The evolutionary context for a self–nonself discrimination

Abstract

This essay was written to illustrate how one might think about the immune system. The formulation of valid theories is the basic component of how-to-think because the reduction of large and complex data sets by the use of logic into a succinct model with predictability and explanatory power, is the only way that we have to arrive at “understanding.” Whether it is to achieve effective manipulation of the system or for pure pleasure, “understanding” is a universally agreed upon goal. It is in the nature of science that theories are there to be disproven. An experimentally disproven theory is a successful one. As they fail experimental test one by one, we end up with a default theory, that is, one that has yet to fail. Here using the self-nonself discrimination as an example, how-to-think as I see it, will be illustrated.

What is so special about thinking; after all, we all do it!

“…The question then became, what were the specificities of the two signals with respect to S and NS, who sent them and who received them? In our 1970 paper (Bretscher and Cohn, 1970), we incorporated the logic of the decision step into a testable explanatory theory referred to as the "two signal model" which I later renamed the Associative Recognition of Antigen (ARA) Model as, over many years it was corrected, refined and extended by Langman and myself (Cohn, 2007(Cohn, , 2010Langman, 1989;Langman and Cohn, 1993b) as well as by Bretscher (1999) from whose laboratory came much of the key supporting data (Bretscher, 1986;Peters et al, 2009;Tucker and Bretscher, 1982).…”

Ten experiments that would make a difference in understanding immune mechanisms

“…This poses the question, what is the origin of the eTh anti-NS necessary to prime the response? Two theories have emerged: (1) naive or initial state Th (iTh) are unique in that they undergo a controlled NSantigen-independent pathway to priming effectors (eTh anti-NS) [12][13][14], and (2) the B-cell acting as an APC can deliver a priming Signal 2 uniquely to naive iTh (a variation on the Bretscher proposal [15]). The B-cell is acting as a primer eTh uniquely for naive iTh.…”

“…Comment 4 If primer eTh are required to initiate an adaptive immune response, then the most thorny lacuna in the ARA Model [14,15] (i.e., the chicken and egg conundrum) would be resolved.…”

“…The mimotope hypothesis [27,28] has been ruled out for the TCR [14,[29][30][31] but remains open for the BCR. Induction of a B-cell requires specific uptake and processing of antigen to nonself [PRII], the ligand for eTh.…”

Comment on: Ten experiments that would make a difference in understanding immune mechanisms

“…Cohn must see faults in the design of all these experiments, and therefore he should provide the experimental design that would satisfy him in terms of the ability to disprove his model. He has previously provided explanations [3][4][5] for several experiments where prior and persistent antigens generated immunity rather than tolerance (tolerance is the [failed] prediction for these experiments, based on ARA). Cohn's view would be much more appealing if he could provide a single unifying explanation for all these failed tests of ARA.…”