Anergy in self-directed B lymphocytes from a statistical mechanics perspective

TL;DR

This paper models B lymphocyte anergy using statistical mechanics, showing how self-reactive clones are naturally inert and interconnected, unifying two major theories of immune tolerance.

Contribution

It integrates Varela's theory and the two-signal model into a unified statistical mechanics framework, revealing the natural emergence of anergy and self-directed clones.

Findings

Helper cells do not activate certain B cell subgroups

Highly connected clones are self-directed due to ontogenetic learning

Clonal deletion and anergy are interconnected phenomena

Abstract

The ability of the adaptive immune system to discriminate between self and non-self mainly stems from the ontogenic clonal-deletion of lymphocytes expressing strong binding affinity with self-peptides. However, some self-directed lymphocytes may evade selection and still be harmless due to a mechanism called clonal anergy. As for B lymphocytes, two major explanations for anergy developed over three decades: according to "Varela theory", it stems from a proper orchestration of the whole B-repertoire, in such a way that self-reactive clones, due to intensive interactions and feed-back from other clones, display more inertia to mount a response. On the other hand, according to the `two-signal model", which has prevailed nowadays, self-reacting cells are not stimulated by helper lymphocytes and the absence of such signaling yields anergy. The first result we present, achieved through disordered statistical mechanics, shows that helper cells do not prompt the activation and proliferation of a certain sub-group of B cells, which turn out to be just those broadly interacting, hence it merges the two approaches as a whole (in particular, Varela theory is then contained into the two-signal model). As a second result, we outline a minimal topological architecture for the B-world, where highly connected clones are self-directed as a natural consequence of an ontogenetic learning; this provides a mathematical framework to Varela perspective. As a consequence of these two achievements, clonal deletion and clonal anergy can be seen as two inter-playing aspects of the same phenomenon too.