Autoimmunity as a Driving Force of Cognitive Evolution

Abstract

In the last decades, increasingly robust experimental approaches have formally demonstrated that autoimmunity is a physiological process involved in a large range of functions including cognition. On this basis, the recently enunciated "brain superautoantigens" theory proposes that autoimmunity has been a driving force of cognitive evolution. It is notably suggested that the immune and nervous systems have somehow co-evolved and exerted a mutual selection pressure benefiting to both systems. In this two-way process, the evolutionary-determined emergence of neurons expressing specific immunogenic antigens (brain superautoantigens) has exerted a selection pressure on immune genes shaping the T-cell repertoire. Such a selection pressure on immune genes has translated into the emergence of a finely tuned autoimmune T-cell repertoire that promotes cognition. In another hand, the evolutionary-determined emergence of brain-autoreactive T-cells has exerted a selection pressure on neural genes coding for brain superautoantigens. Such a selection pressure has translated into the emergence of a neural repertoire (defined here as the whole of neurons, synapses and non-neuronal cells involved in cognitive functions) expressing brain superautoantigens. Overall, the brain superautoantigens theory suggests that cognitive evolution might have been primarily driven by internal cues rather than external environmental conditions. Importantly, while providing a unique molecular connection between neural and T-cell repertoires under physiological conditions, brain superautoantigens may also constitute an Achilles heel responsible for the particular susceptibility of Homo sapiens to "neuroimmune co-pathologies" i.e., disorders affecting both neural and T-cell repertoires. These may notably include paraneoplastic syndromes, multiple sclerosis as well as autism, schizophrenia and neurodegenerative diseases. In the context of this theoretical frame, a specific emphasis is given here to the potential evolutionary role exerted by two families of genes, namely the MHC class II genes, involved in antigen presentation to T-cells, and the Foxp genes, which play crucial roles in language (Foxp2) and the regulation of autoimmunity (Foxp3).

Keywords: Alzheimer's disease; Parkinson's disease; T-cell repertoire; autism; autoimmunity; cognitive evolution; paraneoplastic syndromes; schizophrenia.

Figure 1

Presentation of antigen-derived peptides to T-cells. The activation of CD4 T-cells in an antigen-specific manner requires a process called antigen presentation and performed by specialized immune cells named antigen-presenting cells (APCs). APCs harbor unique abilities to capture extracellular antigens, to process (i.e., cleave) these antigens into short peptides and to expose at the outer surface of their cellular membrane the peptides generated by antigen processing. There, the exposed peptides are “recognized” by T-cells. Importantly, the recognition of antigen-derived peptides by T-cells also requires that such peptides physically associate with molecules of the major histocompatibility complex class II (MHC class II) that are expressed by APCs. The antigen-specific activation of a CD4 T-cell engages only if the TCR (T-cell receptor) expressed at its cell surface binds with a high affinity the molecular complex formed by: (i) a peptide derived from the targeted antigen and (ii) MHC class II molecules into which the antigen-derived peptide is loaded.

Figure 2

Pro-inflammatory brain-autoreactive T-cells (PIBAT cells) in health and disease. Under physiological conditions, the number, secretory profile and homing properties of pro-inflammatory brain-autoreactive T-cells (PIBAT cells) supports finely-tuned cognition-promoting autoimmunity. In particular, PIBAT cells exert at distance trophic effects on neurons via cytokines and neurotrophins that are appropriately synthesized (qualitatively and quantitatively). Cognition-promoting autoimmunity allows an overall harmonious co-development, co-maintenance and co-aging of the nervous and immune systems. It is proposed that alterations in the number, secretory profile and/or homing behavior of PIBAT cells are involved in the pathophysiology of CNS autoimmune disorders, non-CNS autoimmune disorders, psychiatric diseases and neurodegenerative conditions.

Figure 3

Diabetes type 1 viewed as a neural disorder. In this pathophysiological scheme, pathological autoimmunity against GAD65, the main targeted autoantigen in diabetes type 1, would result from both immune and neural alterations occurring concurrently. An immune stress such as, for instance, a viral infection would lead to a drop of Tregs. In parallel, a cognitive or behavioral stress (for instance cognitive overstimulation or mood imbalance) would be responsible for an increased exposure of the immune system to the brain superautoantigen GAD65. Pathological autoimmunity against pancreatic islet cells expressing GAD65 antigen would then result from an increased number, increased activation state and altered homing of GAD65 autoreactive T-cells.

Figure 4

Co-evolution/co-development of the neural and immune repertoires. The co-development/co-evolution model proposes that during evolution, neural and T-cell repertoires have exerted mutual selection pressures. In one hand, the T-cell repertoire directed against brain superautoantigens may have favored the emergence of a neural repertoire expressing brain superautoantigens. On the other hand, the neural repertoire expressing brain superautoantigens may have favored the emergence of a T-cell repertoire directed against brain superautoantigens. As a result, evolution of the immune and nervous systems, the two main systems allowing the sensing of and adaptation to the external environment would have been, at least in part, endogenously-driven. This figure is reproduced with permission and slight modifications from the chapter “Brain superautoantigens: connections between immune and neural repertoires” published in the e-book “Brainimmune” (Nataf, 2017a).

Figure 5

Autoimmunity and the evolutionary genetics of encephalization and cognition. It is suggested that evolution of the Foxp1/2/4 genes have not only contributed to a diversification of neural repertoire but have instructed what could be called a “speciation” of such repertoire i.e., the acquisition of species-specific features. In parallel, evolution of the MHC class II genes have contributed to the diversification and “speciation” of the T-cell repertoire, notably the autoreactive T-cell repertoire directed against brain superautoantigens. Finally, evolution of the Foxp3 gene may have allowed a species-specific control of cognition-promoting autoimmunity. These combined mechanisms would support an endogenously-driven and species-specific processes which would shape encephalization and cognition. By this mean, external cues exerting a selection pressure on a given species would be filtered by the internally-fueled sensing skills of this species. In turn, perceived externals cues would further instruct the diversification and speciation of the neural and T-cell repertoires.