Feline infectious peritonitis (FIP) continues to be a significant disease in domestic cats. The pathogenesis of FIP is complex,
involving feline coronavirus (FCoV) and an inappropriate humoral response to the virus. Only a minority of FCoV-infected cats
develop the lethal disease, and genetic factors are known to play a role in disease development.
Virus factors are important to disease development, as virus strains vary in virulence. It has been theorized that a viral
mutation is responsible for the change in biotype of the virus leading to disease production. Speculation on the genomic locale
of this mutation has involved the gene encoding the spike protein, as well as genes encoding several nonstructural proteins
including 3c, 7a, and 7b. However, no consistent genetic difference between virulent and avirulent biotypes has been found. In fact, a recent study found 100%
homology between the enteric and non-enteric viral genome from a cat with FIP. There do appear to be quantitative differences
in viral RNA levels in the blood of cats with and without FIP. Rising amounts of viral RNA in the blood seen in end-stage
disease may indicate that loss of immune control leads to enhanced viral replication and disease progression. This increased
viral replicative capacity may be a key element of FIP pathogenesis.
The lesions associated with FIP are due primarily to immune-mediated destruction. Type II and III hypersensitivity reactions
are involved, with immune complex formation, activation of complement, and cytotoxicity of infected macrophages releasing
inflammatory mediators. Neutrophils also are attracted to the lesions and release inflammatory mediators as well as cytotoxic
factors. Resultant lesions are associated with the vasculature, especially at serosal surfaces, with increased vascular permeability
and pyogranulomatous changes.
In addition to immune-mediated tissue destruction, lymphocyte depletion, particularly of T lymphocytes, is observed in affected
cats. Despite lack of viral infection of these cells, this lymphocyte depletion is characteristic of the disease, and has
been found to correlate with enhanced viral replication. Activated, but not resting lymphocytes appear to be killed by soluble
mediators; thus, FIPV-specific lymphocytes activated by infection are effectively singled out for destruction. Apoptotic factors
released from phagocytes may be responsible for this depletion. Cell-mediated immunity with cytotoxic T lymphocytes is critical
for protection against FIP; accordingly, this T lymphocyte depletion associated with FIP leads to reduced viral clearance.
Susceptibility to disease following FCoV infection appears to be inherited, with breed and familial predisposition. The host
genetic factors that lead to increased susceptibility are not clear, but seem to involve the immune response to FCoV infection, in particular, a shift from T helper lymphocyte type I (Th1) to Th type 2 (Th2) response to the infection. The former are
important in coordinating cell-mediated immunity, which is protective against FIP, while the latter are important in humoral
response. This shift results in an exaggerated humoral response which is not protective, and in fact actually enhances the
disease progression as it enhances monocyte/macrophage virus infection and mediates the immunopathology. Since lymphocytes
are not target cells of FCoV, it is theorized that secreted factors, including cytokines are critical to the lymphocyte effects,
such as the Th2 response and T lymphocyte depletion. In fact, the T lymphocyte response appears to be the decisive factor
in disease progression.
Cytokines are important mediators of the immune response. Monocytes and macrophages are major cytokine producers, and are
also the target of FIPV infection. T helper lymphocytes are the other major cytokine producer, and determine in large part
whether the cell-mediated (via Th1) or humoral (via Th2) arm of the immune response dominates. The cytokine secretion patterns
from these cells thus determine the magnitude and direction of the immune response. Cytokines associated with cell-mediated
immunity, such as IL-10 and -12, and IFN -γ have been found to decrease in cats that develop FIP. Elevations in cytokines
IL-1β and IL-6 have also been found in affected cats which may contribute to the humoral response. An increase in TNF-α has
been observed in some studies, and may contribute to the T lymphocyte apoptosis. A recent study has shown that FCoV-infected
macrophages produce factors that promote B cell differentiation into plasma cells. This may contribute the exaggerated humoral