What do we need?

140501

Nelson Vaz

The two most important and defining properties of immunity are: unlimited plasticity and delicate specificity. Specific immune responsiveness, the basic pillar of immunity and immunology as a whole, seems to conciliate these two paradoxical qualities. Organisms seem to “respond” in particular, private, “specific” ways - to each one of an apparently unlimited collection of ligands (epitopes). This is believed to happen because they are equiped with a very large collection of lymphocytes, each one of which carrying a different membrane receptor (a paratope) which, nevertheless, was invented without a target. Collectively, this aimless process  allows lymphocytes to “recognize” what was previously unkown, to predict the unpredictable. This is the central dogma in immunology (predicting the undpredictable) and it exists since much before “selective” theories of antibody formation were adopted in the late 1950s (Jerne,1955; Burnet, 1957; Talmage, 1959) he first “selective” theory of antibody formation, was proposed by Paul Ehrlich and was called “the side-chains” theory of antibody formation (Ehrlich, 1900). Before these “selective” theories, antibody specificity was supposed to be molded by the contact with the antigen, acting as a template, an idea that may seem much simpler, but was dead wrong (Mazumdar, 1996). As Maturana generalizes: there are no “instructive” interactions in nature; systems are structure-determined (Maturana, 2002).

Plasticity, or its consequent versatility of actions, is a structural (molecular, cellular) aspect described in a structural domain. It is based on observations of lymphocye receptors (TCR and BCR-immunoglobulins). Specificity, on the other hand, is a relational quality, observed in a interactional domain, e.g., through visible reactions of lymphocytes or immunoglobulins with varied ligands (antigens, epitopes). Specificity is subsidiary to plasticity, i.e., the specific interactions we observe are made possible, or derive from the system structural heterogeneity. 

This standard way of seeing is frontally contradicted by the awkward observation that monoclonal immunoglobulins are less - let me repeat, less specific that whole sera (see Cohen, 2001). How can the essemble of many different specific units - monoclonal antibodies - be more “specific” than each one of them in isolation?

Two different antibodies (paratopes) binding to the same antigen may bind the antigen more tightly - with higher avidity - than each one of them in isolation if they do not “compete” for the same binding site. Thus, if the antigen has different binding sites (epitopes), which is often the case, cooperative forces may be brought forth. The more heterogeneous is the antigen, the more epitopes it may display, the more paratopes it will bind, the more tightly it will be held. Under natural circumstances, foreign materials penetrating the organism are simultaneously exposed to hundreds of thousands of different lymphocytes and immunoglobulins. The foreign materials themselves are also structurally very complex, often consisting of living or non-living aggregates of many macromolecules, thus, expressing many epitopes. Thus, the specificity of isolated receptors is not usually important under natural circumstances.

It becomes important when we decide to understand the sources of immune responsiveness and to accomodate these two paradoxical qualities - plasticity and specificity. WE want to know how can the organism respond in special (specific) ways to each one of an apparently unlimited collection of ligands. And we are puzzled when we learn that single antibodies are less specific than multiple antibodies acting in concert because we ascribe the fine specificity of the whole system to the individual action of its components. Apparently, however, it may be the other way around: the system is able of more specific actions than its components. How come?

Usually, a “promethean” quality is ascribed to immune responsiveness, as if the organism would be able to predict the unpredictable. This is what “recognizing foreign materials” really means (Silverstein, 2009). But, do we really “recognize” what we have never met before? Is immune responsiveness really a way to deal with foreign materials? Or is it time to reconsider these questions after having learned so much about the specificity and plasticity of lymphocytes and immunoglobulins? 

We should start looking at immunologic activity as an aspect of the construction and maintenance of the organism, not exclusively to as a form of protection against foreign invaders. The most commom “invader” macromolecules are harmless: they derive from our daily diet and from our resident microbiota, and we do not make progressive immune responses to these materials. Progressive immune responsiveness (memory) is not the rule. Neither are we “tolerant” to these materials: there are plenty of immunoglobulins and activated lymphocytes interacting with them. We are neither “immune”, nor “tolerant”to them. We should contemplate the robustly stable activity that is always present, but is neither immmnuity, nor tolerace. We need a new terminology. A new paradigm, to be more precise.

Bibliography

Burnet, M. F. (1959). The clonal selection theory of immunity. 

Nashville/London, The Vandrbilt and Cambridge University Presses.

Cohen, I. R. (2001). "Antigenic Mimicry, Clonal Selection and Autoimmunity." 

Journal of Autoimmunity 16: 337-340.

Jerne, N. K. (1955). "The natural selection theory of antibody formation." 

Proc. Natl. Acad. Sci. U.S.A. 41: 849-857.

Maturana, H. (2002). "Autopoiesis, structural coupling and cognition: a history of these and other notions in the biology of cognition."

Cybernetics & Human Knowing 9(3-4): 5-34.

Mazumdar, P. (1996). Species and specificity. An interpretation of the history of Immunology. 

New York, Cambrige University Press.

Silverstein, A. M. (2009). "Immune System: Promethean Evolution." 

Science 324: 329.

Talmage, D. W. (1957). "Allergy and immunology." 

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Vaz, N. M. (2011). "The specificity of immunological observations." 

Constructivist Foundations 6(3): 334-351