Self? Or common encounters? Non-self? Or unusual encounters?

It is easy to see why immunologists have been bamboozled into focusing in on "self/non-self" (epitope!!!) discrimination. First, it is an immediately appealing idea with superficial support, both observational and logical. Second, there is ample evidence that self epitopes are less likely to evoke an aggressive immune response and non-self epitopes more likely to evoke an aggressive immune response. Third, the history of immunology has focused on aggressive immune responses (to the exclusion of tolerant – actively anti-inflammatory – immune responses). Indeed, there was – not so long ago – a prolonged era when active tolerance inducing immunity was ignored or even enathema to the community; it was believed that the only active immunity was aggressive and directed at epitopes (non-self). The discipline then found itself faced by the conundrum of why aggressive responses to self epitopes can occur. The self/non-self theory of "in utero (thymic) priming" seemed to deny that it should ever occur.

So, if vertebrates have developed a system to remember inflammatory stimuli, the logical approach would be to remember the context of encounters; safe and quiet self cell disposal is acceptable; disruptive and damaging tissue debris is unacceptable. Finding your epitope in safe and quiet debris disposal is likely to occur with common, physiologically encountered epitopes. Finding your debris in catastrophic and disruptve cell encounters may well be associated with unusual epitopes characteristic of the "pathogenic material". The most unusual (strange) epitopes are likely to become the focus of aggressive immune amplicifation of inflammation when they are re-encountered. So, rather than "self/non-self" discrimination being the arbiter, it is simply the most unusual (set of) epitope(s) that is(are) selected for subsequent aggressive amplification. In adjuvant arthritis this (eventually) becomes a (set of) common/self epitopes. If certain epitopes are usually "hidden" behind immunologically privileged sites, then this should make these epitopes the first "suspects" for an aggressive response. Does that strike a chord?