Submitted to: Journal of Immunology
Publication Type: Peer reviewed journal
Publication Acceptance Date: 12/30/2003
Publication Date: 2/1/2004
Citation: Lemke, C.D., Haynes, J.S., Spaete, R.J., Adolphson, D., Vorwald, A.C., Lager, K.M., Butler, J.E. 2004. Lymphoid hyperplasia resulting in immune dysregulation is caused by porcine reproductive and respiratory syndrome virus infection in neonatal pigs. Journal of Immunology. 172(3):1916-1925. Interpretive Summary: Porcine reproductive and respiratory syndrome (PRRS) is a disease of swine caused by the PRRS virus (PRRSV). This disease was first observed in 1987 and within a few years it had become the number one disease problem for the swine industry. Several PRRSV vaccines are now available for use, however, they do not always seem to work under field conditions leading to questions about the efficacy of these vaccines. This lack of efficacy is believed due to limited cross-protection that is provided by the vaccines. This apparent lack of vaccine efficacy points out how little is actually known about the PRRSV immune response in swine. There is a critical need for efficacious PRRSV vaccines that can be used to improve current PRRS control and prevention strategies. A better understanding of the PRRSV immune response is necessary for the development of a new generation of PRRSV vaccines. This report describes a study designed to investigate the PRRSV immune response at a basic level. In this study germ-free pigs were used to evaluate the effects of a PRRSV infection on the pig's immune system. Results demonstrated the PRRSV infection induced an increase in lymph node size, a significant increase in all classes of antibodies, and there were antibodies that developed against the pig's own tissues suggesting the PRRSV-infection induced an autoimmune response. Some of the observations, to varying degrees, have been reported in PRRS field cases indicating the germ-free pig model used in this study does mimic a field infection. Moreover, this PRRSV-infected germ-free pig model might be used to further investigate the general mechanisms of virus-induced immune-mediated disease or immunopathology.
Technical Abstract: Amidst growing evidence that numerous viral infections can produce immunopathology, including non-specific polyclonal lymphocyte activation, the need to test the direct impact of an infecting virus on the immune system of the host is crucial. This can best be tested in the isolator piglet model in which maternal and other extrinsic influences can be excluded. Therefore, neonatal isolator piglets were colonized with a benign E. coli, or kept germ-free, and then inoculated with wild-type porcine reproductive and respiratory syndrome virus (PRRSV) or sham media. Two weeks after inoculation, serum IgM, IgG and IgA levels were 30-50, 20-80 and 10-20 fold higher respectively, in animals receiving virus versus sham controls. PRRSV-infected piglets also had bronchial tree-associated lymph nodes and submandibular lymph nodes that were 5-10 times larger than colonized, sham-inoculated animals. Size exclusion FPLC revealed that PRRSV-infected sera contained high molecular weight fractions that contained IgG, suggesting the presence of immune complexes. Lesions, inflammatory cell infiltration, glomerular deposits of IgG, IgM and IgA and antibodies of all three isotypes to basement membrane and vascular endothelium were observed in the kidneys of PRRSV-infected piglets. Furthermore, autoantibodies specific for Golgi antigens and dsDNA could be detected 3-4 weeks after viral inoculation. These data demonstrate that PRRSV induces B-cell hyperplasia in isolator piglets that leads to immunologic injury and suggests that the isolator piglet model could serve as a useful model to determine the mechanisms of virus-induced immunopathology in this species.