antigen specific CD4+ helper lymphocyte populations by γδ-T-cells could be involved in the proliferation of Map and in the development of clinical disease (Chiodini and Davis, 1993). Some of the mechanisms underlying age-related resistance have been explained, but there are still questions about the importance of horizontal transmission in older animals. Age-related susceptibility to Map infection has not been investigated thoroughly in species other than cattle.

Genetic susceptibility to JD has been investigated only in mice, cattle, and humans. The susceptibility of mice to the establishment of mycobacterial infections has been shown to be controlled by a single, dominant, autosomal gene called the Bcg gene locus, which directly regulates the process of T-cell-dependent macrophage activation for antimycobacterial function and, indirectly, the quality and magnitude of the specific immune response to M. bovis (Skamene, 1989). It is thought that the Bcg-resistant allele confers to the macrophage the ability to inhibit the proliferation of mycobacteria (Frelier et al., 1990). Similar genetic resistance has been described for M. intracellulare (Goto et al., 1984). Inbred C57BL/6J mice are more susceptible to infection by Map than are outbred Swiss mice, and resistance to Map and M. bovis is regulated by the same locus or by linked loci (Frelier et al., 1990). The Nramp gene (a component of the Bcg locus) has been linked to resistance in mycobacterial infections, including murine models of JD (Blackwell et al., 1994; Chandler, 1961; Frelier et al., 1990; Hackam et al., 1998; Levin and Newport, 2000; Veazey et al., 1995). The bovine equivalent of that gene has been identified, and based on its homology to the murine Nramp1 gene, it could have similar functions (Feng et al., 1996). However, Barthel and colleagues (2000) were unable to detect an association between resistance or susceptibility to infection with M. bovis and polymorphism in the Nramp1 gene, suggesting that the Nramp1 gene might not determine resistance or susceptibility to M. bovis infections in cattle. The involvement of the Nramp1 gene in the elimination of Map in cattle is currently unknown (Valentin-Weigand and Goethe, 1999). Mutations in other genes critical for macrophage up-regulation, including interferon-γ (IFN-γ), IFN-γ receptor, tumor necrosis factor (TNF) receptor, or interleukin-12 (IL-12), or IL-12-receptor genes, are all associated with decreased resistance to mycobacterial infection in humans (Levin and Newport, 2000). Studies of genetic resistance could be important in the control of JD if they promote the identification or development of resistant cattle (Koets et al., 2000).

Efforts to dissect the immune system and identify the mechanisms that regulate the immune response to pathogens have involved the use of multiple laboratory species, especially the mouse. The use of inbred mouse strains with inherited differences in susceptibility to infectious agents, and knockout mice missing genes encoding molecules involved in development of an immune