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372 Part tHrEE Host Defenses to Infectious Agents

TABLE 25.4 Lesions resulting
From Immunopathology
Primarily involving CD8 T Murine lymphocytic choriomeningitis
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cells acting as cytotoxic T virus;
lymphocytes or sources of Hepatitis B virus (HBV)–induced
proinflammatory cytokines chronic hepatitis
Coxsackie B virus–induced diabetes
Coxsackie B virus–induced
myocarditis
Demyelination caused by some
strains of mouse coronavirus and
Theiler virus
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Primarily involving CD4 T Demyelination caused by some
cells that produce Th1 strains of mouse coronavirus and
cytokines Theiler’s virus;
Herpes simplex virus (HSV)–induced
stromal keratitis FIG 25.5 Example of Herpetic Stromal Keratitis (Hsk) in the
Involvement of CD4 T cells Respiratory syncytial virus (RSV)– Human Eye After Herpes Simplex Virus-1 (HSV-1) Infection.
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that produce Th2 cytokines induced pulmonary lesions
Involvement of antibody Glomerulonephritis in chronic Inflammation of the eye and eyelid can be observed, as well as
hepatitis B neovascularization and substantial necrosis, ulceration, and opacity
Dengue hemorrhagic fever of the cornea.

inflammatory environment that may exacerbate or tip the balance metalloproteinases, and components of the oxygen burst. Although
toward disease in genetically susceptible individuals. coxsackie virus can be a cause of diabetes in the mouse, attempts
Immunopathological reactions involving viruses have several to relate viral infection directly to the etiology of human diabetes
mechanisms, but T cells are usually involved as orchestrators of have so far failed.
inflammatory events (Table 25.4). The clearest example of
immunopathology involving a virus is lymphocytic choriomen- CLINICaL rELEVaNCE
ingitis virus (LCMV) in the mouse. This model has dominated
ideas and has set several paradigms in viral immunology in Hypothesized Role of Viruses in Autoimmunity
general. The first virus-induced immunopathological lesions Molecular mimicry: similar epitopes shared by virus and host
recognized were glomerulonephritis and arteritis, noted in mice Bystander activation: chronic release of cytokines and host antigens
persistently infected with LCMV. The lesions were assumed to activates local autoreactive lymphocytes
represent inflammatory reactions to tissue-entrapped immune Viral persistence: chronic viral antigen presentation on host cells leads
complexes that activate complement. Similar immune complex– to prolonged immunopathology
mediated lesions occur in other infections, including lung lesions
found in severe influenza, respiratory syncytial virus infection, Immunopathological reactions against viruses can also involve
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viral hepatitis, and arthritis. However, only rarely have viral subsets of CD4 T cells, which can be either Th1 or Th17 or
antigens been shown to contribute to the antigen component both. One well-studied example involves persistent infection with
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of the complex. An example where the inclusion of viral antigen Theiler virus in mice. This infection causes a demyelinating
in immune complexes has been demonstrated is chronic HBV syndrome that resembles the autoimmune disease experimental
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infection of humans. Autoimmune diseases, such as SLE, also allergic encephalomyelitis. In both situations, CD4 T cells that
result from immune complex–mediated tissue damage. However, produce Th1 cytokines appear to serve as pathological mediators.
evidence linking viruses to the etiology or pathogenesis of SLE Furthermore, in both models an increase in the involvement of
is scarce, since the immune complexes in SLE do not appear to myelin-derived autoantigens occurs as the disease progresses.
include viral antigens at any stage. Once again, such observations indicate the possible role of a
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Thanks largely to the LCMV model, it is clear that CD8 virus in an autoimmune disease. With the Theiler virus model,
T-cell recognition of viral antigens can result in tissue damage. the virus persists in the nervous system and chronically stimulates
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In LCMV infection, damage occurs in the leptomeninges of CD4 T cells to secrete an array of cytokines. The demyelinating
immunocompetent mice infected intracerebrally. Hepatitis can events appear to result from cytokine action on oligodendrocytes.
also occur in mice infected intravenously. Neither lesion becomes Myelin components, such as myelin basic protein, proteolipid
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evident if the CD8 T-cell response is suppressed. CD8 T protein, and myelin oligodendroglial glycoprotein, may be released
cell–mediated immunopathology can be a causative mechanism and can participate as additional antigen in immunoinflammatory
of chronic hepatitis associated with HCV and HBV infection, events. This scenario is referred to as epitope spreading.
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although the tissue damage also involves inflammatory CD4 T Another model of virus-induced immunopathology that
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cells. Additional viral immunopathology models where lesions mainly involves the Th1 subset of CD4 T cells is stromal keratitis
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result primarily from CD8 T-cell involvement include myocarditis caused by HSV infection (Fig. 25.5). The pathogenesis of this
and insulin-dependent diabetes associated with coxsackie B virus immunopathological lesion is unusual in that it occurs and
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infection. In both instances, CD8 T cells mainly orchestrate progresses when viral antigens can no longer be demonstrated.
events, but tissue damage may result from the bystander effects The chronic immunoinflammatory lesions are mainly orchestrated
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of cytokines and other molecules, such as lipid mediators, by CD4 T cells, but multiple early events induce the subsequent