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It seems to me that you have two lines of thought converging here. One is trying to figure out how to deploy your enterprise certificate authority (CA) in the most secure fashion, and the other has something to do with ISA. I think I know where you are headed, so I'll give it a shot.
Microsoft recommends deploying a standalone certificate authority to protect the root certificate authority from being compromised. Standalone certificate authorities can be taken offline (when they are not being used to generate certificates) which helps to protect the validity of your root certificate authority. The workload of deploying user certificates can be done by subordinates while the root certificate authority is offline. Subordinate certificate authorities can be member servers of the domain and can be used for automating the deployment of certificates.
How can ISA help? ISA can prevent any external users from accessing the certificate authority. And depending on how you configure ISA, it can even help you protect your certificate authority from internal users as well.
I hope this helps. Please respond with a comment to this answer if I'm way off base here.
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Related information from SearchExchange.com:
Reference Center: ISA Server
Reference Center: Permissions and authentication
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