The TH2 bias in CNS immune privilege: Induction of humoral, cellular, and cytokine immune responses to soluble protein antigen administered into the cerebrospinal fluid of mice with normal blood brain barrier permeability.

摘要

For a century CNS immune privilege has been characterized in terms of TH1 immune effector mechanisms. Furthermore, the ability to easily study ocular immune privilege compared to the brain has led many to suggest a single neuroocular mechanism of immune privilege for both of these organs based upon ocular immune studies. In this dissertation, CNS immune privilege is directly characterized by examining humoral, delayed-type hypersensitivity (DTH), and cytokine responses in a mouse model with normal blood-brain barrier permeability.; Methods developed for the rat to administer soluble protein antigen into the cerebrospinal fluid (CSF) without disturbing constitutive CSF outflow pathways, particularly to cervical lymph nodes (CLN), have been adapted to the mouse. Based upon measurement of total choroid plexus mass, a total CSF production rate in the mouse is calculated to be 0.5μl/min. Withdrawing CSF at a rate below the CSF production rate allows relatively large volumes of CSF to be collected for analysis. CSF albumin concentrations in the mouse are not different from the rat. Furthermore, CSF IL12p40 concentrations show constitutive intrathecal synthesis.; Soluble protein antigen administered into CSF elicits a robust, IgG1 dominant, humoral immune response in the periphery but DTH priming is not detectable. In addition, an intrathecal antigen-specific antibody response is measured in CSF. Both the humoral and cellular responses are spleen-independent. Indirect evidence supports a central role for the CLN in these responses. In our experiments, antigen-specific stimulation of TH1 and TH2 cytokines reveal a relative TH2-bias in the draining CLN and spleen, reflected by an elevated T Helper Index (TH Index) when antigen is administered into CSF. These results clearly distinguish a different mechanism of immune regulation than that utilized by the eye to create immune privilege. Ocular immune privilege is spleen-dependent, whereas, brain immune privilege remains intact without a spleen.; This dissertation supports the induction of a TH2 immune response to antigen effluxing from the brain. These studies have ramifications for understanding multiple sclerosis and immune-mediated neuronal dysfunction in Tourette's Syndrome and Sydenham's chorea. In addition, this new perspective on CNS immune regulation will help to advance the development of potential neurodegenerative disease vaccines.