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.

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.

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.

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.

Alloreactive cytotoxic T-cell function, peptide nonspecific.

The recognition requirements necessary for murine alloreactive cytotoxic T-cells to carry out their effector function has been investigated using target cells that express a unique class I major histocompatibility complex (MHC)-peptide pair. The human cell line T2 and the murine cell line RMA-S are defective in peptide transport components needed to effectively express stable MHC class I molecules at the cell surface. When T2 cells were infected with a vaccinia virus that encoded the Kd gene and provided with a Kd-motif peptide from the nucleoprotein of influenza virus (NPP), these cells could be lysed by polyclonal allo Kd-reactive cytotoxic T-lymphocytes (CTL). Similar results were obtained with the murine RMA-S-Kd cell line, transfected with cDNA able to express some 'empty' Kd that is heat-labile. Adding another Kd-motif peptide from influenza virus haemagglutinin (HAP) stabilized the surface expression of Kd and allowed the RMA-S-Kd cells to be lysed before or after heat shock. At 27 degrees C anti-Kd alloreactive CTL-lysed target cells in the presence and absence of HAP peptide. Alloreactive CTL appear to have a more stringent requirement for a high density of MHC class I on cell surfaces relative to peptide-specific MHC-restricted CTL. We conclude that while Kd-restricted CTL activity is strictly peptide-specific, anti-Kd-specific alloreactivity is MHC allele-specific, but peptide-nonspecific. This conclusion is at odds with the Standard Model of T-cell receptor (TCR) function, but consistent with the predictions of a Competing Model of TCR function.

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.

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.

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.

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.

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.

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.

A theory of the ontogeny of the chicken humoral immune system: the consequences of diversification by gene hyperconversion and its extension to rabbit.

The immune system's repertoire is generated in two stages: Stage I results in a small size high copy number repertoire that is diversified by "mutation" to result in a large size low copy number repertoire referred to as Stage II. The Stage I or high copy number repertoire is derived from information stored directly in the genome by two mechanisms. (a) The copy-cassette mechanism: the Ig-locus has one rearrangeable V gene segment which acts as recipient for controlled gene conversion in cis from a set of donor V gene segments that results in a family of subunits, L and H. This is illustrated by the avian systems. (b) The cassette-exchange mechanism: the Ig-locus has many rearrangeable V gene segments which are fused into transcription units, the products of which are a family of L and H subunits identical in function to those resulting from the copy-cassette mechanism. This is illustrated by the murine or human systems. It is possible for a species to use both mechanisms, copy-cassette at one Ig locus and cassette-exchange at the other Ig locus. This seems to obtain in the rabbit system. Further, it is possible to encode the high copy number repertoire directly in the genome as tandemly repeated rearranged transcription units as one sees in shark (a genomic analogue of the cassette-exchange mechanism). We have discussed here and elsewhere (Cohn and Langman, 1990) the consequences of these mechanisms for haplotype exclusion and functional responsiveness to antigen. The Stage I or high copy number repertoire generated by any of the above mechanisms is now a substrate for "mutation" which generates the low copy number or Stage II repertoire. These three species are compared in table V. The high copy number repertoire is small but the response to any antigen that it recognizes is rapid. The low copy number repertoire is large but responsiveness to any antigen it recognizes is slow. Cooperativity between the two repertoires optimizes the overall responsiveness with respect to rapidity of response and range of responsiveness. The use of a copy-cassette mechanism requires that the phi B cell undergoing gene conversion have a single rearranged L- and H-chain haplotype (L+/oH+/o). The reason is that conversion can correct an aberrantly rearranged transcription unit and generate an unacceptable level of doubles. In order to have one chromosome functionally rearranged and the homologue in the germline configuration, a selection mechanism is required.(ABSTRACT TRUNCATED AT 400 WORDS)

What is the selective pressure that maintains the gene loci encoding the antigen receptors of T and B cells? A hypothesis.

The dominant view is that the gene loci encoding the B cell antigen receptor (BAr) or the T cell antigen receptor (TAr) specify a vast array of combining sites. The 'germline' repertoire is estimated to be > 10(10) by multiplying numbers of subunit complements by DN-region variability. This implies that the germline can be maintained by a selection imposed by all or most of the antigenic universe. Its unchallenged popularity, notwithstanding, this neo-germline view is untenable and hence the need for a competing concept, as presented here. The immunoglobulin (Ig) loci are under a totally different selection from the T loci. The Ig loci are selected upon largely by carbohydrate determinants on pathogens that vary more slowly than the proteins produced by the Ig loci, which are necessary to rid these selective antigens. By contrast, the T loci are selected to recognize the allele-specific determinants on restricting elements encoded in the major histocompatibility complex (MHC). The expression of the germline results in a high copy number (HCN) repertoire; this repertoire is the substrate for 'mutation' that yields the low copy number (LCN) repertoire. For the B cell, these two repertoires interact to optimize the response to the unexpected. For the T cell, only the LCN repertoire is functional. The immunoglobulin (Ig) loci are selected upon as light(L)-heavy (H) pairs; the T loci are selected upon as single units alpha or beta (i.e. the VT-gene segments act as a single pool). This competing concept carries with it many important and testable consequences.