Towards a Liquid Self: How Time, Geography, and Life Experiences Reshape the Biological Identity

Abstract

The conceptualization of immunological self is amongst the most important theories of modern biology, representing a sort of theoretical guideline for experimental immunologists, in order to understand how host constituents are ignored by the immune system (IS). A consistent advancement in this field has been represented by the danger/damage theory and its subsequent refinements, which at present represents the most comprehensive conceptualization of immunological self. Here, we present the new hypothesis of “liquid self,” which integrates and extends the danger/damage theory. The main novelty of the liquid self hypothesis lies in the full integration of the immune response mechanisms into the host body’s ecosystems, i.e., in adding the temporal, as well as the geographical/evolutionary and environmental, dimensions, which we suggested to call “immunological biography.” Our hypothesis takes into account the important biological changes occurring with time (age) in the IS (including immunosenescence and inflammaging), as well as changes in the organismal context related to nutrition, lifestyle, and geography (populations). We argue that such temporal and geographical dimensions impinge upon, and continuously reshape, the antigenicity of physical entities (molecules, cells, bacteria, viruses), making them switching between “self” and “non-self” states in a dynamical, “liquid” fashion. Particular attention is devoted to oral tolerance and gut microbiota, as well as to a new potential source of unexpected self epitopes produced by proteasome splicing. Finally, our framework allows the set up of a variety of testable predictions, the most straightforward suggesting that the immune responses to defined molecules representing potentials antigens will be quantitatively and qualitatively quite different according to the immuno-biographical background of the host.

A generalized quantitative antibody homeostasis model: antigen saturation, natural antibodies and a quantitative antibody network

“…In Zvi Grossman's horizontal networks (30) "the relative probability of maturation increases with antigen dose and with affinity" and "proliferation can be uncoupled from differentiation under certain predictable conditions", which are key assumptions in our model as well. Grignolio et al recently compiled factors that potentially influence immunological identity, focusing on the changing nature of immunological self, which they conceptualize as "liquid self" (31). The concept of immunological homunculus by Irun Cohen et al (32) states that non-reactivity can only create chaos, self-reactivity is required for control and order.…”

Evolutionary Views of Tuberculosis: Indoleamine 2,3‐Dioxygenase Catalyzed Nicotinamide Synthesis Reflects Shifts in Macrophage Metabolism

“…[ 31–32 ] Even our immunological “languaging” does not well characterize homeostasis between host endogenous and exogenous microbial flora. [ 33–34 ] What distinguishes a commensal organism from a pathogen remains a murky question: for example, many organisms, such as Neisseria meningitidis or Streptococcus pneumoniae , are able to switch between commensal and pathogenic behaviors. [ 35–37 ] An improved understanding of immune tolerance may lead to insights into infectious disease pathophysiology, particularly for M. tuberculosis .…”

Literature review in support of adjuvanticity/immunogenicity assessment of proteins

“…The cells of the IS are not only able to recognize external and internal stressors but also to adapt and modify according to the variety of stimuli they are exposed to, this basic characteristic of the IS as a whole is known as plasticity 286 . For this reason, it has been suggested that together with the type of molecular stimuli and their doses also the temporal sequence is critical.…”

“… Liquid self: According to Grignolio et al 286 , the full integration of the immune response mechanisms into the host body's ecosystems, i.e., in adding the temporal, as well as the geographical/evolutionary and environmental dimensions.…”