The reverse side of immune responses and tolerance

The reverse side of immune responses and tolerance

The study of immune responses may be the exact opposite of what would be required for understanding the immunological activity. Immune responses, both those induced experimentally and those occurring during natural infections, involve oligoclonal expansions, and these reactions constitute the main source of immune pathology. In other words, the establishment of an immune “memory”, i.e. a readiness for more intense and faster immune responses when repeating the encounter with a given antigen — the “secondary type” reactivity — is the explicit goal of using anti-infectious vaccines and is considered one of the fundamental phenomena in the maintenance of immunological health. However, this same exacerbated reactivity is also the basic phenomenon in “allergic” reactions and can also be invoked in episodes of “autoimmune” aggressions and chronic “autoimmune” diseases” in which, apparently, the body performs immune responses to its own tissues.

For several years we have insisted that the most common and daily forms of exposure to antigenic materials, which come from diet and from the native microbiota that lives on the skin and mucous membranes of the body, do not lead to immunological “memory”, thus they do not result in a progressive reactivity with each new antigenic encounter. The body is said to become immunologically “tolerant” to these materials, just as it becomes “tolerant” to its own tissues — the natural tolerance or self-tolerance proposed by Burnet in the clonal selection theory (1959). However, in a stimulus-response framework, where the default state of the system is inertia, tolerance is understood as a form of non-reactivity.

However, if the default state of the imune system is of activity – but not and expansive activity -, “tolerance” may be seen as steady state. Between responding or not responding to a stimulus, is the possibility of conserving a dynamic endogenous activity that is constantly underway as part of the (self) construction and maintenance of the system itself and of the organism to which it belongs. The firse way of looking is antigen-centered; the second is organism-centered.

In organism-centered way of seeing, specific immune responses are disturbances in the conservation of immunological activities which, physiologically, are always plural and therefore multi-specific. Viewed as a conservative physiology, immunological activity maintains patterns of activity that are reflected, for example, in reactivity profiles of natural immunoglobulins (Nóbrega et al., 2002; Cohen, 2013) and can also be registered in the reactivity of T lymphocytes (Miyama et al., 2017).

These reactivity profiles are robustly conserved during healthy living (Mouthon et al., 1995) but may undergo characteristic changes during autoimmune diseases (Ferreira et al., 1993) and parasite infections (Vaz et al., 2001; Fesel et al., 2005). In some cases, for example, in murine experimental schistosomiasis, a single epitope detected by a single T cell line is responsible for the severe (granulomatous) forms of the disease (Finger et al., 2005). These changes in the “global” reactivity profiles, however, do not refer to a specific antigen and are not immune responses in the sense of the term; they are changes of state involving the entire system or much of its structure.

In this sense, specific immune responses can be seen as the reverse of immunological activity understood as a conservative physiology, which keeps the organism in harmony with its antigenic environment.


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