deposited in small blood vessels and kidney glomeruli over periods of weeks, months, or even years, leading to impairment of glomerular filtration and eventually to chronic glomerulonephritis.

A classic example is lymphocytic choriomeningitis infection in mice infected in ufero or as neonates Viral antigens are present in the blood, and small amounts of nonneutralizing antibody are formed, giving rise to immune complexes which are progressively deposited on renal glomerular membranes; the end result may be glomerulonephritis, uremia, and death. Circulating immune complexes may also be deposited in the walls of the small blood vessels in skin, joints, and choroid plexus, where they attract macrophages and activate complement Prodromal rashes, which are commonly seen in exanthematous diseases, are probably caused in this way. A more severe manifestation of the deposition of antigen-antibody-complement complexes in capillaries is erythema nodosum (tender red nodules in the skin); when small arteries are involved, as occasionally seen with hepatitis B, periarteritis nodosa results.

In addition to these local effects, by mobilizing soluble mediators antigen-antibody complexes may generate systemic reactions, such as fever, malaise, anorexia, and lassitude, that occur in most viral infections. Little is known about their causes, but fever can be attributed to interleukin-1 and tumor necrosis factor (produced by macrophages), and possibly lo interferons. These and other soluble mediators produced by leukocytes, or released from virus-infected cells, may be responsible for other general symptoms as well.

Rarely, systemic immune complex reactions may activate the enzymes of the coagulation cascade, leading to histamine release and increased vascular permeability. Fibrin is deposited in the kidneys, lungs, adrenals, and pituitary gland, causing multiple thromboses with infarcts and scattered hemorrhages, a condition known as disseminated intravascular coagulation. This is seen in the hemorrhagic fevers, many of which are zoonoses caused by arenaviruses, bunyaviruses, filoviruses, or flaviviruses; it probably also occurs in other severe systemic diseases.

Type IV—Cell-Mediated Hypersensitivity

Unlike the previous types, the type IV "delayed hypersensitivity" reactions are mediated by cells rather than antibody. They are T-lymphocyte-mediated immune reactions, involving inflammation, lymphocytic infiltration and macrophage accumulation, and activation by lymphokines secreted by Td cells. Such reactions, involving infected endothelial cells of small cutaneous blood vessels, are largely responsible for the maculopapular rash of measles; they also play a role in production of the pustular lesions of smallpox, in which extensive viral replication occurs in the cutaneous epithelium.

The classic model of death due to a cell-mediated immune response is lymphocytic choriomeningitis (LCM) virus infection after primary infection of adult mice by intracerebral inoculation The virus replicates harmlessly in the meninges, ependyma, and choroid plexus epithelium for about a week, until a Tc-Iymphocyte-mediated immune response occurs, causing severe meningitis, cerebral edema, and death Elsewhere than in the central nervous system, Tc cells help to control infection, but within the rigid confines of the skull these changes are fatal The death of mice infected m this way can be completely prevented by chemical immunosuppression, by X irradiation, or by antilymphocyte serum.

Although instructive, intracerebral inoculation of mice with LCM virus is a very unnatural experimental system. When mice are infected with influenza virus by the natural (intranasal) route they develop a lethal pneumonia. In one study it was found that adoptive transfer of influenza virus-primed CD8 1 cytotoxic T cells protects mice against intranasal challenge, but CD4( Thl cells actually accelerate their demise. In general, although occasionally the cause of immunopathology, cell-mediated immune responses are an important component of the process of recovery from viral infections (see Chapter 8), as becomes evident if they are abrogated by cytotoxic drugs, or are absent, as in some immunodeficiency diseases.


Autoantibodies directed against host proteins can be detected quite commonly in viral infections, although usually only transiently and in low titer. In one study, 4% of a large panel of monoclonal antibodies raised against several viruses were found to react with normal tissues. For example, a monoclonal antibody directed against the neutralizing domain of coxsackie B4 virus also reacts against heart muscle; this virus is known to target muscle, including the heart, and to cause myocarditis.

A likely explanation for the widespiead cross-reactivity has emerged in the course of computer searches of the international data banks that now contain complete amino acid sequences of thousands of viral and cellular proteins. It transpires that viral proteins share identical or near-identical stretches of 6-10 amino acids with cellular proteins far more frequently than would be predicted by chance. For instance, there is partial homology of amino acid sequence between myelin basic protein (MBP) and several viral proteins, some of which are shown in Table 9-1. Such molecular mimicry may be involved in the neurologic disorders associated with the lentivirus infections visna and caprine arthritis-encephalitis, and in the rare occurrence of postvaccinia! encephalitis in humans. Inoculation of a neuritogenic epitope in

Table 9-1

Epitope Mimicry between Myelin Basic Protein and Viruses Causing Demyelinating Diseases"

Table 9-1

Epitope Mimicry between Myelin Basic Protein and Viruses Causing Demyelinating Diseases"



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