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).

The promoter regions of intellectual disability-associated genes are uniquely enriched in LTR sequences of the MER41 primate-specific endogenous retrovirus: an evolutionary connection between immunity and cognition

“…Excluding this hypothesis would lead to consider a related and barely less provocative view in which the last steps of our cognitive evolution might have promoted our immune defenses against human-specific infectious agents; for instance, evolving different languages as a sort of "protective barrier" against infectious diseases for the human groups speaking them. In any case, our work reinforces the notion of neuroimmune co-evolution that we previously put forward (Benítez-Burraco and Uriagereka, 2016;Nataf, 2017a). In this general frame, we would like to propose that, besides the potential role of endogenous immune cues (Nataf, 2017a(Nataf, , 2017b…”

“…In any case, our work reinforces the notion of neuroimmune co-evolution that we previously put forward (Benítez-Burraco and Uriagereka, 2016;Nataf, 2017a). In this general frame, we would like to propose that, besides the potential role of endogenous immune cues (Nataf, 2017a(Nataf, , 2017b…”

Common neurodegeneration-associated proteins are physiologically expressed by antigen-presenting cells and are interconnected via the inflammation/autophagy-related proteins TRAF6 and SQSTM1

“…We previously proposed that the genetic polymorphism of the HLA-DRB1 locus, which, among primates, is extremely high in the human species (106), might allow the allele-specific presentation of distinct sets of "brain superautoantigens" (107,108). In turn, distinct sets of cognition-promoting T-cells would be generated, leading possibly to a high level of cognitive diversity, and thus cognitive complementarity, in Homo sapiens.…”

Immune System Challenge Improves Cognitive-Behavioural Responses and Reverses Malaria-Induced Cognitive Impairment in Mice

“…There is considerable evidence for the existence of strong interactions between the immune and nervous cognitive systems 1–7 . Immunomodulation of the nervous system does exist and can either be physiological or pathological.…”

“…Immunomodulation of the nervous system does exist and can either be physiological or pathological. The maturation and homeostasis of the nervous cognitive abilities require the participation of elements of the immune system 6–7 . Exogenous immune stimuli may also have positive or negative effect on the nervous system, depending on the nature and intensity of the immune response elicited 1–4,6 .…”