Uncertainties about the self and the issue of the proper theoretical model in immunology

Theoretical immunology constitutes a critical basis of all medical discoveries. Immunology has been dominated since the 1940s by the self/nonself model. Here we try to shed light on the origins of this theoretical model and to show how and why this model has been called into question during the last thirty years. This paper has three aims. Firstly, we explore the sources of the immune self, going upstream from immunology to ecology-biology, psychology and eventually philosophy. Here the key questions : is the immune self really analogous with the philosophical and psychological selves in which it originates? What is the signification and adequacy of such a conceptual borrowing? We suggest that the < self > vocabulary in immunology is not clear and precise. Secondly, we present the experimental inadequacies of the self/non-self model. We show then how both the vagueness of the term < self > and these experimental flaws casted doubt on theories of immunology. Among the several models that have been proposed recently, none has attracted a consensus. Some immunologists have even suggested that immunology should rid itself of theorical concerns and concentrate on molecular aspects. This suggestion, however, is unacceptable\; hence it is still necessary to find a theoretical framework for immunology. Finally, we try to suggest a way to escape this uncomfortable situation of doubt. The immune < self > and the immune < system > (< network >) are rooted in strong metaphysical conceptions of identity, the main characteristic of which is to consider the organism as an enclosed and self-constructing entity. By contrast, based on experimental data about immune tolerance and host-pathogen interactions, we propose to consider organisms as open entities. To what theory does this conception lead? What would be the consequences of such a theory with regard to medical aspects?     

The Self Model and the Conception of Biological Identity in Immunology

The self/non-self model, first proposed by F.M. Burnet, has dominated immunology for 60 years now. According to this model, any foreign element will trigger an immune reaction in an organism, whereas endogenous elements will not, in normal circumstances, induce an immune reaction. In this paper we show that the self/non-self model is no longer an appropriate explanation of experimental data in immunology, and that this inadequacy may be rooted in an excessively strong metaphysical conception of biological identity. We suggest that another hypothesis, one based on the notion of continuity, gives a better account of immune phenomena. Finally, we underscore the mapping between this metaphysical deflation from self to continuity in immunology and the philosophical debate between substantialism and empiricism about identity.     

Foreignness as a matter of degree: the relative immunogenicity of peptide/MHC ligands

The ability of T lymphocytes (T cells) to recognize and attack foreign invaders while leaving healthy cells unharmed is often analysed as a discrete self/non-self dichotomy, with each peptide/MHC ligand classified as either self or non-self. We argue that the ligand immunogenicity is more naturally treated as a continuous quantity, and show how to define and quantitate relative ligand immunogenicity. In our theory, self-tolerance is acquired through reduction of the relative immunogenicity of autoantigens, whereas xenoantigens, typically not presented during induction of deletional tolerance, retain a high degree of relative immunogenicity. Autoantigens that are not prominently presented in deletional tolerance likewise retain a high relative immunogenicity and remain essentially foreign. According to our analysis, any given autoantigen can attain a high level of relative immunogenicity, provided it is presented at sufficiently high levels. Our theory provides a quantitative tool to analyse the immunogenicity of tumour-associated neoantigens and the ætiology of autoimmune disease.     

Implications of self/non-self discrimination for spatial patterning of clonal plants

Many clonal plants are characterised by tussock growth forms, but the mechanisms that account for their formation and maintenance are still vague. Here we examine the possible effects of the recently identified phenomenon of self/non-self discrimination on the spatial distribution and patterning of ramets, tussocks and clones in stands of clonal plants. Spatially explicit ramet-based simulation modeling of growth and competition have shown that compact tussocks can be generated as a transient phenomenon that typically disappears at equilibrium. We introduced self/non-self discrimination into a spatial model by decreasing competition between neighbouring ramets on the same clonal fragment. The results demonstrate that self/non-self discrimination can have significant effects on clonal growth and architecture with a clear tendency to generate long-lasting and self-sustaining clumps. Interestingly, this effect was qualitatively independent of other architectural and growth attributes of the plants, making it a candidate mechanism of stable clumped growth forms observed in many clonal plants and communities. Furthermore, the introduction of self/non-self discrimination shifted competition from the level of ramets to that of clonal fragments, which in turns strongly increased genet extinction rates. Our results stress the need for greater attention to the rather neglected scaling up of physiological and morphogenetical controls to the population and community levels.     

Effect of physiological integration in self/non-self genotype recognition on the clonal invader Carpobrotus edulis

Aims Biological invasions represent one of the most important threats to the conservation of biodiversity; however, the mechanisms underlying successful invaders remain unsolved. Many of the most aggressive invaders show clonal growth, and capacity for clonal integration has been pointed out recently as an important trait explaining the success of invasive plants. We aim to determine the role of physiological integration in the capacity for self/non-self genotype recognition in the clonal invader Carpobrotus edulis and the implications of this capacity for the expansion of this aggressive invader.Methods We used connected and severed ramets of identical or different genotype and we determined the capacity for self/non-self recognition by comparing changes in biomass partitioning to avoid competition for resources between pairs of ramets.Important findings Physiological integration allowed self/non-self genotype recognition in the invader C. edulis. Results showed a significant effect of physiological integration on the biomass allocated to roots by genetically identical ramets: older ramets specialize in acquisition of soil-based resources and younger ramets specialize in lateral expansion. This specialization could be considered a form of division of labour, which reduce intra-genotype competition. This is the first evidence that division of labour could be interpreted as a form of self/non-self recognition between genetically identical ramets. Capacity for self/non-self discrimination could contribute to increase the colonization capacity of the aggressive invader C. edulis. This is the first study showing an association between self/non-self recognition and invasiveness in a clonal plant.     

Identification of major lysine residues of S(3)-RNase of Petunia inflata involved in ubiquitin-26S proteasome-mediated degradation in vitro

S-RNase-based self-incompatibility has been identified in three flowering plant families, including the Solanaceae, and this self/non-self recognition mechanism between pollen and pistil is controlled by two polymorphic genes at the S -locus, S-RNase and S-locus F-box ( SLF ). S-RNase is produced in the pistil and taken up by pollen tubes in a non- S- haplotype-specific manner. How an allelic product of SLF interacts with self and non-self S-RNases to result in growth inhibition of self pollen tubes is not completely understood. One model predicts that SLF targets non-self S-RNases for ubiquitin/26S proteasome-mediated degradation, thereby only allowing self S-RNase to exert cytotoxic activity inside a pollen tube. To test this model, we studied whether any of the 20 lysine residues in S₃-RNase of Petunia inflata might be targets for ubiquitination. We identified six lysines near the C-terminus for which mutation to arginine significantly reduced ubiquitination and degradation of the mutant S₃-RNase, GST:S₃-RNase (K141–164R) in pollen tube extracts. We further showed that GST:S₃-RNase (K141–164R) and GST:S₃-RNase had similar RNase activity, suggesting that their degradation was probably not caused by an ER-associated protein degradation pathway that removes mis-folded proteins. Finally, we showed that PiSBP1 ( P. inflata S-RNase binding protein 1), a potential RING-HC subunit of the PiSLF ( P. inflata SLF)-containing E3-like complex, could target S-RNase for ubiquitination in vitro . All these results suggest that ubiquitin/26S proteasome-dependent degradation of S-RNase may be an integral part of the S-RNase-based self-incompatibility mechanism.     

Self-recognition affects plant communication and defense

Animals have the ability to distinguish self from non-self, which has allowed them to evolve immune systems and, in some instances, to act preferentially towards individuals that are genetically identical or related. Self-recognition is less well known for plants, although recent work indicates that physically connected roots recognize self and reduce competitive interactions. Sagebrush uses volatile cues emitted by clipped branches of self or different neighbours to increase resistance to herbivory. Here, we show that plants that received volatile cues from genetically identical cuttings accumulated less natural damage than plants that received cues from non-self cuttings. Volatile communication is required to coordinate systemic processes such as induced resistance and plants respond more effectively to self than non-self cues. This self/non-self discrimination did not require physical contact and is a necessary first step towards possible kin recognition and kin selection.     

Self/non-self discrimination in angiosperm self-incompatibility

Self-incompatibility (SI) in angiosperms prevents inbreeding and promotes outcrossing to generate genetic diversity. In many angiosperms, self/non-self recognition in SI is accomplished by male-specificity and female-specificity determinants (S-determinants), encoded at the S-locus. Recent studies using genetic, molecular biological and biochemical approaches have revealed that angiosperms utilize diverse self/non-self discrimination systems, which can be classified into two fundamentally different systems, self-recognition and non-self recognition systems. The self-recognition system, adopted by Brassicaceae and Papaveraceae, depends on a specific interaction between male and female S-determinants derived from the same S-haplotype. The non-self recognition system, found in Solanaceae, depends on non-self (different S-haplotype)-specific interaction between male and female S-determinants, and the male S-determinant genes are duplicated to recognize diverse non-self female S-determinants.     

Immunological discrimination between self and non-self by precursor depletion and memory accumulation

We study processes by which T-lymphocytes "learn" to discriminate "self" from "non-self". We show that intrinsic features of the T cell activation and proliferation process are sufficient to tolerize (self) reactive T-lymphocyte clones. Self vs non-self discrimination therefore develops without any down-regulatory (e.g. suppressive) interactions. T-lymphocyte clones will expand by proliferation only if the IL2 concentration is high enough to induce a proliferation rate larger than the rate of cell decay. This concentration is the proliferation threshold. Because effector T cells are short-lived the proliferation threshold must be quite high. Such high numbers of cells producing IL2 are achieved only when sufficient (memory) precursors are activated. Self and non-self antigens differ with respect the number of (memory) precursor cells they accumulate, as a result of two processes, i.e. precursor depletion and memory accumulation, and can thus be discriminated. Precursor depletion: the dynamics of long-lived precursors can cause tolerization. In neonatal circumstances precursor influx is still low, newborn cells reacting with self antigens are immediately activated, generating (few), i.e. fewer than the proliferation threshold, effectors that decay rapidly. Thus total lymphocyte numbers remain low, yielding self tolerance. Conversely, large doses of similar antigens introduced in mature systems push "their" lymphocyte clone over the proliferation threshold because a large (accumulated) precursor population is rapidly activated. Small doses are however low zone tolerized. Memory accumulation: peripheral T-lymphocyte populations in fact consist of a mixture of virgin precursors and memory cells. If the formation process of (long-lived) memory cells is taken into account and virgin precursors are made short-lived, the proliferation threshold again accounts for self non-self discrimination. Memory cells accumulate when antigenic restimulation is low; it is low when the antigen concentration and/or the antigen affinity is low. Therefore self antigens, which are present in relatively high concentrations, fail to accumulate high affinity memory cells, and are hence tolerated. Memory cells crossreacting to self antigens with low affinity, however accumulate neonatally, pushing those clones over the proliferation threshold whenever "their" high affinity antigen enters the immune system. Thus the model generates differences in the antigenicity (i.e. memory precursor frequency) of self and non-self.(ABSTRACT TRUNCATED AT 400 WORDS)     

Physiologically-Mediated Self/Non-Self Root Discrimination in Trifolium repens has Mixed Effects on Plant Performance

Recent studies suggest that plant roots can avoid competition with other roots of the same plant, but the mechanism behind this behavior is yet largely unclear and their effects on plant performance hardly studied. We grew combinations of two ramets of Trifolium repens in a single pot that were either intact, disconnected for a shorter or longer time, or that belonged to different genotypes. Interconnected ramets developed lower root length and mass than any other combination of ramets, supporting the notion that self/non-self discrimination in T. repens was based entirely on physiological coordination between different roots that develop on the same plant, rather than biochemical allorecognition. These responses were consistent among eight field-collected genotypes, suggesting that self/non-self discrimination is a common feature in wild populations of white clover. There were no significant treatment x genotype interactions suggesting that genetic variation for self/non-self discrimination may be limited. Self-interactions resulted in lower to similar shoot biomass and number of ramets, but higher flowering probabilities, compared to non-self interactions. Thus, our results demonstrated that the performance consequences of self/non-self discrimination may be more complicated than previously thought.Key Words: biomass allocation, clonal plants, competition, flowering, phenotypic plasticity, physiological coordination, plant growth, Trifolium repens, self/non-self discrimination     

Mass extinctions,biodiversity explosions and ecological niches

The logistic model proposed by Courtillot and Gaudemer to describe the growth of biodiversity during geological ages is more explored here and further developed. A new parameterisation is first proposed. Another expression of this model is obtained by introducing a new variable representing the number of ecological niches. It appears that the rates of increase of biodiversity during Jurassic and Cretaceous periods is quite different from other ones. The classical literature essentially focuses on possible extinction mechanisms, but explosions in biodiversity must be more precisely explored. For this purpose, on the basis of data analysis through different expressions of the logistic model, different ecological mechanisms can be assumed (e.g., qualitative and quantitative niches changes, possible appearance of new kinds of ecological relationships, such as 'niche-sharing', which involves coexistence or cooperation), even if genetic processes must also be involved. Finally, we emphasise the astonishing speed of biological diversification following a 'catastrophic' mass extinction. We could refer to this feature as 'catastrophic biological diversification'.     

Increased root oxygen uptake in pea plants responding to non-self neighbors

Recent studies have demonstrated that plants alter root growth and decrease competition with roots of the same individual (self); however, the physiological traits accompanying this response are still widely unknown. In this study, we investigated the effect of root identity on gas exchange in the model species pea (Pisum sativum L.). Split-root plants were planted so that each pot contained either two roots of the same plant (self) or of two different plants (non-self), and the responses of biomass, photosynthesis, and respiration were measured. The photosynthetic rate was not affected by the identity of the root neighbor. We found a reduction of leaf dark respiration by half, accompanied by an increase in nocturnal root respiration by 29 % in plants neighboring with non-self. The activity of the alternative oxidase (AOX) pathway increased when plants responded to non-self neighbors. The increased activity of AOX in plants responding to non-self indicates carbon imbalances in roots, possibly as a consequence of increased root exudation and communication between individuals. If such an effect occurs more widely, it may change the assumptions made for the quantity of respiration as used in carbon budget models.     

Self- and cross-fertilization in the solitary ascidian Ciona savignyi

Solitary ascidians are hermaphrodites that release sperm and eggs simultaneously. However, many species are self-sterile, owing to a self/non-self recognition system operating at the outer surface of the chorion during sperm-egg interaction. In Ciona intestinalis, self-incompatibility is thought to have a genetic basis. Here, we report a survey of the self-fertilization potential of a Santa Barbara, California, population of Ciona savignyi, a close relative of C. intestinalis. We found that, in contrast to reports on C. intestinalis, C. savignyi is highly self-fertile. However, using two nonlethal recessive mutant strains, aimless (aim) and immaculate (imc), and a stable transgenic strain that expresses green fluorescent protein (GFP) in the notochord to follow offspring genotype, we demonstrate that non-self sperm outcompete self-sperm in fertilization competition assays. When the chorion was removed, both self- and non-self sperm performed equally well in the competition assay. Thus the non-self/self gamete recognition in C. savignyi is not absolute but relative, and is mediated by one or more components in the chorion. We discuss the significance of this finding in the context of natural populations in the wild, where individuals of C. savignyi are typically found growing in large groups that spawn in unison and where self-fertilization would be expected to be very rare.     

不同社会等级雄性根田鼠对自身和同性陌生气味的辨别

采用两两遭遇法确定雄性根田鼠的社会等级,然后以新鲜尿作气味源,在行为选择箱中观察不同社会等级雄性根田鼠对自身气味和非自身气味的行为响应模式,结果表明:种群中从属个体对自身尿液存在明显偏好,其对自身尿液的接近潜伏期显著短于非自身尿液,而访问时间、自我修饰频次都显著高于非自身尿液;种群中优势个体则优先访问非自身尿液,其对非自身尿液的访问时间、嗅舔时间、自我修饰及反标记均显著高于自身尿液;对非自身尿液,不同社会等级雄性个体之间存在明显不同的行为反应模式。这说明,不同社会等级雄性根田鼠具有自我识别的能力且模式不同,同时其对非自身尿气味响应模式的差异也与自身的社会等级有关。     

免疫耐受的形成机制

免疫系统如何识别“自己”和“非己”,这是免疫学理论的核心问题。由于在胚胎期自身反应性细胞克隆被排斥,即形成对自身抗原的耐受;但对外源性“非己”成分能产生免疫应答予以清除,此即免疫系统识别“自己”和“非己”的机制。近年来研究证实外周成熟淋巴细胞中存在着自身反应性T细胞,但处于功能失活状态;谓之外周耐受。目前已明确免疫耐受的形成涉及多种机制的参与,包括免疫细胞的相互作用、免疫细胞的分子识别、信号传递、基因表达等不同层次的调节。对免疫耐受机理的研究可为阐明免疫应答及免疫调节的机制提供依据,必将推动免疫学基础理论研究的发展。     

Carbohydrate moiety of the Petunia inflata S3 protein is not required for self-incompatibility interactions between pollen and pistil.

For Petunia inflata and Nicotiana alata, which display gametophytic self-incompatibility, S proteins (the products of the multiallelic S gene in the pistil) have been shown to control the pistil's ability to recognize and reject self-pollen. The biochemical mechanism for rejection of self-pollen by S proteins has been shown to involve their ribonuclease activity; however, the molecular basis for self/non-self recognition by S proteins is not yet understood. Here, we addressed whether the glycan chain of the S3 protein of P. inflata is involved in self/non-self recognition by producing a nonglycosylated S3 protein in transgenic plants and examining the effect of deglycosylation on the ability of the S3 protein to reject S3 pollen. The S3 gene was mutagenized by replacing the codon for Asn-29, which is the only potential N-glycosylation site of the S3 protein, with a codon for Asp, and the mutant S3 gene was introduced into P. inflata plants of the S1S2 genotype. Six transgenic plants that produced a normal level of the nonglycosylated S3 protein acquired the ability to reject S3 pollen completely. These results suggest that the carbohydrate moiety of the S3 protein does not play a role in recognition or rejection of self-pollen and that the S allele specificity determinant of the S3 protein and those S proteins that contain a single glycan chain at the same site as the S3 protein must reside in the amino acid sequence itself.     

Parasitism and maintenance of diversity in a fungal vegetative incompatibility system: the role of selection by deleterious cytoplasmic elements

In fungi, horizontal transmission of deleterious cytoplasmic elements is reduced by the vegetative incompatibility system. This self/non-self recognition system may select for greater diversity of fungal incompatibility phenotypes in a frequency-dependent manner but the link between the diversity of fungal phenotypes and the virulence of cytoplasmic parasites has been poorly studied. We used an epidemiological model to show that even when transmission between incompatibility types is permitted, parasite pressure can lead to high levels of polymorphism for vegetative incompatibility systems. Moreover, high levels of polymorphism in host populations can select for less virulent cytoplasmic parasites. This feedback mechanism between parasite virulence and vegetative incompatibility system polymorphism of host populations may account for the general avirulence of most known mycoviruses. Furthermore, this mechanism provides a new perspective on the particular ecology and evolution of the host/parasite interactions acting between fungi and their cytoplasmic parasites.     

Preferential recognition of self antigens despite normal thymic deletion of CD4(+)CD25(+) regulatory T cells

T cell tolerance to self Ags is in part established in the thymus by induction of apoptosis or anergy of potentially autoreactive thymocytes. Some autospecific T cells nevertheless migrate to peripheral lymphoid organs but are kept under control by the recently identified CD4(+)CD25(+) regulatory T cell subset. Because these cells inhibit autoimmunity more efficiently than useful non-self Ag-specific immune responses, they are probably autospecific, posing important questions as to how they develop in the thymus. In this study we show that significantly more peripheral CD4(+)CD25(+) regulatory T cells recognize self than non-self Ags. However, we also show for a large panel of endogenous superantigens as well as for self peptide/MHC complexes that autospecific CD4(+)CD25(+) thymocyte precursors are normally deleted during ontogeny. Combined, our data firmly establish that the repertoire of regulatory T cells is specifically enriched in autospecific cells despite the fact that their precursors are normally susceptible to thymic deletion.     

Therapeutic targeting of the innate immune system in domestic animals

Since first being described in the fruit fly Drosophila melanogaster, the knowledge regarding Toll-like receptors (TLRs) has transformed our understanding of immunology. TLRs are a family of conserved pattern recognition receptors (PRR) that recognise specific microbial-associated molecular patterns and allow the cell to distinguish between self and non-self materials. The very property of the TLRs, to link innate and adaptive immunity, offers a novel opportunity to develop vaccines that engage TLR signalling. The presence of TLR ligands as adjuvants in conjunction with a vaccine is shown to increase the efficacy and response to the immunisation with a particular antigen. Here, we focus on the findings pertaining to TLR ligands as adjuvants and discuss the importance of these studies in the development of an optimal vaccine in farm and companion animals.