Rodney E. Langman

At last: Serious consideration

For a long time, several natural phenomena have been considered unproblematically selection processes in the same sense of “selection.” In our target article we dealt with three of these phenomena: gene-based selection in biological evolution, the reaction of the immune system to antigens, and operant learning. We characterize selection in terms of three processes (variation, replication, and environmental interaction) resulting in the evolution of lineages via differential replication. Our commentators were largely supportive with respect to variation and environmental interaction but critical with respect to replication, in particular its appeal to information. With some reservations, our commentators think that our general analysis of selection may fit gene-based selection in biological evolution and the reaction of the immune system but not operant learning. If nothing else, this article shows that the notion of selection is not as straightforward as it may seem.

The ‘complete’ idiotype network is an absurd immune system

Idiotypic networks have attained the status of unavoidable necessities in the regulation of immune responses. In this article Rod Langman and Mel Cohn contend that the conceptual foundations for such idiotypic networks are formal absurdities.

The proportion of B-cell subsets expressing κ and λ light chains changes following antigenic selection☆

Using a mixture of ‘top-down’ 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 (κ)- to lambda (λ)-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.

Models for the rearrangements of immunoglobulin genes: a computer view

Abstract Substantial data on the rearrangements of immunoglobulin genes in mouse and man have been available since 1981. Various models have been proposed to interpret these data, but none have been quantitatively tested. We use computer simulations to pinpoint some key features in this system.

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.

Molecular economy and antibody function: the evolution of a Protecton

SummaryThe 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 mouses 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 >1010 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.

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 > 1010 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 histocompati‐bility 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 α or β (i.e. the VT‐gene segments act as a single pool). This competing concept carries with it many important and testable consequences.

The essential self: a commentary on Silverstein and Rose “On the mystique of the immunological self”

Historical precedent supports an argument that a variety of factors, including the physical and chemical nature of the antigen, dose, timing, mode of access to the immune system, etc., combine to make a self‐nonself discrimination. This argument requires that specificity be ignored and the myriad of parameters that affect the class and magnitude of the response be dealt with — what might be called the immunogenicity‐tolerogenicity discrimination. Just as there can be no immune response if there are no specific receptors available, so the presence of immune receptors does not guarantee that an immune response will occur, and factors that contribute to the regulation of the magnitude and class of the immune response cannot be used to determine if a receptor is anti‐self or anti‐nonself.