus infection (Notkins et al., 1970).
In some infections, such as lymphocytic chorio- meningitis, the immune response of the host may be the principal cause of the pathological mani- festations while in other infections it may be of less importance. In most if not all virus infections, the host's immune response probably contributes somewhat to the pathological picture. It should be emphasized, however, that in the majority of cases the overall effect of the immune response is more likely to be beneficial than harmful.
Recent studies on virus-induced immunopatho- logical reactions in domestic and experimental ani- mals have led to the development of concepts and technical methods that may be useful in investi- gating certain viral diseases in man, including hepa- titis. Progress in the field of viral immunopathology has been rapid, and it was felt that a summary and critical review of present knowledge would encourage its wider application to clinical problems. Only selected references have been included, since the breadth of the subject made a complete review of the literature impracticable. Suggestions for further lines of investigation in viral immunopathology in general and in viral hepatitis in particular will be offered in Part 2 of this Memorandum, to be pub- lished later.
EFFECTS OF VIRUSES ON THE IMMUNE SYSTEM
It has long been known that certain virus infec- tions can alter the morphology of lymphoid organs. Electron microscopy studies have demonstrated the presence of virus particles in cells of the lympho- reticular system, such as macrophages, lymphocytes, neutrophils, thymocytes, Kupffer cells, and stem cells. More recent investigations have shown that certain viruses are able to replicate in macrophages (e.g., arboviruses, murine hepatitis virus, lactate dehydrogenase virus [LDV], and herpes simplex virus [RSV]) while others can replicate in lymphocytes (e.g., lymphocytic choriomeningitis virus [LCMV], leukaemia viruses, and Epstein-Barr virus [EBV]). Several viruses appear to replicate only in lyrnpho-
cytes that have undergone blast transformation fol- lowing exposure to specific antigen or phytohaemag- glutinin. Not all infections of the immune system, however, result in cell destruction; some lead to a persistent infection. For example, infection with EBV can result in the establishment of a continuous lymphoid cell line in vitro, while infection with the leukaemia viruses may be followed by malignant transformation.
Recent studies indicate that certain virus infections can affect the function of the immune system. These investigations have utilized the immune response to a variety of antigens unrelated to the infecting virus in order to evaluate immunologic function. Mur- Me leukaemia viruses have received the most atten- tion. These viruses usually depress the immune system, under certain circumstances to a significant extent (Dent, 1972). For example, the number of antibody-producing cells as determined by the haemolytic plaque test (Jerne) may reportedly be depressed by as much as 99 %. In general, infection prior to the injection of antigen was found to result in immunodepression, whereas infection after antigen administration had considerably less effect. The degree of immunodepression was dependent on the dose of virus and on the nature and concentration of the particular antigen. Moreover, some evidence has been adduced that the leukaemia viruses (parti- cularly Friend virus) can exert " selectively " depres- sive effects, i.e. that they produce a greater depression of the 7S than of the 19S immune response. Selective effects also have been described in connexion with other viruses. Infection with Aleutian disease virus (ADV) can result in the appearance in the serum of an excess of monoclonal immunoglobulin. It also has been claimed that LDV and LCMV can produce an acute and " selective " depression of T cells, but these results need to be confirmed and extended. Several non-oncogenic viruses (e.g., ADV, LCMV, and Junin virus) are also able to depress the humoral immune response. In addition, certain viruses, such as LDV, LCMV, and Venezue- lan equine encephalitis virus (VEEV), can prevent the development of experimentally-induced immuno- logic tolerance.
Although most studies of viral effects have been concerned with the humoral immune response, recent investigations of cell-mediated immunity and reticulo- endothelial function demonstrate that these too can be depressed. For example, allograft rejection is profoundly depressed in animals infected with Gross leukaemia virus and mildly depressed in animals in-