Although the CNS is an early and frequent target of HIV, the pathogenesis of HIV encephalopathy remains unknown. According to classical theory, the normal CNS is isolated from the immune system and the immune effector mechanisms extend to this organ only following disruption of brain barrier membranes. Further, some have proposed that Th1 responses provide better protection against HIV infection, than Th2 responses. However, in recent studies, including many from this laboratory, researchers have shown that afferent and efferent connections between the CNS and the secondary lymphoid organs (cervical lymphatics and spleen) are intact following infection, that the CNS (brain, CSF, and anterior chamber of the eye) is a site where Th2 immunity predominates, that cell-mediated immunity is suppressed selectively whereas humoral immunity is normal or enhanced, that the humoral response is biased toward specific immunoglobulin isotypes and that it includes B cell penetration into brain and intrathecal antibody synthesis, and that this Th2-dominant immunity provides an explanation for the selective vulnerability of nervous tissue to HIV infection. The objective of the proposed research is to characterize further the Th2-dominant immunity of the normal brain by the evaluation of the afferent and efferent limbs of the immune response to CNS-administered protein antigens, including the HIV structural antigens, with emphasis on the tissue-specific features mediating and regulating the induction and expression of immunity.
The specific aims are: (A) to examine the role of Th-cell subsets in the cervical lymph nodes and spleen in mediating and regulating the afferent limb of the humoral immune response to CNS-administered antigen; (B) to identify factors mediating and regulating B cell recruitment to the normal brain; (C) to characterize the ontogeny of the local humoral immune response within the brain; and (D) to determine the immunoregulatory role of the local microenvironment in the induction and expression of immunity within the normal CNS. The experiments will be conducted in a Lewis rat model, distinguished by the presence of a normal blood-brain barrier following immunization by way of the brain, CSF, or the anterior chamber of the eye.
