sexta-feira, 18 de janeiro de 2013

07-12-14-Dancing with the immune system (final)

Por Nelson Vaz

The idiotypic network theory (Jerne, 1974a) is now almost forty years old and has definitely failed to influence the central tenets of immunological thinking. This is unfortunate because it was the only theory proposing something different from the traditional description of immunological phenomena as derived from independent actions of lymphocytes clones. The clonal selection theory (Burnet, 1957) and all its variants are theories about the behavior of lymphocyte clones, not about an immune system. As soon as 1974, Jerne's visionary ideas suggested, that the problems raised by clonal selection would be replaced by something he called  "systems analysis", more than three decades before the current flurry of interest in the still foggy notion of "systems biology" (Cornish-Bowden, 2006; Hood et al., 2005; Keller, 2005; Kirschner, 2005; Kitano, 2002; Van Speybroeck et al., 2005). But Jerne’ predicition was not fulfilled: "systems analysis", whatever it means now, is as yet to raise the interest of immunologists.

Jerne introduced the idea of anti-antibodies, or anti-idiotypic antibodies, as a way to interconnect lymphocyte clones in a web, or network. Immunological activity is usually seen as atomized in isolated (specific) clones which either expand or are impeded to expand. However, any “systemic” view requires connections among these components. The simplest way to link these clones among each other would be to display on each lymphocyte (on its clonal receptors) an exclusive, distinctive element (an idiotope) recognizable by other lymphocytes. The resultant complex multiconnected network of interactions was what Jerne identified as the immune system itself, embodying the true nature of immunological activity, no longer dispersed into independent clones (Jerne, 1972; 1973).  In his 1974 annual report to the Basel Institute of immunology, he wrote:

The known recognition elements are the combining sites (paratopes) of the V-domains that occur on antibody molecules and at the surface of lymphocytes. The fact that V-domains have been shown also to carry idiotopes that are immunogenic even in the individuals that produce these V-domains  forces us to reconsider the validity of "linear" ideas about the immune system (i.e., the notion that the immune response of lymphocytes is solely antigen-driven and is independent of lymphocytes and antibody molecules that do not recognize this antigen), in favor of a "network" notion (i.e., the idea that every lymphocyte is under the continuous surveillance of other lymphocytes and of antibody molecules by idiotope-paratope interactions). The fact that animals have been shown to produce anti-idiotypic antibodies to their own antibodies proves that these anti-idiotypic antibodies were already present, since clonal selection requires antibodies to be present prior to an antigenic stimulus. In order to recognize all idiotopes, all antibodies must be anti-idiotypic antibodies. Contrary to the notions of the 1960's,  which regarded the huge set of paratopes of an  immune system as an "open" set of recognizing elements, most of which would never meet a fitting  antigen, we must now accept that the immune system is essentially "closed" or self-sufficient in this  respect: the paratope of any V-domain will recognize idiotopes on many other V-domains, and the idiotope of any V-domain will be recognized by the paratopes of many other V-domains (Jerne, 1974b). (italics added)

This notion of “operational closure” of the immune system was not further mentioned by Jerne, neither in the papers proposing the network theory, (Jerne, 1973; Jerne, 1974a,b,c), nor in an important preceding paper (Jerne, 1971). A few years later, the late Francisco Varela and I published a paper  emphasizing that the notion of closure - organizational closure -,  is central for the a proper description of the immune system. The paper received laudatory comments of Jerne, but remained otherwise unknown (Vaz and Varela, 1978).
The tenets of the network theory has unforeseen consequences not mentioned (or not acknowledged) by Jerne. The operational closure of the immune system is necessary to stabilize the network because, if there are anti-antibodies, there would be also anti-anti-antibodies, in an infinite regression which would make the system explode in a feed-forward cascade (Gell. & Kelus, 1967). Instead of the systemic idea of closure, Jerne used the local notion of suppressive interactions; he proposed that most interactions among lymphocytes were suppresive, i.e., inhibitory and, thus, lost the opportunity to make a generalizing proposal. This was a crucial point because, when Jerne proposed that all  antibodies  (all immunoglobulins) are auto-antibodies (Jerne, 1974b, quoted above) [1], the class of non-auto-antibodies becomes empty and the prefix “auto” becomes meaningless. If all antibodies are auto-reactive, auto-antibodies are not a special class of entities; there is no longer sense in auto-immune diseases and related concepts. Thus, network theories are actually incompatible with self/nonself discrimination, a notion that is central in the clonal selection theory. This is not usually acknowledged.

From a strict point of view, network notions are not even compatible with the notions of specific immune responses, immunological memory and tolerance, notions that have been defined in terms of clonal expansions and contractions. But Jerne’s theory failed to provide alternative explanations for these immunological phenomena and, as a result, was gradually forgotten (Coutinho, 1995; Eichmann, 2008).  

[1] something Jerne himself questioned 10 years later (Jerne, 1984)

To properly approach these issues, we must first consider elementary definitions about networks as systems. In their simplest definition, systems are a collection of interconnected elements in which interfering with one component, influences all the other components. Our main interest here are complex, dynamic systems, such as living systems. What do complex dynamic systems do? How to study them?

Donella Meadows, who wrote mostly about social and economic systems, but offered general conclusions, said that systems are impossible to control and we can only "dance" with them (Meadows, 2000). The aim to "regulate" a system is misleading because the very notion of regulation  is synonimous with the notion of systems. The concept of homeostasis is a second synonimous to dynamic systems. because there are no “non-homeostatic” systems.

These ideas are formalized and greatly expanded by Maturana in his Biology of Cognition (Maturana, 2002: Maturana and Poerlsen, 2004; Maturana & Varela, 1980). In his way of seeing, systems accept no inputs and have no outputs, cannot be stimulated and do not respond to anything; they undergo perturbations, which are structural changes either derived from their internal dynamics or resulting from their interaction with the medium in which they operate. Perturbation is possibly a bad name, because dynamic systems never reach in a  non-perturbed state. These perturbations require compensative changes, otherwise the system is destroyed. However, perturbations are not inputs (stimuli) and compensative changes are not responses (outputs), because both these terms refer to the operation of a larger compound entity (the system) which is perturbed and undergoes compensative changes. Stimulus and reponses belong to a way of seeing linked to the idea of causes, whereas the notion of systems is related the ideas such as autonomy and independent operations, and, as mentioned above, the notion of operational closure (Vaz and Varela, 1978).

Closure does not mean isolation. This point is frequently misunderstood even by famous network immunologists (see Coutinho, 2003). All systems operate in a medium with which they interact and all systems are necessarily open for these interactions, although closed in their dynamics, their ways of changing their structure. Systems remind us of the French proverb: "the more it changes, the more it remains the same."

The organization of a system is that which remains invariant while everything else in the system may change. Dynamic systems, such as living systems, continuously replace their components, i.e., change their structure, without changing its organization. The organization defines the class-identity of a system. The organization chair is a set of relations among components of a chair which are present in all chairs regardless of their structure and their structural changes. When these relations are modified, chairs becomes something else. Functional descriptions do not help us to understand the organization of systems; chair can be used as objects for sitting as well as for many other functions (Figure 1).

Figure 1. Damian Ortega (1997), "Puente" (Bridge); Photo Eduardo Eckenfels. Inhotin,
Contemporary Art Museum, Brumadinho, MG, Brazil.

Living systems are characterized by a self-maintaining dynamic organization which Maturana has named autopoietic, or self-producing  (Maturana and Varela, 1980; 1987; Maturana and Mpodozis, 2000; Maturana, 2002; Maturana and Poerksen, 2004). In the structural domain, living organisms may be described as molecular machines that produce themselves; and when they stop changing in this particular manner - when they change their ways of changing -  they desintegrate and die.

The fundamental living systems are cells and unicellular organisms, first-order autopoietic entities. In multicellular organisms, second-order autopoietic systems,  we may distinguish sub-systems, such as the nervous and immune systems. Our aim is finding a proper way to describe these sub-systems and say something about their organization; for example, to ask: What remains invariant in the nervous system? What remains constant in the immune system in spite of their coninuous activity and their ceaseless replacement of cellular and molecular components?

The immune system
These questions are not commonly made because immunology is entirely focused on a special kind of changes of lymphocyte activity, called specific immune responses, which are believed to be expressions of its physiology.On the other hand, we are interested in constancy and conservation, on what remains invariant during variations (Vaz, 2006; Vaz et al., 2006).  Our aim is to define an organization for the immune system, thus, that which remains invariant amid variation.

Usually, it would be considered impossible to understand how something utterly complex is organized. However, it is not necessary to describe all the components of living systems and all the relations among them to postulate that they form self-producing, self-maintaining molecular machines, organizationally closed. It is not necessary to describe all the details of the relations among neurons to describe the nervous system as a closed network of neuronal interactions, in which relative states of neuronal activation can only lead to other relative states of neuronal activation. Neuronal activities may be seen as closed upon themselves, beginning and ending within the nervous system itself Maturana & Varela, 1980).

It is also important to remember that every system operates in a medium, which makes it possible and with which it interacts. The medium in which the nervous system operates is the organism of which it is a component. The nervous system is perturbed by the activity of the organism and undergoes compensative structural changes which, in its turn, trigger perturbations in the organism; which again trigger perturbations in the nervous system, in a ceaseless dance that goes on as long as living exists.

Similarly, the immune system may be described as a closed network of lymphocyte interactions, in which relative states of lymphocyte activation can only lead to other relative states of lymphocyte activation, i.e., lymphocyte activities are closed upon themselves, and they begin and end within the immune system itself. The immune system is in continuous interaction with the organism of which it is a component; it is  perturbed by its own dynamics and by interactions with the organism and undergoes compensative structural changes; in its turn, these changes trigger perturbations in the organism, which again trigger perturbations in the immune system, in a endless dance that goes on as long as living exists. Self/nonself discrimination is a pseudoproblem that dominated immunology for more than half a century.

Obviously, from the traditional way of seeing all this sounds as nonsense and seems to be in flagrant contradiction with common sense and abundant experimental evidence showing that both the nervous and the immune system interact  not only with the organism to which they belong, but also, and perhaps mainly, with the medium in which the organism, as a whole, operates. Is it not utterly apparent that the organism forms specific antibodies to invading antigens?  Is it not obvious that these antibodies specifically bind to the antigen in a variety of in vitro tests?  Are not antigens believed to determine (specify) antibody formation?  Just to mention a single example:

 "...(I)n healthy human subjects, not previously exposed to the rabies virus, nearly 2% of the circulating B lymphocytes were committed to the production of antibodies that bound the virus. These B cells expressed the surface CD5 molecule. The antibodies they produce were polyreactive IgM that displayed a relatively low affinity for the virus components. After immunization, different anti-virus (IgG and IgA) antibody-producing cells consistently appeared in the circulation and increased from less than 0.005% to greater than 10% of the total B cells committed to the production of IgG and IgA, respectively. Most of such B cells do not express CD5 and produce monoreactive antibodies of high affinity for rabies virus." (Ueki et al., 1990).

These traditional beliefs are examples of what Maturana calls the "fallacy of instructive interactions" (Maturana, 2002). The structural changes which dynamic systems undergo in their operation cannot be and are not determined (specified) by interactions with the medium in which they operate; these interactions can only trigger structural changes which are determined (specified) by the  dynamics of the system itself. Actually, it is the structure of the system that determines (specifies) which elements of the medium can interact with the system; except for destructive alterations, all the changes a system undergoes are determined (specified) by the system itself.

However, as observers, we can describe the operation of living systems in two separate non-intersecting domains: we may see their dynamic organismic/cellular/molecular structure and  we may also see the organism, as a whole entity, interact with its medium; and we may note that certain structural changes take place concomitantly or immediatlely after certain interactions with the medium; and we may we be misled to believe that the interactions determined (specified, caused) the structural changes. But this is not so. (Maturana, 2002; Maturana and Poerksen, 2004).

How can antigens, therefore, provoke the formation of specific antibodies?

The specificity of immunological obervations
The answer to this question demands what is actually much more than a radical revision of basic immunological tenets: it invites us to consider the crucial role played by deliberate human actions coordinated by human languaging (Maturana, 2002) in generating experimental findings, which are generally considered objective.

In our way of seeing, "antibodies" are functional labels pasted on natural immunoglobulins by means of serological tests designed and performed with the specific aim of characterizing and/or quantitating their very presence.  Specific antibodies are tautologies created by our way of observing (Vaz, 2011a,b,c).

Natural immunoglobulins and specific antibodies are described in different domains of description. Natural immunoglobulins emerge spontaneously in an antigen-free intracellular compartment and are then placed on the membrane of B lymphocytes, where they become BCR (B cell clonal receptors). As BCR, these molecules eventually bind a variety of elements present in their vicinity. Most of them will bind molecules which are components of the organism itself, including other immunoglobulins (Varela and Stewart, 1990), but also a variety of other molecules (Nóbrega et al., 2002; Merbl et al., 2007). Some of these ligands, however, may be invading molecules that were not produced by the organism, such as materials derived from the gut, as dietary components and elements from the bacterial flora, or, derived from infections by virus, germs or parasites. Both kinds of reactions - i.e., those triggered by materials derived from internal or external sources - may contribute to the activation and differentiation of the B lymphocyte, with or without the "help" ot T lymphoctes, to produce and secrete immunoglobulins with the same specificity of the BCR to the extracellular fluid. Some of these immunoglobulins may then be identified in the circulation as specific antibodies by serological testing.

In describing this sequence of events, we moved between two separate domains of description.  Natural immunoglobulins are produced without definite targets; on the other hand, antibody specificity is ascribed to some of these immunoglobulins by means of tests which were designed with exactly this directionality. In short, immunoglobulins are structural components of the organism; specific antibodies are functional labels that emerge in the coordinations of actions among immunologists; as entities, antibodies are more like verbs, than nouns. And if we approach natural immunoglobulins within this new way of seeing, some of their known properties acquire a different meaning.

Polyreactivity and its hidden aspects
For a long time now, it is recognized that natural immunoglobulins may be polyreactive (Varela and Stewart, 1990). The notion that specific antibodies admit "cross-reactions" is present since the every origin of immunological practice. The first and most effective anti-infectious vaccine, that against smallpox, is a blatant example of cross-reactivity,  in which immunity  to the smallpox virus is achieved by exposure to  different virus: the vaccinia virus. There are examples of clinically important serological tests which explore cross reactions, of which the Wassermann test for diagnosis of syphilis is a major example that motivated an important book in the philosophy of science (Fleck, 1935); but there are several other cases, such as the Paul Bunnel reaction for the diagnosis of infectious mononucleosis. But cross-reactivity in serological testing is just one of the many consequences of polyreactive immunoglobulins and not the ones we want to focus at this moment.

During B lymphocyte development, antibodies are assembled by mechanisms of reassortment  of gene segments, believed to happen at random; this generates a vast number of different structures (V-regions), but, due to the randomness of the process, some of the antibodies produced are self-reactive.  Is this self-reactivity detrimental to the organism, as usually believed, or is it an essential aspect of the organization of the immune system, as we believe?.

A possible explanation for polyreactivity is that the antigen-binding ‘pocket’ of many antibody molecules is more flexible than previously thought and can change conformation to accommodate different antigens (Notkins, 2004). Polyreactive natural immunoglobulins, specially IgM, have been indicated as the major source of a "physiologic autoreactivity". However, this is not an adequate description of the situation  because this auto-reactivity is granted almost as an indulgence, as accessory to a responsiveness directed mostly outward, to external antigenic targets.

The polyreactivity of natural immunoglobulins include other immunoglobulins among their many internal ligands and t this has unforeseen consequences. Polyreactivity has been considered an artifact generated during isolation procedures that partially denature immunoglobulins (McMahon and O'Kennedy, 2000; Bouvet et al., 2001) but this is highly unlikely. Polyreactive immunoglobulins may be collected in the fresh supernantants of B cell cultures submitted to no further isolation procedure. Moreover, when monoclonal immunoglobulins are tested upon complex mixtures of ligands, they rarely form single bands, i.e., most of them react detectably with many ligands. Thus, polyreactivity sems to be a natural property of immunoglobulins, specially IgM, but also present in IgG and IgA.

The first and most notable unforeseen consequence the polyreactivity of natural immunoglobulins is that immunoglobulins, when isolated from serum, display hidden "neo-reactivities" with a wide array of ligands, with which they did not react while in whole serum. These "hidden" reactivities again disappear when they are added back to the serum (Adib et al., 1990; Benerman et al., 1993; Sigounas et al., 1994) .

The problem of polyreactive immunoglobulins is minimized in the study of immunology because  it is seen as an imprecision, a nuisance, which generates cross-reactions as negative events in the dominant way of conceiving specific immunity; and also the possibility of auto-reactivity, which is usually seen as unnatural and potentially pathogenic. But polyreactive antibodies can hardly be ignored.

Although generally considered a minor and exceptional fraction of natural antibodies, polyreactive immunoglobulins may actually include all immunoglobulins. A large proportion of circulating B cells from healthy subjects are committed to the production of IgM antibodies that are polyreactive and bound a variety of self- and exogenous Ag. In contrast, significantly higher frequencies of cell precursors producing monoreactive IgG autoantibodies to thyroid Ag (thyroglobulin and thyroid microsomal Ag) and ssDNA were found in Hashimoto's disease and SLE patients, respectively (Nakamura et al., 1988). The reactivity of IgG in normal mouse serum to mouse actin and tubulin, DNA, and TNP groups is very low compared to that of the IgM, but this activity was considerably increased when IgG was separated from serum, by affinity chromatography on protein A-Sepharose, whereas no difference in the IgM activity was observed. Addition of IgM to IgG isolated from the same serum resulted in the inhibition of IgG binding to these Ag  (Adib et al., 1990). IgG auto-reactivities are only marginally expressed in whole unfractionated sera because of IgM-IgG, IgG-IgG and other, still unidentified, interactions (Berneman et al., 1993). In other studies, human plasma showed only minimal, if any, reactivity with a panel of antigens as measured by ELISA but IgM affinity-purified from plasma showed much more reactivity with the same panel of antigens. When plasma was added back to the affinity-purified IgM, the reactivity of the IgM with antigens was completely inhibited. When the affinity-purified IgM was affinity-purified a second time by passage through antigen-specific columns (e.g., insulin or Fc or beta-galactosidase), the eluted antibodies bound not only to the antigen used for purification, but also to a panel of unrelated antigens, indicating that the antibodies were polyreactive. It is concluded that polyreactive IgM antibodies are present in the circulation but are masked by binding to circulating antigens (Sigounas, et al., 1994).

In short, both IgM and IgG antibodies include a substantial proportion of polyreactive antibodies. Furthermore, the universal existence of idiotypic connections amplify this problem, because monospecific immunoglobulins may have direct or indirect connections to multispecific ones.

A second but not less important implication of polyreactivity is that immunoglobulins produced in vitro are usually studied  as if  they were representative of the immunoglobulins present in blood serum. This may be a misleading assumption because nascent immunoglobulins have to percolate body tissues before they accumulate in the circulation and all those binding to body components wil be rapidly removed. The most drastic example of this situation are immunoglobulins which have been named "autobodies", because they react with themselves and are cleared immediately after they are secreted from their producing cells, if they manage to escape intracellular aggregation ((Kang  and Kohler,  1986; Kaveri et al., 1990; 1991).

A third most important aspect of natural immunoglobulins is that they display robustly stable patterns of reactivity revealed either by reactions with complex mixtures of protein ligands (tissue and bacterial extracts) in modified forms of Immunoblotting (Nóbrega et al., 2002), or, collections of hundreds of different purified proteins assemble in micro-array (Merbl et al., 2007; Madi et al., 2012). Similar findings concerning the T cell repertoire may be in the horizon (Davis, 2007; ).

These ideas are of paramount importance since they have a profound implication on the way we think on the physiology of immunological activity. The application of methods of lymphocyte repertoire analysis holds a great promise in diagnosis of immunological diseases, such as infections, allergies and autoimmune diseases.

Adib, M., Ragimbeau, J., Avrameas, S. and Ternynck, T. (1990) IgG autoantibody activity in normal mouse serum is controlled by IgM. J Immunol 145, 3807-3813.
Berneman, A., Guilbert, B., Eschrich, S. and Avrameas, S. (1993) IgG auto- and polyreactivities of normal human sera. Molecular Immunology 30, 1499-1510. 
Bouvet, J.P., Stahl, D., Rose, S., Quan, C.P., Kazatchkine, M.D. and Kaveri, S.V. (2001) Induction of natural autoantibody activity following treatment of human immunoglobulin with dissociating agents. J Autoimmun 16, 163-72   
Cornish-Bowden, A. (2006) Putting systems back into systems biology.
            Perspectivesin Biology and Medicine 49, 475-489.
Coutinho, A., Kazatchkine, M.D. and Avrameas, S. (1995) Natural autoantibodies.
            Curr Opin Immunol 7, 812-8.
Coutinho, A. (1995) The network theory: 21 years later.
            Eur.J.Immunol. 42, 3-8.
Coutinho, A. (2003) A walk with Francisco Varela from first- to second-generation networks: in search of the structure, dynamics and metadynamics of an organism-centered immune system. Biol Res 36, 17-26   
Davis, M.M. (2007) The alphabeta T cell repertoire comes into focus.
            Immunity 27, 179-80   
Eichmann, K. 2008. The Network Collective - Rise and Fall of a Scientific Paradigm,
            Berlin, Birkhauser.
Fleck, L. (1935) Genesis and development of a scientific fact.
            University of Chicago Press, Chicago.
 Gell, P. G. & Kelus, A. S. 1967. Anti-antibodies.
            Adv Immunol, 6, 461-78.
Hood, L., Heath, J.R., Phelps, M.E. and Lin, B. (2004) Systems Biology and New Technologies Enable Predictive and Preventative Medicine. Science 306, 640-643.
Jerne, N.K. (1971) What precedes clonal selection ? In: Ciba Foundation Symposium, 1971 : Ontogeny of acquired immunity. Elsevier, Amsterdam, p. 1-15.
Jerne, N.K. (1973) The immune system.
            Sci.Amer. 228, 52-60.
Jerne, N.K. (1974a) Towards a network theory of the immune system.
            Ann. Immunol. 125C, 373-392.
Jerne, N. K. (1974b)  Network notions.
            Annual Report of the Basel Institute for Immunology, 1974,, BII Report <>, 6.
Jerne, N. K. (1974c). The immune system: a web of V-domains.
            Harvey Lect, 70 Series, 93-110.
Jerne, N. K. (1984d). Idiotypic networks and other preconceived ideas.
            Immunol.Rev., 79, 1-14.
Kang, C.Y. and Kohler, H. (1986) Immunoglobulin with complementary paratope and idiotope. J Exp Med 163, 787-96 
Kaveri, S.V., Halpern, R., Kang, C.Y. and Kohler, H. (1990) Self-binding antibodies (autobodies) form specific complexes in solution. J Immunol 145, 2533-8   
Kaveri, S.V., Halpern, R., Kang, C.Y. and Kohler, H. (1991) Antibodies of different specificities are self-binding: implication for antibody diversity. Mol Immunol 28, 773-8   
Keller, E.F. (2005) The century beyond the gene.
            J. Biosci. 30, 3–10.
Kirschner, M. (2005) The Meaning of Systems Biology.
            Cell 121, 503-504.
Kitano, H. (2002) Systems Biology: A Brief Overview.
            Science 295, 1662-1664.
Madi, A., S. Bransburg-Zabary , et al. (2012). "The natural autoantibody   repertoire in newborns and             adults : a current overview." Adv Exp Med Biol. 750: 198-212.
Maturana, H. (2002) Autopoiesis, structural coupling and cognition: a history of these and other notions in the biology of cognition. Cybernetics & Human Knowing 9, 5-34.   
Maturana, H.R. and Varela, F. (1980) Autopoiesis and cognition: the realization of living. Reidel, Amsterdam.
Maturana, H.R. and Varela, F.J. (1987) The Tree of Knowledge.Biological Basis of Human Understanding. New Science Library, Boston.
Maturana, H. and Mpodozis, J. (2000) The origin of species by means of natural drift. Revista Chilena de Historia Natural 73:261-310 (2000) 73, 261-310   
            see also
 Maturana, H. and Poerksen, B. (2004) From Being to Doing: The Origins of Biology of Cognition. Carl-Auer, Heidelberg.
McMahon, M.J. and O'Kennedy, R. (2000) Polyreactivity as an acquired artefact, rather than a physiologic        property, of antibodies: evidence that monoreactive antibodies may gain the ability to bind to multiple antigens after exposure to low pH. J Immunol Methods 241, 1-10   
 Merbl, Y., Zucker-Toledano, M., Quintana, F.J., Cohen, I.R. and A, B. (2007) Newborn humans manifest autoantibodies to defined self molecules detected by antigen microarray informatics. J. Clin. Invest. 117, 712–718.
Nakamura, M., Burastero, S.E., Ueki, Y., Larrick, J.W., Notkins, A.L. and Casali, P. (1988)
 Probing the normal and autoimmune B cell repertoire with Epstein-Barr virus. Frequency of B cells producing monoreactive high affinity autoantibodies in patients with Hashimoto's disease and systemic lupus erythematosus. J Immunol 141, 4165-72   
Nobrega, A., Stransky, B., Nicolas, N. and Coutinho, A. (2002) Regeneration of natural antibody repertoire after massive ablation of lymphoid system: robust selection mechanisms preserve antigen binding specificities. J Immunol 169, 2971-8   
Notkins, A.L. (2004) Polyreactivity of antibody molecules.
            Trends in Immunology 25, 175-179   
Sigounas, G., Kolaitis, N., Monell-Torrens, E. and Notkins, A.L. (1994) Polyreactive IgM antibodies in the circulation are masked by antigen binding. J Clin Immunol 14, 375-381. 
Ueki, Y., Goldfarb, I.S., Harindranath, N., Gore, M., Koprowski, H., Notkins, A.L. and Casali, P. (1990) Clonal analysis of a human antibody response. Quantitation of precursors of antibody-producing cells and generation and characterization of monoclonal IgM, IgG, and IgA to rabies virus. J Exp Med 171, 19-34   
Van Speybroeck, L., De Backer, P., Van Poucke, J. and De Waele, D. (2005) The conceptual challenge of Systems Biology. BioEssays 27, 1305–1307.
Varela, F.J. and Stewart, J. (1990) Dynamics of a class of immune networks. I. Global stability of idiotype interactions. J.Theoret.Biol. 144, 93-101.
Vaz, N.M. and Varela, F.G. (1978) Self and nonsense: an organism-centered approach to immunology. Med. Hypothesis 4, 231-257.
Vaz, N. (2006) Evolution and conservation ofimmunological activity. Brazilian Journal of Medical and Biological Research 39, 1521-1524   
Vaz, N.M., Ramos, G.C., Pordeus, V. and Carvalho, C.R. (2006) The conservative physiology of the immune system.A  non-metaphoric approach to immunological activity. Clinical and Developmental Immunology 113, 133-142  
Vaz, N. M. (2011a). The specificity of immunological observations.
            Constructivist Foundations, 6, 334-351.
Vaz, N. M. (2011b) Observing Immunologists.
            Neurociências, 7, 140-146.
Vaz , N. M., Mpodozis, J. M., Botelho, J. F. & Ramos, G. C. (2011c). Onde está o organismo? - Derivas e outras histórias na Biologia e na Imunologia, Florianópolis, editora-UFSC.

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