quarta-feira, 8 de janeiro de 2014

Not just a container

Not just a container
Nelson Vaz
The understanding of the relationship of the immune system to the body to which it belongs has been hindred by the concept of natural tolerance built in the Clonal Selection theory, which demands the elimination or permanent inhibition of self-reactive (forbidden) clones. It this most usual way of seeing, the organism is simply the container of the immune system, the place, space or dimmension in which clonal expansions take place; an entity to be protected, but which requires no further definition. According to Darwinian evolutionary theory, the “environment” is also simply the space or dimmension in which natural selection of species takes place. 
The origin and conservation of lineages through the phylogenic natural drift proposed by Maturana & Mpodozis (1992, 2000) allow us to describe the participation of the environment as an ontogenic niche in the conservation or shifting of an ontogenic phenotype. As commented by Vargas (2005):
“The organism is the starting point for the definition of its niche, and the niche itself can be distinguished as part of a greater medium that contains it. The medium, therefore, participates not only as a general container, but it operates fundamentally as the domain of the realization of the ontogenic niche of the living systems that it contains. It provides an independent source of opportunities for the shifting of ontogenic phenotypes, and for the realization of variations in epigenesis along the history of conservation and diversification of lineages.”

Similarly, the organism and, within the organism, the lymphoid system with its organs and lymph vessels, provide a niche for the development and maintenance of the immune system, as a source of opportunities for the shifting of lymphocyte repertoires, and for the realization of variations in their epigenesis along the history of conservation and diversification of these lymphocytes.

In the preface of a book we wrote long ago (Vaz and Faria, 1993), Maturana wrote:
When we renounce the idea of a primarily defensive immune system, we may see the organism as a dynamic entity that lives in congruence with an environment which makes possible its existence. The organism is no longer in oppositon to an aggressive medium, but rather integrated to it. The internal medium where the immune system operates is not simply a container, it acquires a dynamic relational character. The organism is no longer an aggregate of cells, organs and functions, it becomes a network of molecular and cellular productions which exists as a whole in the realization of this dynamics in the medium. But, at the same time, as a network of  relations of molecular and cellular productions, the organism is also the realm of realization of many other relational networks that are interconnected with it and are configured as entities in other spaces. The internal space becomes a closed molecular and cellular dynamics that defines the identity of the organism instead of being defined by the organism.”  (Maturana, 1993)

Self-nonself discrimination
The prohibition of auto-reactive clones, better known as self-nonself discrimination, is at the heart of the clonal selection theory. Although almost universally accepted until a few years ago, it is presently untennable for a number of theoretical and experimental reasons. Theoretically, it is a war-like description that precludes the participation of the immune system in development and other physiologic phenomena, for example, in the routine daily relation of the organism with its macromolecular diet and products of an abundant and diversified commensal microbiota (Vaz et al., 1997). It also isolates the immune system from the organism to which it belongs and forbids the connectivity among lymphocytes, making impossible the proposition of truely systemic theories. In addition, it runs against solid experimental evidence, some of which was already avaliable when the clonal selection theory was proposed. For example, the immunosuppressive effect of x-rays is more intense when radiation is used before rather than during or soon after antigenic exposure, when it would coincide with antigen-driven clonal expansions (Taliaferro and Talliaferro, 1951). The same happens with immunosuppresive drugs, such as hydroxyurea (Cumano et al., 1986; Aroeira et al., 1993). These experiments suggest that immune responses recruits clones which were already activated before the contact with antigen, and  this is not what the clonal selection idea proposed. The theory was unable to predict the importance of  the thymus and of T lymphocytes (Miller, 1961) and denied the possibility of connections among the lymphocytes and anti-antibody reactivity (idiotypy), which was clearly demonstrated in the 1960s (Oudin and Michel, 1963; Kunkel, 1970). Idiotypy included the phenomenon known as the “Oudin-Cazenave enigma”, which is defined in the title of their important paper: "Similar idiotypic specificities in immunoglobulin fractions with different antibody functions or even without detectable antibody function." (Oudin and Cazenave, 1971). Subsequent developments confirmed that the specificity of lymphocyte clonal receptors is degenerated or polyspecific (Wucherpfennig et al., 2007; Wooldridge et al., 2011) and that this is relevant for lymphocyte development, activation and disease processes. In itself, this polyspecificity denies the possibility of self-nonself discrimination.
Above all, self-nonself discrimination either derives from a cognitive entity which separates friend from foe, as in the understanding of the public, or, it is based on the sorting out of random mutations by a natural selective filter, as originally proposed by Burnet (1959). But lymphocytes, either individually or in populations, are incapable of cognitive decisions, and, yet, there are many displays of order deriving from their activity, for example, in the profiles or signatures of the reactivity of natural immunoglobulins, which are robustly maintained throughout healthy living (Nobrega et al., 2004; Cohen, 2013). Thus, they are not random. Immunological activity is an important display of biological order where it is difficult to identify a cognitive entity. Elsewhere, I have presented arguments suggesting that this cognitive aspect arises during immunological observations and derives from the actions of the immunologist acting as a human observer  involved in human languaging (Vaz, 2011).

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Wucherpfennig, K. W., P. M. Allen, et al. (2007). "Polyspecificity of T cell and B cell receptor recognition." Semin Immunol 19(4): 216-224.

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