On how the immune system preferentially interacts with antigen‐specific molecules bound to antigen over unbound molecules, with emphasis on B cell receptor signalling

Abstract

Antigen‐specific molecules of the immune system, namely antibodies, the membrane immunoglobulins (mIgs) of B cells and T cell receptors (TcRs), can all signal their interaction with antigen. There are different mechanisms by which this signalling could occur. These mechanisms can be divided into two general categories: allosteric and non‐allosteric. In allosteric mechanisms, the monovalent binding of the antigen to the receptor triggers a conformational change at the binding site that is propagated to an invariant part of the receptor, a change recognized by a sensing unit. We argue allosteric mechanisms are implausible. Non‐allosteric mechanisms depend on steric effects due to the antigen's size and/or multivalency. We consider two non‐allosteric mechanisms by which the mIg of B cells has been envisaged to signal its interaction with antigen: the popular cross‐linking model and the dissociation activation model. We argue, on the basis of both experimental observations and physiological considerations, that the dissociation activation model, developed by Reth and his colleagues, is uniquely plausible.

Analyzing some concepts of immune regulation of the last three decades: Fostering greater research resilience despite the information overload. A personal view

“…I was greatly relieved to discover a few years ago that Michael Reth and others had shown that sIg self-aggregates in the membrane of B cells in the absence of antigen, and that small, monomeric antigens could disrupt such aggregation, initiating the generation of signal 1 (57). This discovery resolved the major uneasiness I had harboured for years concerning the two-signal model (56). Reth's studies also accounted for the original observations on which the crosslinking model was based (57).…”

“…I have been most uneasy about this idea since it’s proposal. Monomeric, foreign proteins, from which aggregated protein had been carefully removed, are potent in their ability to inactivate B cells ( 56 ). This is paradoxical in terms of the sIg-cross linking model.…”

“…Even more important to my mind was the idea that there should be minimal “physical” restraints on what self-antigens can inactivate their B cells. The crosslinking model implies that many self-antigens, monomeric in nature, would not inactivate their corresponding B cells, with substantial consequences for the generation of autoimmunity ( 56 ). I was greatly relieved to discover a few years ago that Michael Reth and others had shown that sIg self-aggregates in the membrane of B cells in the absence of antigen, and that small, monomeric antigens could disrupt such aggregation, initiating the generation of signal 1 ( 57 ).…”

Increased B Cell Understanding Puts Improved Vaccine Platforms Just Over the Horizon

“…Despite canonical BCR signaling pathways being decreased in GCBCs relative to those in naive B cells ( 25 ), GCBCs can transmit BCR-mediated signals via synaptic interactions between GCBCs and FDCs, which encourage an improved response to membrane-bound Ags in an affinity-dependent manner ( 26 ). This and other studies, alluded to in recent reviews ( 27 28 29 ), have similarly concluded that that the immune system preferentially interacts with membrane-bound Ag over soluble molecules.…”

On T cell development, T cell signals, T cell specificity and sensitivity, and the autoimmunity facilitated by lymphopenia

“…Such a conformational change is envisaged to occur uniquely when a TcR binds an agonist peptide/MHC complex, but not on binding an endogenous peptide/MHC complex 39‐45 . We have argued against the plausibility of such a possibility 46 …”