"Bovine leukemia virus (BLV) is a delta-retrovirus that is the causative agent of enzootic bovine leukosis (EBL). BLV is extremely prevalent in US dairy herds. Over 83% of dairy herds are predicted to be BLV-infected, and with an average within-herd prevalence nearing 50%, it is estimated that over 40% of all dairy cows in the United States are BLV+. Although the prevalence of BLV infection is quite high, it is fairly uncommon for dairy producers to monitor infection within their herds: a recent survey found that less than 13% of dairy producers even test for BLV. It is likely this disinterest is the result of the low incidence of clinical disease. While BLV infection does cause lethal lymphosarcomas, fewer than 5% of infected cattle are expected to develop cancer as a result of BLV infection. Despite the low incidence of oncogenesis, BLV infection has been associated with decreased milk production and decreased longevity in infected cows. It is now hypothesized that BLV actually impairs immune function in infected cattle and that BLV+ cows are more at risk for contracting secondary infections, and that those secondary infections are responsible for impaired production and health observed in BLV+ cows. Although there was strong evidence for abnormal immune cell populations and functions in vitro, there were only a few studies investigating how well the immune system of BLV+ cows functioned in vivo. The goal of this dissertation was to investigate the in vivo function of the immune system in BLV+ cows. To investigate the in vivo function of the immune system in BLV+ cows, we tracked B and T cell responses to a routine vaccination and to a primary and secondary antigenic exposure. We found that BLV+ cows consistently exhibited lower levels of antigen-specific IgM and equal levels of IgG1 in comparison to BLV- cows. Based on our data, it is also possible that BLV+ cows produce less antigen-specific IgG2, although our data suggests that altered IgG2 production would not be observed across all antigens and that impaired IgG2 production requires a high level of antigen exposure in BLV+ cows. We also observed reduced circulating effector or memory B and gamma-delta T cell populations in BLV+ cows, as well as abnormal B and T cell responses to antigenic and mitogenic stimulation in vitro. Overall, we observed both reduced and abnormal immune function in the B and T cell compartments in BLV+ cows relative to BLV- cows. When we investigated possible virulence mechanisms by which BLV interferes with IgM production, we found that B cells from BLV+ cows exhibited reduced IGJ, BLIMP1, and BCL6 expression. In addition, markers of BLV transcription were negatively correlated with IgM levels and BLIMP1 and BCL6 expression. In particular, BLIMP1 and BCL6 may be direct targets of BLV miRNAs. Overall, we observed a possible mechanism by which IgM production in BLV+ cows is impaired, although the data would suggest a global, as opposed to IgM-specific, pathway of impaired antibody production. All together, our data demonstrate that BLV infection in dairy cattle has a much greater effect on the host beyond lymphoma development. Indeed, our data support overall impairment of antibody production and interference with T cell immunity, which likely contributes to an increased risk of secondary infections in BLV+ cattle."--Pages ii-iii.
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