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Melvin Cohn

Publications and source records attributed to Melvin Cohn.

18 recordsLinked to original sources
PubMed2007

On a key postulate of T-cell receptor restrictive function: the V-gene loci act as a single pool encoding recognition of the polymorphic alleles of the species major histocompatibility complex.

The proposition that single Valpha or Vbeta gene segments specify the recognition of the allele-specific determinants expressed on the major histocompatibility complex-encoded restricting elements of the species has as its consequence a totally different picture of the functioning of the T-cell receptor. This commentary justifies this assumption and outlines some of its most important consequences.

Alleles↗
PubMed2006

Does the signal for the activation of T cells originate from the antigen-presenting cell or the effector T-helper?

The present view is that the antigen-presenting cell (APC) processes and presents simultaneously on its surface several different antigens that are displayed randomly (with respect to their being Self or Nonself) as peptide-MHC complexes. The naive T-cell interacting with its ligand on the APC is activated by "co-stimulation," the first step on the pathway to effectors. This view ignores the requirement for associative recognition of antigen (ARA) in mediating both the Self-Nonself discrimination and the regulation of effector class. The introduction of ARA as a requirement for these two decision functions highlights a critical role for the effector T-helper (eTh) and necessitates rethinking the contribution of the APC.

Animals↗
PubMed2006

What are the commonalities governing the behavior of humoral immune recognitive repertoires?

The humoral repertoire of immune systems is large, random and somatically selected. It is derived from a germline selected repertoire by a variety of diversification mechanisms, complementation of subunits, mutation and gene conversion. However derived, the end-product must be able to recognize and rid a vast variety of pathogens. This is accomplished by viewing antigens as combinatorials of epitopes, an astuce that permits a small repertoire to respond sufficiently rapidly to a vast antigenic universe. A somatically generated repertoire, however, requires a solution to two problems. First, a somatic mechanism for a self-nonself discrimination has to be put in place. Second, the repertoire has to be coupled to the effector mechanisms in a coherent fashion. The rules governing these two mechanisms are species-independent and delineate the parameters of all immune repertoires, whatever the somatic mechanism used to generate them.

Allergy and Immunology↗
PubMed2005

The Tritope Model for restrictive recognition of antigen by T-cells I. What assumptions about structure are needed to explain function?

Given that the recognition of the allele-specific determinants expressed by MHC-encoded restricting elements (R) is germline encoded and selected, whereas the recognition of peptide (P) is somatically encoded and selected, then two different combining sites must be under selection. This necessitates a multirecognitive-single T-cell antigen-receptor (TCR) with anti-R and anti-P paratopes that function in concert to signal restrictive reactivity. The consequences of this "two repertoire" postulate not only gives us a concept of TCR structure quite distinct from that at present generally accepted, but, in addition, resolves many existent contradictions. The problems of the positive and negative selection, alloreactivity, Self-Nonself (S-NS) discrimination, the nature and size of the repertoire, and the related experimental interpretations, are discussed. Further the Tritope Model is compared with previously proposed models to justify why a competing model is warranted.

Animals↗
PubMed2005

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.

Animals↗
PubMed2005

Degeneracy, mimicry and crossreactivity in immune recognition.

Degeneracy of recognition of antigen by the immune system is being used as an argument that the self-nonself discrimination cannot be a property of the specificity of its antigen-receptors, TCR and BCR, but must rely on emergent properties derived from a set of complex interactions and pathways. This essay analyzes an alternative view by showing that degeneracy and specificity are not mutually exclusive properties. The self-nonself discrimination is the sole evolutionary selection pressure for the specificity of the TCR and BCR, which can be quantitated as a "Specificity Index." Degeneracy is a non-issue for the self-nonself discrimination largely because it is a problem of chemistry, not of biology.

Animals↗
PubMed2005

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.

Animals↗
PubMed2004

Whither T-suppressors: if they didn't exist would we have to invent them?

Arriving at an understanding of the role of suppressor T-cells (regulatory T-cells, CD4(+)CD25+) depends on whether their functional repertoire is somatically selected to be anti-Self or anti-Nonself. Immunologists are ambivalent; often publications espousing opposite views share an author. Here the arguments are detailed that the suppressor repertoire is not somatically selected to be anti-Self, but rather it is anti-Nonself. Therefore, suppression cannot regulate the Self-Nonself discrimination; its function is to regulate the magnitude and class of the anti-Nonself effector response.

Animals↗
PubMed2004

An alternative to current thinking about positive selection, negative selection and activation of T cells.

Given that recognition by the T-cell receptor (TCR) of allele-specific determinants on major histocompatibility complex (MHC)-encoded restricting elements (Rs) is germline encoded, whereas recognition of peptide (P) is somatically encoded, two combining site repertoires, anti-R and anti-P, are implied. As a consequence, the three pathways of T cells, positive selection, negative selection and activation, must be signalled by qualitatively distinct interactions engaging the TCR. These are spelled out as they provide an alternative to the current thinking that these pathways depend on affinity-based quantitatively distinguishable interactions.

Cell Differentiation↗
PubMed2003

Does complexity belie a simple decision--on the Efroni and Cohen critique of the minimal model for a self-nonself discrimination.

The immune system somatically generates a large and random paratopic repertoire that must be sorted into those specificities (anti-self) which, if expressed, would debilitate the host and those specificities (anti-nonself) which, if not expressed, would leave the host unprotected from infection. The critique of Efroni and Cohen that minimal models are misleading and without heuristic value is evaluated by illustrative examples.

Computer Simulation↗
PubMed2003

A computerized model for the self-non-self discrimination at the level of the T(h) (Th genesis). II. The behavior of the system upon encounter with non-self antigens.

In the final analysis, the self (S)-non-self (NS) discrimination is regulated by the sufficiency or insufficiency of effector T(h) (eT(h)) specific for the given antigen. We have described a model (Th genesis) for the origin of eT(h) based on an antigen-independent pathway from initial state T(h) (iT(h)) to eT(h), and on obligatory associative recognition of antigen (ARA) by an iT(h) and an eT(h) in order for the iT(h) to be activated. A computer analysis (referred to as Th genesis) was developed to evaluate this model that is extended here to describe the response to NS antigen. Th genesis fills in the missing element of the two-signal or ARA model for the S-NS discrimination, i.e. the origin of the primer eT(h). The conclusions from this analysis are compared with those of the other models for the origin of eT(h).

Animals↗
PubMed2002

Haplotype exclusion: the solution to a problem in natural selection.

Antibody that possesses two identical paratopes (bivalent) is aggregated by antigen to trigger effector function. Antibody that possesses two different paratopes behaves as functionally monovalent. If these two antibodies interact with a given epitope, the monovalent antibody will block the aggregation of the bivalent antibody thereby inhibiting effector activation. We advance the hypothesis that haplotype exclusion is driven by the necessity to reduce the level of monovalent antibody. This assumption is compared to previous suggestions and quantitated. Further, several mechanisms of haplotype exclusion used by various species are analyzed in the light of this hypothesis.

Animals↗
PubMed2002

The immune system: a weapon of mass destruction invented by evolution to even the odds during the war of the DNAs.

Living systems operate under interactive selective pressures. Populations have the ability to anticipate the future by generating a repertoire of elements that cope with new selective pressures. If the repertoire of such elements were transcendental, natural selection could not operate because any one of them would be too rare. This is the problem that vertebrates faced in order to deal with a vast number of pathogens. The solution was to invent an immune system that underwent somatic evolution. This required a random repertoire that was generated somatically and divided the antigenic universe into combinatorials of determinants. As a result, it became virtually impossible for pathogens to escape recognition but the functioning of such a repertoire required two new regulatory mechanisms: 1) a somatic discriminator between Not-To-Be-Ridded ('Self') and To-Be-Ridded ('Non-self') antigens, and 2) a way to optimize the magnitude and choice of the class of the effector response. The principles governing this dual regulation are analyzed in the light of natural selection.

Animals↗
PubMed2002

A computerized model for the self-non-self discrimination at the level of the T(h) (Th genesis). I. The origin of 'primer' effector T(h) cells.

The ability of the immune system to respond by ridding a pathogen without debilitating the host depends upon the ability of the effector T(h) (eT(h)) to make a discrimination between 'self' and 'non-self' antigens. This ability is somatically learned and involves the sorting of the somatically generated random repertoire of initial state T(h) (iT(h)) into two classes of specificity: one, anti-self, the functional expression of which must be inactivated; the other, anti-non-self, the functional expression of which must be activated. We propose a model for the origin of a sufficiency of eT(h) anti-non-self and an insufficiency of eT(h) anti-self based on two postulates. (i) An antigen-independent pathway to a priming level of eT(h) anti-non-self under conditions where iT(h) anti-self are effectively deleted by interaction with self. This state is established during a window of fetal development and maintained throughout life because self is persistent. (ii) Associative recognition of antigen (peptide-MHC class II) on an antigen-presenting cell between iT(h) and 'primer' eT(h) that results in the rapid induction of an effective level of helper activity to non-self antigen. A computer simulation is provided that enables evaluation of this model.

Autoantigens↗
PubMedDate not supplied

If the immune repertoire evolved to be large, random, and somatically generated, then...

The evolution of the somatically generated random combining site repertoire of the "adaptive" immune system depended on the concurrent appearance of a somatic process that sorted the repertoire into anti-self and anti-nonself. Unlike the germline-selected sorting process characteristic of "innate" defense mechanisms, somatic sorting of the repertoire requires that antigens be classified based on their behavior, not on their physical or chemical properties. As specific recognitive combining sites (paratopes) define antigenic determinants (epitopes), the sorting of the repertoire operates epitope-by-epitope. By contrast, the coupling of the paratope to effector function must operate antigen-by-antigen because the response to each epitope on the antigen must be in the same effector class (i.e., coherent). This distinction resolves a long standing debate and provides a basis for analyzing the various models.

Animals↗