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". 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.
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 (Z&H) 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.
Since I no longer have access
to a suitable search engine to find out who is citing me, I'd be grateful to
anyone who is able to do this on my behalf and let me know through
Feedback.
Thanks to Jez Roff for a Jul 2005 update