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R E Langman

Publications and source records attributed to R E Langman.

At least 19 recordsLinked to original sources
PubMed2002

To be or Not to be ridded?--That is the question addressed by the associative antigen recognition model.

The reasons that germline-encoded recognitive sites cannot sort the immune system's large and random somatically generated repertoire into anti-Not-to-be-ridded ('self ') and anti-To-be-ridded ('nonself ') specificities are analysed. The immune system cannot use 'nonself '-markers of To-be-ridded antigens ('Danger', toll receptors, pathogenicity, localization, etc.) to sort the repertoire; it may, however, use them to determine the magnitude and class of the effector response.

Animals↗
PubMed2001

A general account of selection: biology, immunology, and behavior.

Authors frequently refer to gene-based selection in biological evolution, the reaction of the immune system to antigens, and operant learning as exemplifying selection processes in the same sense of this term. However, as obvious as this claim may seem on the surface, setting out an account of "selection" that is general enough to incorporate all three of these processes without becoming so general as to be vacuous is far from easy. In this target article, we set out such a general account of selection to see how well it accommodates these very different sorts of selection. The three fundamental elements of this account are replication, variation, and environmental interaction. For selection to occur, these three processes must be related in a very specific way. In particular, replication must alternate with environmental interaction so that any changes that occur in replication are passed on differentially because of environmental interaction. One of the main differences among the three sorts of selection that we investigate concerns the role of organisms. In traditional biological evolution, organisms play a central role with respect to environmental interaction. Although environmental interaction can occur at other levels of the organizational hierarchy, organisms are the primary focus of environmental interaction. In the functioning of the immune system, organisms function as containers. The interactions that result in selection of antibodies during a lifetime are between entities (antibodies and antigens) contained within the organism. Resulting changes in the immune system of one organism are not passed on to later organisms. Nor are changes in operant behavior resulting from behavioral selection passed on to later organisms. But operant behavior is not contained in the organism because most of the interactions that lead to differential replication include parts of the world outside the organism. Changes in the organism's nervous system are the effects of those interactions. The role of genes also varies in these three systems. Biological evolution is gene-based (i.e., genes are the primary replicators). Genes play very different roles in operant behavior and the immune system. However, in all three systems, iteration is central. All three selection processes are also incredibly wasteful and inefficient. They can generate complexity and novelty primarily because they are so wasteful and inefficient.

Behaviorism↗
PubMed2000

A minimal model for the self-nonself discrimination: a return to the basics.

An immune system is required in any host that evolves slowly relative to the pathogens that attack it. This immune system must somatically generate and regulate new specificities. We propose a mechanism that results in a self-nonself discrimination that is a one-time regulatory event, which occurs early in development when maternal protection ensures an environment that is free of nonself. Our proposed mechanism considers all T and B cells to arise in an i-state which is incapable of effector reactions. Uniquely in iTh (helpers) a prolonged absence of antigen permits their differentiation to eTh (only nonself antigens are absent). In all i-state cells antigen induces an anticipatory a-state which, in the presence of eTh and via associative recognition of antigen results in the e-state, and which in the absence of eTh results in cell death.

Antigens↗
PubMed2000

The specificity of immunological reactions.

Specificity is an imprecise but widely used concept in immunology. Usually specificity is described in practical terms, such as the ability of one antibody to bind one and not another member of a family of chemically related substances. Karl Landsteiner's pioneering work "The Specificity of Serological Reactions" set the standard in experimental immunology over 50 years ago. Today, a more general yet precise concept of specificity is needed to describe the behavior of all antigen-specific recognitive components of the immune system. The necessary degree of specificity for antigen recognition in the immune response is determined by evolutionary selection pressures that result in the ridding of pathogens. Potent bio-destructive effector mechanisms are under the direction of specificity-determining elements (e.g. antibodies), and these must accurately distinguish Self (S) components (not to be destroyed) from Nonself (NS) components (to be destroyed). Binding reactions between antigen and antibody are necessary, though not sufficient, for the execution of the protective bio-destructive effector reactions, which, for example, require more than one antibody molecule to be bound before that antigen can be ridded. While the total number of different specificities will determine the precision with which S and NS are distinguished, a concept of relative specificity can be formulated in terms of a Specificity Index (SI), or the ratio of anti-S to anti-NS in the repertoire. A further question concerns whether specificity applies per receptor, or per paratope, when the number of paratopes per receptor is greater than one. The analyses and concepts developed here are based on immunoglobulin structure and function and extrapolated to include the less well studied T cell receptor system.

Antibody Specificity↗
PubMed1999

The standard model of T-cell receptor function: a critical reassessment.

The Standard Model of T-cell receptor (TCR) function is the distillation of many views. Here we provide a summary that is intended to capture the flavour of the whole, without assigning particular blame, or credit, to any one part. The Standard Model is based on the notion of a single TCR-combining site that sums the binding contributions of MHC and peptide to produce a single signal to the T cell. How this signal is interpreted can vary with the state of the T cell. A growing number of creaks in the tweaks needed to maintain the Standard Model suggest that it may be timely to make a critical reassessment of the facts and their interpretation. The result of this effort has been to uncover a long-overlooked fact that T cells do not recognize hybrid class II major histocompatibility complex alleles; they recognize only those haplotypes directly associated with each alpha- or beta- subunit of class II. Our attempts to tweak the Standard Model to deal with lack of recognition of hybrid class II alleles led us, by surprise, to a quite different framework with which to view TCR function.

Animals↗
PubMed1999

Away with words: commentary on the Atlan-Cohen essay 'Immune information, self-organization and meaning'.

Drawing on metaphors from linguistics and information theory, Atlan and Cohen challenge us to take a very different view of the immune system, one that engages in constant chatter among the constituents and allows the immune system to arrive at a decision about what to, and not to, destroy. Our commentary responds to this challenge and points out many logical biological flaws in their view. We seem to agree that specificity is important, and that there is some kind of somatic selection process at work to distinguish self from non-self. Our analysis of models depends on the basis of how self and non-self are separated. There are only two possibilities, time or space; and space-based models are all but ruled out. There are two major kinds of time-based model, one based on the time taken for an organism to develop from embryo to adult, the other based on the time taken for a cell to differentiate from one state to another. With so many ambiguities in the metaphors and so little attention to mechanism, the Atlan and Cohen challenge is, we suspect, based on time measured in cell differentiation units. They also make the common mistake of assuming repertoires that are transcendental in size (>10(10)), making it impossible to have a functional immune system in animals smaller than a rabbit--a feature that does not instill confidence in the biological relevance of such models.

Animals↗
PubMed1996

Cutting edge: terra firma: a retreat from "danger".

The danger model differs from the associative recognition model solely with respect to the origin of effector T helpers (eTh). More properly, the danger model should be juxtaposed to the Ag-independent model for the origin of eTh cells (i.e., the primer question). The introduction of danger in no way challenges the need to make a self-nonself discrimination, nor, for that matter, does it challenge the need to define self as those Ags encountered in the absence of eTh and that persist, whereas nonself are those Ags encountered in the presence of eTh and that are transient. The clarification of these points is our goal here.

Animals↗
PubMed1996

The immune system: a look from a distance.

The self-nonself discrimination is germline encoded for defense mechanisms, but it is somatically learned for the immune system and this is the fundamental difference between the two. When referring to the defense mechanisms of vertebrates, immunologists like to use the term "innate immune systems" to describe the germline encoded class of defense mechanism. It was the acquisition of a somatically learned S-NS discrimination during vertebrate evolution that permitted the immune system to develop large recognitive repertoires compared to those of defense mechanisms. This seemingly boundless immune repertoire has fascinated immunologists for almost a century. Today we have a better understanding of the size and function of the antibody repertoire. Humoral antibody effector functions depend upon secreted immunoglobulin and the concentration of antibody must reach a minimum effective threshold in a short enough time to stop a growing pathogen before it becomes lethal. This requires that initially an equivalent number of B-cells per ml respond to the pathogen. This number of B-cells must respond for each and every milliliter of animal. Consequently, the humoral immune system must be iterated. This straightforward conclusion has far reaching implications, some of which are explored in this review.

Animals↗
PubMed1996

A short history of time and space in immune discrimination.

The destructive effector functions of the immune system pose a problem that has aptly been described as 'horror autotoxicus'. This problem demands a solution that offers an effective self-nonself discrimination mechanism. Unlike all other defence mechanisms, the immune system makes the self-nonself discrimination somatically, and not at the germline level. This discrimination requires a way of separating self from nonself. Two proposals to accomplish this are based on separation in time or in space. In this paper the authors show that separation in time remains the only viable solution. A generally accepted solution to the mechanism of the self-nonself discrimination is overdue as it strongly influences the way in which much of immune regulation is interpreted.

Models, Immunological↗
PubMed1995

The proportion of B-cell subsets expressing kappa and lambda light chains changes following antigenic selection.

Using a mixture of 'top-down' theory and 'bottom-up' extrapolation from experimental observation, Rodney Langman and Melvin Cohn discuss some of the conflicting points of view regarding the ratio of kappa (kappa)- to lambda (lambda)-expressing B cells. Despite the somewhat arcane nature of the subject, the authors make a strong general case for the use of computer simulations as a means of reconciling top-down generalizations with quantitative bottom-up extrapolations. With the appearance of two recent papers, the authors show how the top-down theory prevailed in a resolution of the controversy.

Animals↗
PubMed1992

Molecular economy and antibody function: the evolution of a Protecton.

The humoral immune response protects against a very large array of pathogens which attempt to escape immune recognition by changing the antigens they display. When looked at from the point of two competing sets of DNA (i.e., the pathogens vs. the host), there is a vastly larger pool of mutating pathogen DNA than in, say, a mouse. The stratagems that allow a tiny fraction of the mouse's genome to effectively compete with a hugely diverse array of pathogens is analyzed in terms of how antibody functions and how the immune system avoids such pitfalls as self-recognition and destruction. This review is a more general description of a lengthy series of papers which detailed the evolution of the Protecton. Starting from the obvious, that is the concentration-dependence of antibody function, it is apparent that the functional antibody repertoire must be relatively small if a sufficient concentration of specific antibody is to be produced in time to arrest the growth of pathogens and eventually eliminate them. Thus, commonly quoted estimates of antibody repertoires in the range from greater than 10(10) to "complete" (infinite?) must be seriously in error. Other well known "facts", such as D-diversity, and B cell signaling by receptor aggregation are also shown to be lacking in biological commonsense.

Animals↗