Dimensions of antigen recognition and levels of immunological specificity.

Although recognition and specificity are among the most fundamental concepts in immunology, there is a common tendency to equate these notions with the fit, especially in terms of molecular shape, between interacting molecules. Even in the case of monovalent recognition, there are factors that contribute to the energetics of the interaction that are not readily accounted for by detailed structural analysis of the interacting (epitopic and paratopic) molecular surfaces. Consequently, recognition involves more than just the three spatial dimensions and time. Factors such as solute-solvent interactions, molecular crowding, and confinement, not directly related to the details of the intermolecular interface, can play crucial roles in determining both intrinsic affinity and differential intrinsic affinity. Furthermore, stating that a given structural subunit (e.g., amino acid) is recognized in a given noncovalent interaction does not clarify whether the structural subunit in question participates in the interaction through van der Waals contact, contribution to intrinsic affinity, or differential contribution to relative intrinsic affinities for two or more different ligands. Additional factors become relevant in considering the specificity exhibited in multivalent interactions, cell activation, and activation of the whole immune system. Therefore, specificity as defined for a monovalent binding event can diverge from specificity as it is defined for higher-order interactions. A corollary of this conclusion is that the composition of epitopes and paratopes, defined in terms of the structural elements for which substitutions have an effect on the specificity-defining measurement, can differ in different contexts despite complete conservation of the structures that physically make direct contact. An analysis of specificity at the organismal level suggests that the immune system does not recognize or respond to substances that correspond precisely to either nonself substances or to dangerous substances. An alternative notion for the molecular origins of immunological discrimination does not require that there be any single reason for immune responsiveness. This concept of what the immune system recognizes and responds to derives from the recognition that the ultimate function of the immune system is to contribute to survival and reproductive success through any available means.