So..... who is citing me?
Not many people! I suspect that this is disproportionate to the importance of the concept and I suggest that it is a pity that this concept is not getting an airing.
It is becoming increasingly clear that academia has, for some reason or other, decided to keep my contribution to the literature on Immunology "in Coventry". (This edition of Avant 2012 illustrates this point.) I get virtually no feedback. I have had the odd "sideways" stroke including being asked to referee a couple of articles concerned with "immunological models" and the recent publications in the September 2006 and December 2007 issues of the Scand J Immunol. It is a lonely and frustrating world being so isolated and cut off from feedback. The beginning of the film 1492 (on Christopher Columbus) starts with the following wording and it certainly sums up how I feel.
"Of all the words my father (Christopher Columbus) wrote, and there were many, I remember these the most."
"Nothing that results in human progress is achieved with unanimous consent and those who are enlightened before the others are condemned to pursue that light in spite of others."
Darwin wrote
"False facts are highly injurious to the progress of science, for they often endure long; but false views, if supported by some evidence, do little harm, for everyone takes a salutary pleasure in proving their falseness."
and also
"Without speculation there can be no good and original observation."
It is largely left to me to make people aware of the existence of these articles.
If you find the ideas challenging then please consider whether science (particularly bio–medical science) would benefit from disseminating them – either with or without credit to me or this site.
In November 2007 these were sum total of the citations (I have found):
Chan WF, Perez-Diez A, Razavy H, Anderson CC.
The ability of natural tolerance to be applied to allogeneic tissue: determinants and limits.
Background: Transplant rejection has been considered to occur primarily because donor antigens are not present during the development of the recipient's immune system to induce tolerance. Thus, transplantation prior to recipient immune system development (pre-immunocompetence transplants) should induce natural tolerance to the donor. Surprisingly, tolerance was often not the outcome in such 'natural tolerance models'. We explored the ability of natural tolerance to prevent immune responses to alloantigens, and the reasons for the disparate outcomes of pre-immunocompetence transplants. Results: We found that internal transplants mismatched for a single minor-H antigen and 'healed-in' before immune system development were not ignored but instead induced natural tolerance. In contrast, multiple minor-H or MHC mismatched transplants did not consistently induce natural tolerance unless they carried chimerism generating passenger lymphocytes. To determine whether the systemic nature of passenger lymphocytes was required for their tolerizing capacity, we generated a model of localized vs. systemic donor lymphocytes. We identified the peritoneal cavity as a site that protects allogeneic lymphocytes from killing by NK cells, and found that systemic chimerism, but not chimerism restricted to the peritoneum, was capable of generating natural tolerance. Conclusion: These data provide an explanation for the variable results with pre-immunocompetence transplants and suggest that natural tolerance to transplants is governed by the systemic vs. localized nature of donor antigen, the site of transplantation, and the antigenic disparity. Furthermore, in the absence of systemic lymphocyte chimerism the capacity to establish natural tolerance to allogeneic tissue appears strikingly limited.
Biol Direct. 2007 Apr 16;2:10
Bakácsa T, Mehrishic J N, Szabadosd T, Vargae L, Szabóf M, Tusnádya G.
T Cells Survey the Stability of the Self: A Testable Hypothesis on the Homeostatic Role of TCR-MHC Interactions.
In the lifetime of an individual, every single gene will have undergone mutation on about 1010 separate occasions. Nevertheless, cancer occurs mainly with advancing age. Here, we hypothesize that the evolutionary pressure driving the creation of the T cell receptor (TCR) repertoire was primarily the homeostatic surveillance of the genome. The subtly variable T cells may in fact constitute an evolutionary link between the invariable innate and hypervariable B cell systems. The new model is based on the homeostatic role of T cells, suggesting that molecular complementarity between the positively selected TCR and the self peptide-presenting major histocompatibility complex molecules establishes and regulates homeostasis, strictly limiting variations of its components. Notwithstanding, the 'homeostatic role of T cells' model offers a more realistic explanation as to how a naïve clonal immune system can cope with the much faster replicating pathogens, despite a limited repertoire that is capable of facing only a small fraction of the vast antigenic universe at a time.
Int Arch Allerg Immunol 2007;144:171-182
Colditz I G.
Six costs of immunity to gastrointestinal nematode infections.
The strength of the immune response and the outcome of the interaction of a host with a parasite are influenced by genetic and phenotypic characteristics of both parties, and by environmental variables. Allocation of host resources to immune defence reduces resources available for other life-history traits. This review identifies six potential costs to the host from immune activation. The costs are likely to be broadly applicable to other immune responses in vertebrate species. Five phenotypic costs arise from: (i) increased metabolic activity; (ii) reduced nutrient availability due to anorexia; (iii) altered priorities for nutrient utilization; (iv) change in size and turnover of pools of immune cells and proteins; and (v) immunopathology from inappropriate or excessive immune activation. Subsumed by these costs is the cost of altered efficiency of nutrient use. A sixth cost is the genetic cost which arises from a change in the capacity of offspring to express production and life-history traits following selection for parasite resistance. The sensitivity of immune responses to the phenotypic status of the host, and the role the immune system shares with the neuroendocrine system in controlling use of resources underpin the importance of immunocompetence to the life-history of the host.
Parasite Immunology (OnlineEarly Articles). doi:10.1111/j.1365-3024.2007.00964.x
Twycross J., Aickelin U.
Biological Inspiration for Artificial Immune Systems.
Artificial immune systems (AISs) to date have generally been inspired by naive biological metaphors. This has limited the effectiveness of these systems. In this position paper two ways in which AISs could be made more biologically realistic are discussed. We propose that AISs should draw their inspiration from organisms which possess only innate immune systems, and that AISs should employ systemic models of the immune system to structure their overall design. An outline of plant and invertebrate immune systems is presented, and a number of contemporary systemic models are reviewed. The implications for interdisciplinary research that more biologically-realistic AISs could have is also discussed.
http://www.cs.nott.ac.uk/~uxa/papers/07icaris_jamie.pdf
Cohn M, Mata J.
Quantitative modeling of immune responses.
No abstract
"Immunol Rev. 2007 Apr;216:5-8
Cohn M.
If we were to agree that....., then......
No abstract
http://www.cig.salk.edu/papers/If_we_agree_that.pdf
Anderson C.C.
Time, Space and Contextual Models of the Immunity Tolerance Decision: Bridging the Geographical Divide of Zinkernagel and Hengartner's 'Credo 2004'
In Credo 2004, Zinkernagel and Hengartner have continued their challenge to the immunological community to reconsider assumptions regarding the most fundamental aspects of adaptive immunity. They have appropriately championed the role of persistent, widely distributed antigen in tolerance induction, parameters that do not figure prominently in most other models. The global theory of immunity they have developed is predominately based on observations from studies with viruses and tumours. I suggest here that a more successful approach to generating a theory of the default rules of immunity can be obtained through the study of immunity versus tolerance in the setting of transplantation. Transplantation studies lack the confounding variable of competing evolution present in responses to specific infectious agents and tumours and, therefore, more clearly elucidate default rules of immunity. The geographical model in Credo 2004, primarily a one-signal model regulated by antigen, is contrasted with (1) Cohn's time-based two-signal model and (2) a development–context model that postulates distinct central and peripheral tolerance mechanisms.
Scand J Immunol. 2006 Apr;63(4):249-256
Cohn M.
The common sense of the self-nonself discrimination.
The vertebrate immune system was evolutionarily selected to express a large random somatically generated paratopic repertoire coupled to effector mechanisms invented, in large measure, by non-vertebrates. The self-nonself discrimination is determined by Decision 1, the sorting of this repertoire into those specificities (anti-self) which, if expressed, would debilitate the host and those specificities (anti-nonself) which, if not expressed, would result in the death of the host by infection. Decision 1, the sorting of the repertoire, is mediated by a somatic learning process operating epitope-by-epitope that deletes anti-self specificities leaving the residue as anti-nonself. The activation of anti-nonself is the first step on entry into Decision 2, which optimizes the choice and magnitude of the effector class that rids the pathogen without significantly debilitating the host. The principles governing Decision 1, the self-nonself discrimination are analyzed here.
Springer Semin Immunopathol. 2005 Jun;27(1):3-17
Cohn M.
A biological context for the self-nonself discrimination and the regulation of effector class by the immune system.
An effective immune response to an antigen requires two sets of decisions: Decision 1, the sorting of the repertoire, and Decision 2, the regulation of effector class. The repertoire, because it is somatically generated, large, and random, must be sorted by a somatic mechanism that subtracts those specificities (anti-self) that, if expressed, would debilitate the host, leaving a residue (anti-nonself) that, if not expressed, would result in the death of the host by infection. The self-nonself discrimination is the metaphor used to describe Decision 1, the sorting of the repertoire. In order to be functional, the sorted repertoire must be coupled to a set of biodestructive and ridding effector functions, such that the response to each antigen is treated in a coherent and independent manner. Although a reasonably complete framework for Decision 1 exists, Decision 2 lacks conceptualization. The questions that must be considered to arrive at a proper framework are posed. It should be emphasized that manipulation at the level of Decision 2 is where clinical applications are likely to be found.
Immunol Res. 2005;31(2):133-50
Dembic, Z
About theories and the integrative function of the immune system
In recent years, dendritic cells have been placed centrally in starting and shaping the immune response, and a number of complex theories have been proposed to explain the immune response to antigen, Here, Zlatko Dembic overviews the Danger, Stranger and Integrity theories among others, and provides a broad look at early immune responses.
Immunologist Nov-Dec 2000, 141-147 (not listed in Medline)
Dembic, Z
Immune system protects integrity of tissues
The immune system neither discriminates between 'Self and Nonself, nor it acts when confronting 'Danger', rather, it reacts to disruption of tissue integrity allowing its renewal. The 'integrity' hypothesis proposes three groups of signals that coordinate actions of dendritic cells and immunocytes during the initiation of the specfic immune response, and suggests explanations for tolerance, memory formation, and repertoire selection, including differences with other theories.
Mol. Immunol Aug 2000, 563-569
McLellan, AD, Brocker, EB, Kampgen, E
Dendritic cell activation by danger and antigen-specific T-cell signalling
Recent transplantation, animal and in vitro studies suggest a dependence of some immune reactions on tissue damage. Although many factors involved in enhancing immune responses through tissue damage have yet to be identified, recent data suggests that one of the targets of these cellular stress factors is the bone marrow derived dendritic cell (DC). DC are potent initiators of primary immune responses and hold the key to immune reactions through their ability to sense changes in their local environment and respond appropriately to induce T-cell immunity, or possibly tolerance. in the lymph node, DC are also influenced by antigen-specific signalling from T cells, which may extend and amplify DC antigen presenting capabilities, especially for the stimulation of cytotoxic responses. It now appears that both tissue damage and antigen-specific T-cell derived signals act together on the DC to promote the appropriate immune reaction to antigen. Thus DC antigen presenting behaviour is not only dependent on the context of antigen encounter in the periphery, but also on the availability of antigen-specific T cells and their T-cell receptor specificities.
Exp. Dermatol.Oct 2000, 313-322
Jacobson, JS, Workman, SB, Kronenberg, F
Research on complementary/alternative medicine for patients with breast cancer: A review of the biomedical literature
Purpose: This article reviews English-language articles published in the biomedical literature from 1980 to 1997 that reported results of clinical research on complementary and alternative medical treatments (CAM) of interest to patients with breast cancer. Methods: We searched 12 electronic databases and the bibliographies of the retrieved papers, review articles, and books on CAM and breast cancer. The retrieved articles were grouped by end point: breast cancer (eg, tumor size, survival), disease-related symptoms, side effects of treatment, and immune function. Within each end point, we organized the articles by modality and assessed study design, findings, and qualitative aspects. Results: Of the more than 1,000 citations retrieved, 51 fit our criteria for review. Of the articles reviewed, 17 were randomized clinical trials; three of these were trials of cancer-directed interventions, two of which involved the same treatment (melatonin). Seven articles described observational studies, and the remainder were reports of phase I or II trials. Relatively few CAM modalities reportedly used by many breast cancer patients were mentioned in articles retrieved by this process. Most articles had shortcomings. Conclusion: Although many studies had encouraging results, none showed definitively that a CAM treatment altered disease progression in patients with breast cancer. Several modalities seemed to improve other outcomes (eg, acupuncture for nausea, pressure treatments for lymphedema). If CAM studies are well-founded, well-designed, and meticulously conducted, and their hypotheses, methods, and results are reported clearly and candidly, research in this controversial area should acquire credibility both in the scientific community and among advocates of unconventional medicine. by American Society
J Clin Oncol 18:668-683. 2000
Naisberg, Y, Weizman, A
Biophysical shunt theory for neuropsychopathology: biphasal homeostatic dysregulation
Objective. We challenge Freud's psychodynamic theory using a systematic modus operandi which has been outlined in detail in a succession of articles. Here, we deal with Freud's first assumption of human psychological primacy in forming goal- directed behavior. According to our theory, biphasal homeostatic dysregulation is the underlying mechanism of clinical phenomenology. Model: Evolutionary neurobiology has provided humans with a precise technical solution for optimal organismic survival. Humans are armed with an accurate negative feedback mechanism that operates within the alternating upper and lower thresholds of biphasal homeostatic maintenance and is coupled with a basal indicator of individual sensation of the degree of the given organismic well-being in any unit of time. This originates the organismic pleasure principle (OPP). The latter is achieved by a straightforward quantal injection of endorphins according to one of eight possible body operational regimens. Thanks to the essential duality of the dynamic interactions, stipulated by the complex harmonics of term- dependent and event-dependent adaptation when one or more of the essential elements for homeostasis goes above or below its predetermined threshold, certain branches of the organismic defense system (ODS) are 'turned on' in the second phase of homeostasis. The individual then adapts behavioral modifications directed toward a long-lasting search for the optimal resources needed for normal survival. This evolutionary biphasal homeostatic design has an intrinsic, methodical expression that confirms changes and correctly informs the individual about them, further imposing behavioral modifications, when necessary. In cases of a homeostatic derangement, the OPP is replaced by an erratic inclusion of pain, tension or depression, all components of the alarm system of the ODS, which may lead to disordered behavioral patterns. Conclusions: The underlying biological mechanism of goal- directed assignments for biphasal homeostatic maintenance is described. The intrinsic rules and regulations that guide both normal and abnormal survival may be clinically manifest. Normal survival behavior is necessary to regain organismic homeostasis.
Med. Hypotheses, Mar 1999, 179-182
Langman, RE, Cohn, M
A short history of time and space in immune discrimination: Reply
Scand. J. Immunol.Aug 1997, 113-116
AU Chigira, M
Transplantation and chimera as extended self
Transplantation can be considered as an artificial reconstitution of symbiosis called chimera, since the donor and recipient carry different DNAs. In successful transplantation, engrafted tissues and cells should be recognized as self by the immune system, as shown in external pathogens. The external milieu introduced by transplantation and infection can only be immunologically recognized as self when it forms a symbiotic relationship with somatic cell society. Immunological identity is a posteriori educated recognizing immunological self and genetic self may be ignored in self-recognition. For example, transplanted bone marrow immunocytes recognize somatic cell society which is selected previously by other immunological standards as self. Dissociation between genetic self and immunological self originates in the development and differentiation of multicellular organisms a priori, since alteration of DNA sequences is necessary in the development and differentiation of multicellular organisms and symbiosis is the essential nature of it.
Med. Hypotheses Jan 1997, 63-69
Also - "Morphostasis" and "Cunliffe" were fleetingly mentioned in the "Sense of Self" debate in HMS Beagle (BioMedNet). This was the first indication that someone had, at last, noticed its existence.
Current citations:
. . . can be seen in Google Scholar
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