In traditional descriptions immunological activity is neither systemic nor historical and is never “physiological.” Since it is dominated by reductionist, teleological and cognitivist approaches. After deconstructing hegemonic immunology way of seeing, we proposed previously a constructivist explanation to immunological physiology, namely, The Conservative Physiology of the Immune System (Vaz NM Clin Dev Immunol 2006), theory based on our own experimental evidences and referenced on Humberto Maturana’s Biology of Cognition. In this paper we propose an immanent mechanism for immunological pathophysiology and disease development.

This paper provides a conceptual framework to accommodate important recent developments in immunology (genetic determination, cellular interactions, suppression). The basic idea is to look at the immune system as a closed network of interactions which self-determines its ongoing pattern of stability and its capacities of interaction with its environment. Thus, all immune events are understood as a form of self-recognition, and whatever falls outside this domain, shaped by genetics and ontogeny, is simply non-sensical. This paradigm, stemming from the ideas of Jerne, represents almost a logical inversion of the Burnetian idea of self-discrimination. A detailed discussion of the immunological evidence that substantiates this view is presented, together with some new concepts (eigenbehavior, cognitive domains). Although the paper is addressed to biologists and immunologists, we make extensive use of system-theoretic notions in a non-mathematical form (recursion, nets and trees, self-organization).

Key words: immune networks, models, biological, immunosuppression, anti-idiotipic antibodies, immunoregulation, recursion

Francisco Varela, a leading neurobiologist and cognitive scientist, made a 10-year-long incursion into immunology. His in-depth contributions aimed to develop a systemic description to replace the standard stimulus/response/regulation scaffold that has governed immunology since its inception in the 19th century. Many of these efforts involved expansions of the notions introduced by Niels Jerne in his idiotypic network theory (Jerne, 1974a, 1974b) with the added notion of organizational closure, derived from the autopoietic theory. However, today, just like yesterday, the immunological community remains inclined to neglect these efforts and instead rests satisfied with half-a-century old clonal selection concepts (Burnet, 1959).

Key words: Francisco Varela, immunology, networks

When we consider the immune system as a cognitive system, as most immunologists do, our questions and the criteria we use to validate the answers to these questions, will inevitably follow what we understand as cognition. An alternative is to ascribe cognition to what immunologists do when they operate as human observers and generate descriptions of immunological activities. In this uncommon way of seeing, which I prefer, we ascribe the specificity of immunological observations to what we do as humans observers operating in human language, rather than to what cells and molecules, such as lymphocytes and immunoglobulins, do as components of the immune system. In this alternative way of seeing, we, immunologists, are the true cognitive entities in immunology.

Upshot: According to Biology of Cognition and Language (Maturana’s approach) the immune system is not a cognitive system and defining of a cognitive paradigm is not what we understand as a Maturanian approach to immunology. The true cognitive actions in immunology are performed by immunologists acting as observers, not by body organs or systems. Stimuli and responses are not adequate concepts in the description of systems. As a closed network of cellular/molecular interactions, the immune system yields patterns of activity as is transparent in robust conserved profiles of reactivity of natural immunoglobulins, as investigated by Nóbrega et al. and Cohen et al., which offer the opportunity to unravel its natural, spontaneous activity. Dietary materials, products of the commensal microbiome are the most abundant and common elements continuously incorporated to the network activity and, thus, also represent an important avenue of investigation.

Context: Immunity includes cognitive concepts: the organism is thought to specifically recognize foreign materials and develop a memory of these encounters. Vaccines are thought to work by enhancing this immunological memory. Lymphocytes are key cells and specific antibodies are key molecules in immune recognition. Antibodies are blood proteins called “immunoglobulins.” Spontaneously formed immunoglobulins are seen as “natural” antibodies to dietary components and commensal bacteria. Immune cognition is used simply as a didactic metaphor. Problem: Do the cognitive aspects of immunology stem from the activities of cells and molecules, or are they ascribed by the immunologist operating as a human observer? (1) An immense variety of immunoglobulins may bind to the same antigen with different binding energies. It is the immunologist who arbitrates the boundary between those that are specific (and declared antibodies) and those that are not. Specific antibodies serve as functional labels pasted onto natural immunoglobulins, as if they were recognizing elements. Is this “arbitration” the true cognitive event ascribed to immunoglobulins and lymphocytes? (2) A major impasse exists between progress in experimental immunology and its translation into clinical results. A proper understanding of immunological activity demands a wider view of an organism’s biology and, also, of the interference of human observers in delineating experimental realities, such as the specificity of immune recognition. Maturana’s biology of cognition and language provides one such approach. Method: Use of Maturana’s biology of cognition and language concepts to describe immunological activity. Results: A whole new understanding of immunological activity is suggested. Implications: A major change in the way of seeing is proposed that may eventually help the translation of this knowledge into clinical results. Furthermore, the immune system may also become a proper model for cognitive analyses.

Key words: immunology, antibody, immunoglobulin, specificity, observer, reality

Abstract: The composition of living systems is subject to constant change. This suggests a focus on processes rather than entities. So, if questioning the rigid ontological foundations of immunology leads to the question of whether another immunology is possible, a possible candidate is “process immunology.” In the target article, I claimed that antibodies are constructed, but I am also open to the view that immunoglobulins are formed by the same naming process. Furthermore, I point out that the problem with “oral tolerance” is that it implies a stimulus-response-regulatory framework. I also draw attention to the “epistemological trap of language,” as it is relevant for the public understanding of vaccination. Finally, I discuss the theoretical and practical consequences of accepting Maturana’s or Varela’s position in explaining the immune system, including the question of whether the activity of our immune system has any influence on our behavior and thus influences our inter-personal world. I conclude by emphasizing that Maturana’s biology of cognition and language is not mechanistic because it points to realities “in parentheses” that emerge in the history of human observers.

Context: From the perspective of mainstream immunology, immune activity is presented as cognitive and anticipatory in the sense that vaccines condition the organism for more effective specific immunity. This perspective works with terms alluding to cognition and portrays the immune system in a defensive, militaristic way. Problem: Almost all attempts to invent new vaccines fail. Something seems to be conceptually mistaken. This and other cases call for a change of view in the experiential scope of immunology, and, by changing this, the view of the organism is changed. I describe immune phenomena as biological, observer-dependent phenomena. Method: Maturana explicitly included the observer in descriptions and stated that we do not have access to an objective reality, as we explain our experiences in terms of the coherence of our experiences. I apply these notions to immunology and claim that the immune system is not passively moved by antigenic contacts, nor does it live in its own interiority, where anything is possible. Between these two pitfalls we discuss anti-infectious immunity and the specific nature of immunological phenomena. In particular we expose pitfalls in the current languaging used to think about immunological phenomena. Results: In mainstream science, immunoglobulins are seen as biochemical reagents produced by the body in its own defense. This amounts to a cognitive proposition. I map this cognitive stance to the actions of the immunologist’s observations, that is, the specificity of antibodies belongs to the eye of the beholder, the expectations of the immunologist operating as an observer in human language. Implications: Immunoglobulins and antibodies are different entities: as components of the vertebrate organism, immunoglobulins emerged in natural phylogenetic drift hundreds of millions of years ago, while antibodies were invented by immunologists in the 1890s as identifying labels pasted on immune sera. By keeping an eye on what we do as observers in describing the immune system, we move away from focusing on specific immune responses and come to appreciate the conservative aspect of the immune system’s dynamics and its operational congruence with the organism of which it is a component subsystem. In doing so, the main focus of attention shifts to what we do as observers operating in human language.

Key words: Antibodies, autopoiesis, immunoglobulins, immune system, observer.

Upshot: Mpodozis and Maturana endorsed our way of seeing and enrich the debate, offering their own arguments. Stewart and Cohen criticize some points of our article. Stewart thinks that we are “watering down” Varela’s enactivism and approaching objectivism; we show why this is not what we believe. Cohen offers a long (generous) description of his own functional idea of immunological activity and we show why our positions are incommensurable; agreeing with Mpodozis’s comment, we claim that nothing is gained by ascribing cognitive properties to immunological activity.