> Context • The dominant theory in immunology is straight neo-Darwinian, almost 60 years old and does not address
its epigenetic foundation. In traditional immunology, cognitive notions are used only as metaphors: Cognitive
notions derived from enaction (Varela) and biology of cognition (Maturana) may be applied to immunology.
> Problem • Why is there a huge gap between the rapidly growing knowledge in experimental immunology and
applying this knowledge to medical issues? Could the difficulty be conceptual? > Method • We review the history of
Varela’s involvement in immunology to contribute to the genealogical and cartographic understanding of his work,
and we highlight the key questions that still need to be addressed. > Results • From our perspective, a phenomenon
known as “oral tolerance” (stabilization of immune activity in relation to dietary and microbiota antigens) is crucial in
the promotion of a change in paradigms. Applying non-metaphorical approaches to what is traditionally understood
as immune cognition can be of great theoretical importance. For example, computer simulations of immunological
activity were able to predict experimental results on oral tolerance. Reciprocally, experimental results, for example,
the (adoptive) transfer of “oral tolerance” with mouse T lymphocytes, is critically important for immunological theory:
“tolerance” understood as non-responsiveness cannot be transferred, thus it must be seen as an active phenomenon.
> Implications • The article emphasizes the importance of Varela (and his collaboration with Coutinho and Stewart,
in Paris) for the development of immunological theory. > Constructivist content • The organism, as a whole, is not a
biochemical listing of properties, or the result of a genetic program but it is rather a process of continuous construction
and maintenance. > Key words • Immunology, cognitive science, epistemology, Maturana, oral tolerance.