Cancer cells seem to exploit mechanisms that evolve as part of physiological tolerance, which is a complementary and often beneficial form of defense. The study of physiological systems of tolerance can therefore provide insights into the development of a state of host tolerance of cancer, and how to break it. Analysis of these models has the potential to improve our understanding of existing immunological therapeutic targets, and help to identify future targets and rational therapeutic combinations. The treatment (...) of cancer with immune checkpoint inhibitors aims to reverse the progression to tolerance of cancer, and achieve an immunogenic, rather than tolerogenic, homeostasis. Broadening the efficacy and durability of checkpoint inhibitors focuses on reversing tolerance and stimulating immunogenicity in the cancer, host, and environment. Two examples of important physiological states of tolerance that may inform tolerance of cancer are microbial infection and placental reproduction. These states of tolerance result from bilateral shaping of host and non‐self, akin to immunoediting in cancer, and offer reliable models to study the immune tolerance paradigm. (shrink)

The vertebrate adaptive immune system has well defined functions in maintaining tolerance to self‐tissues. Suppression of autoreactive T cells is dependent on the regulatory cytokine transforming growth factor‐β (TGF‐β) and regulatory T (Treg) cells, a distinct T cell lineage specified by the transcription factor Foxp3. Although TGF‐β promotes thymic Treg (tTreg) cell development by repressing T cell clonal deletion and peripheral Treg cell differentiation by inducing Foxp3 expression, a recent study shows that TGF‐β suppresses autoreactive T cells independent (...) of Foxp3+ Treg cells. These findings imply that as an ancestral growth factor family member, TGF‐β may have been co‐opted as a T cell‐intrinsic mechanism of self‐tolerance control to assist the evolutionary transition of vertebrate adaptive immunity. Later, perhaps in placental mammals upon their acquisition of a TGF‐β regulatory element in the Foxp3 locus, the TGF‐β pathway is further engaged to induce peripheral Treg cell differentiation and expand the scope of T cell tolerance control to innocuous foreign antigens. (shrink)

Chemokines (chemotactic cytokines) drive and direct leukocyte traffic. New evidence suggests that the unusual CCR6/CCL20 chemokine receptor/ligand axis provides key homing signals for recently identified cells of the adaptive immune system, recruiting both pro‐inflammatory and suppressive T cell subsets. Thus CCR6 and CCL20 have been recently implicated in various human pathologies, particularly in autoimmune disease. These studies have revealed that targeting CCR6/CCL20 can enhance or inhibit autoimmune disease depending on the cellular basis of pathogenesis and the cell subtype most (...) affected through different CCR6/CCL20 manipulations. Here, we discuss the significance of this chemokine receptor/ligand axis in immune and inflammatory functions, consider the potential for targeting CCR6/CCL20 in human autoimmunity and propose that the shared evolutionary origins of pro‐inflammatory and regulatory T cells may contribute to the reason why both immune activation and regulation might be controlled through the same chemokine pathway. (shrink)

To enable microbial colonisation of the gut mucosa, the intestinal immune system must not only react to danger signals but also recognize cues that indicate safety. Safety recognition, paradoxically, is mediated by the same environmental sensors that are involved in signalling danger. Indeed, in addition to their well established role in inducing inflammation in response to stress signals, pattern recognition receptors (PRRs) and a variety of metabolic sensors also promote gut-microbiota symbiosis by responding to "microbial symbiosis factors", "resolution-associated molecular (...) patterns", markers of energy extraction and other signals indicating the absence of pathogenic infection and tissue damage. Here we focus on how the paradoxical role of immune receptors and other environmental sensors define the microbiota signature of the individual. (shrink)

Adaptive immunity provides the unique ability to respond to a nearly infinite range of antigenic determinants. Given the inherent plasticity of the adaptive immune system, a series of tolerance mechanisms exist to reduce reactivity toward self. While this reduces the probability of autoimmunity, it also creates an important gap in adaptive immunity: the ability to recognize microbes that look like self. As a variety of microbes decorate themselves in self‐like carbohydrate antigens and tolerance reduces the ability of (...) adaptive immunity to react with self‐like structures, protection against molecular mimicry likely resides within the innate arm of immunity. In this review, we will explore the potential consequences of microbial molecular mimicry, including factors within innate immunity that appear to specifically target microbes expressing self‐like antigens, and therefore provide protection against molecular mimicry. (shrink)

I propose a T‐cell receptor (TcR)‐based mechanism by which immunity mediates both “genetic self” and “microbial self” thereby, connecting microbiome disease with autoimmunity. The hypothesis is based on simple principles. First, TcR are selected to avoid strong cross‐reactivity with “self,” resulting in selection for a TcR repertoire mimicking “genetic self.” Second, evolution has selected for a “microbial self” that mimics “genetic self” so as to share tolerance. In consequence, our TcR repertoire also mimics microbiome antigenicity, providing a novel mechanism (...) for modulating tolerance to it. Also, the microbiome mimics the TcR repertoire, acting as a secondary immune system. I call this TcR‐microbiome mimicry “holoimmunity” to denote immune tolerance to the “holobiont self.” Logically, microbiome‐host mimicry means that autoimmunity directed at host antigens will also attack components of the microbiome, and conversely, an immunological attack on the microbiome may cross‐react with host antigens producing “holoautoimmunity.”. (shrink)

Resident microorganisms, known as the microbiota, are essential for many physiological functions including protection against pathogens. Microbiota is indeed required for proper immune system development and function, and can also host-independently protect against infections. Thus, a co-constructed view of host protection involving both host and microbiota, named ’co-immunity,’ has been proposed, and the idea of an ’immunological holobiont’ has been suggested. Yet this view of co-immunity might be too limited, as experimental work has shown that the immune system (...) is involved in functions other than protection, essentially development and repair. Microbiota, through co-immunity, is thereby most likely involved in these functions, although strong evidence is currently lacking. Moreover, as our point of view is mainly host-centered, we may miss the implications of co-immunity at broader scales, including cellular and population levels. Intriguingly, co-immunity effects could be beneficial for one function and/or one level, while being detrimental for others. All these elements should be taken into consideration for microbiota manipulation, in order to avoid potentially harmful side effects. (shrink)

According to immunology’s prevailing paradigm, immunity is based on self/nonself discrimination and thus requires a construction of identity. Two orientations vie for dominance: The original conception, conceived in the context of infectious diseases, regards the organism as insular and autonomous, an entity that requires defense of its borders. An alternate view places the organism firmly in its environment in which both benign and onerous encounters occur. On this latter relational account, active tolerance allows for cooperative relationships with other organisms (...) in the larger ecological economy. These contending orientations —one derived from biomedicine and the other from the ecological sciences— have drawn the attention of social scientists and culture critics. On the one hand, feminists have portrayed immune theory as based upon borrowed social notions of identity that reflect male aggressive values and thus distort more balanced accounts of immunity; and, on the other hand, other commentary projects immune theory as a framework in which analysis of Western societies putatively reveals analogous patterns of ‘self’ and ‘other’ interactions, where autoimmunity and immunization are understood as expressions of the insular understanding of identity. Here, a meta-interpretation is presented that shows how these critiques place the immune self on a spectrum stretching from its formulation as an autonomous agent, a modernist conception of the independent individual, to a postmodern portrayal in which this conception of selfhood has been deconstructed. Accordingly, immunology is drawn into a wide-ranging debate about agency, where differing interpretations of immunity serves as a template in which competing understandings of human social intercourse is modeled.Según el paradigma dominante en inmunología, la inmunidad está basada en la discriminación entre yo/noyo y requiere, por tanto, una construcción de la identidad. Dos orientaciones compiten por dominar: la concepción original, concebida en el contexto de las enfermedades infecciosas contempla al organismo como aislado y autónomo, como una entidad que necesita defender sus fronteras. Una visión alternativa sitúa firmemente al organismo en su entorno, en el cual suceden tanto encuentros beneficiosos como costosos. En este enfoque relacional, la tolerancia activa permite relaciones cooperativas con otros organismos en una economía ecológica más amplia. Estas orientaciones en liza —una derivada de la biomedicina y otra de las ciencias ecológicas— han llamado la atención de los científicos sociales y de los críticos de la cultura. Por una parte, el feminismo ha descrito la teoría inmunológica como basada en nociones sociales prestadas de identidad que reflejan los valores agresivos del macho y que, de este modo, impiden una explicación más equilibrada de la inmunidad. Por otra parte, otro comentario proyecta la teoría inmunológica como un marco en el que el análisis de las sociedades occidentales revela aparentemente patrones análogos de interacciones ‘yo’ y ‘otros’, en las que la autoinmunidad y la inmunización son entendidas como expresiones de la comprensión insular de la identidad. Se ofrece aquí una meta-representación que muestra cómo estas críticas sitúan al yo inmune en un espectro que va desde su formulación cómo un agente autónomo, una concepción modernista del individuo independiente, a una visión postmoderna en la que esta concepción de la identidad ha sido deconstruida. De acuerdo con esto, la inmunología recoge un amplio debate sobre la agencia en el que diferentes interpretaciones de la inmunidad sirven como molde en el que se modelan comprensiones competidoras de la comprensión de las relaciones sociales humanas. (shrink)

Both concepts of the holobiont and the immune system are at the heart of an ongoing scientific and philosophical examination concerning questions of the organism’s individuality and identity as well as the relations between organisms and their environment. Examining the holobiont, the question of boundaries and individuality is challenging because it is both an assemblage of organisms with physiological cohesive aspects. I discuss the concept of immunity and the immune system function from the holobiont perspective. Because of the (...) host-microbial close relations of codependence and interdependence, the holobiont is more often than not confused with the host, as the host is the domain in which this entity exists. I discuss the holobiont unique ecological characteristics of microbial assemblages connected to a host in a network of interactions in which the host is one of the organisms in the community but also its landscape. Therefore, I suggest viewing the holobiont as a host-ecosystem and discuss the implication of such a view on the concept of immunity and the meaning of protection. Furthermore, I show that viewing the holobiont as a host ecosystem opens the possibility of using the same ecological definition of boundaries and immunity dealing with an ecological system. Thus, the holobiont’s boundaries and immunity are defined by the persistence of its complex system of interactions integrating existing and new interactions. This way of thinking presents a notion of immunity that materializes as the result of the complex interdependence relations between the different organisms composing the holobiont similar to that of an ecosystem. Taking this view further, I discuss the notion of immunogenicity that is ontologically heterogeneous with various causal explanations of the processes of tolerance and targeted immune response. Finally, I discuss the possible conceptualization of already existing and new biomedical practices. (shrink)

Antifertility vaccination is a proposed method of contraception that induces infertility through an immunological response to specific reproductive targets. The following essay analyzes several peer-reviewed articles to identify these potential targets and then determines the bioethical implications of vac­cine use through the lens of Thomistic personalism. Vaccines that intentionally utilize a contraceptive action violate the principles of totality, integrity, and inseparability; while vaccines that intentionally utilize a contragestive action additionally violate the principles of inviolability of human life and non-maleficence. An (...) exception may exist in cases where application is directed at the treatment of specific pathologies. These cases may be tolerated using the principle of double effect when certain conditions are met. Furthermore, the safeguarding of informed consent may prove problematic if contraception is integrated with established vaccine programs. (shrink)

In this commentary of Koonin’s target paper, we defend an extended view of CRISPR-Cas immunity by arguing that CRISPR-Cas includes, but cannot be reduced to, defence against nonself. CRISPR-Cas systems can target endogenous elements and tolerate exogenous elements. We conclude that the vocabulary of “defence” and “nonself” might be misleading when describing CRISPR-Cas systems.

Resident microbiota do not just shape host immunity, they can also contribute to host protection against pathogens and infectious diseases. Previous reviews of the protective roles of the microbiota have focused exclusively on colonization resistance localized within a microenvironment. This review shows that the protection against pathogens also involves the mitigation of pathogenic impact without eliminating the pathogens (i.e., “disease tolerance”) and the containment of microorganisms to prevent pathogenic spread. Protective microorganisms can have an impact beyond their niche, interfering (...) with the entry, establishment, growth, and spread of pathogenic microorganisms. More fundamentally, we propose a series of conceptual clarifications in support of the idea of a “co-immunity,” where an organism is protected by both its own immune system and components of its microbiota. -/- . (shrink)

Immunology — though deeply experimental in everyday practice — is also a theoretical discipline. Recent advances in the understanding of innate immunity, how it is triggered and how it shares features that have previously been uniquely ascribed to the adaptive immune system, can contribute to the refinement of the theoretical framework of immunology. In particular, natural killer cells and macrophages are activated by transient modifications, but adapt to long-lasting modifications that occur in the surrounding tissue environment. This process facilitates (...) the maintenance of self-tolerance while permitting efficient immune responses. In this Essay we extend this idea to other components of the immune system and we propose some general principles that lay the foundations for a unifying theory of immunity — the discontinuity theory. According to this theoretical framework, effector immune responses (namely, activated responses that lead to the potential elimination of the target antigen) are induced by an antigenic discontinuity; that is, by the sudden modification of molecular motifs with which immune cells interact. (shrink)

NIK1 is a receptor‐like kinase involved in plant antiviral immunity. Although NIK1 is structurally similar to the plant immune factor BAK1, which is a key regulator in plant immunity to bacterial pathogens, the NIK1‐mediated defenses do not resemble BAK1 signaling cascades. The underlying mechanism for NIK1 antiviral immunity has recently been uncovered. NIK1 activation mediates the translocation of RPL10 to the nucleus, where it interacts with LIMYB to fully down‐regulate translational machinery genes, resulting in translation inhibition of host and (...) viral mRNAs and enhanced tolerance to begomovirus. Therefore, the NIK1 antiviral immunity response culminates in global translation suppression, which represents a new paradigm for plant antiviral defenses. Interestingly, transcriptomic analyses in nik1 mutant suggest that NIK1 may suppress antibacterial immune responses, indicating a possible opposite effect of NIK1 in bacterial and viral infections. (shrink)

This article reviews and discusses emerging evidence suggesting an evolutionarily‐conserved connection between injury‐associated exposure of cytoskeletal proteins and the induction of tolerance to infection, repair of tissue damage and restoration of homeostasis. While differences exist between vertebrates and invertebrates with respect to the receptor(s), cell types, and effector mechanisms involved, the response to exposed cytoskeletal proteins appears to be protective and to rely on a conserved signaling cassette involving Src family kinases, the nonreceptor tyrosine kinase Syk, and tyrosine phosphatases. (...) A case is made for research programs that integrate different model organisms in order to increase the understanding of this putative response to tissue damage. (shrink)

Langerhans cells (LCs), residing in the epidermis, are able to induce potent immunogenic responses and also to mediate immune tolerance. We propose that tolerogenic and immunogenic responses of LCs are directed by signaling from the epidermis and involve counter‐acting gene circuits that are coupled to a core maturation gene module. We base our analysis on recent genetic and genomic findings facilitating the understanding of the molecular mechanisms controlling these divergent immune functions. Comparing gene regulatory network (GRN) analyses (...) of various types of dendritic cells (DCs) including LCs we integrate signaling‐dependent (TGFβ, EpCAM, β‐Catenin) and transcription factor (IRF4, IRF1, NFκB) regulated gene circuits that appear to orchestrate the distinctive LC functional states. Our model proposes, that while epidermal signaling in the steady‐state promotes LC tolerogenic function, the disruption of cell‐cell contacts coupled with inflammatory signaling induces LC immunogenic programing. The conceptual framework emphasizes the sensing of discrete epidermal and inflammatory cues by resident LCs in dictating their genomic programing and cell state dynamics. (shrink)

What counts as an individual in the living world? What does it mean for a living thing to remain the same through time, while constantly changing? Immunology answers these questions with its theory of "self" and "nonself" which has dominated the field since the 1940s. Thomas Pradeu argues that this theory is inadequate, because immune responses to self constituents and immune tolerance of foreign entities are the rule, not the exception.

Some societies tolerate or encourage high levels of chickenpox infection among children to reduce rates of shingles among older adults. This tradeoff is unethical. The varicella zoster virus (VZV) causes both chickenpox and shingles. After people recover from chickenpox, VZV remains in their nerve cells. If their immune systems become unable to suppress the virus, they develop shingles. According to the Exogenous Boosting Hypothesis (EBH), a person’s ability to keep VZV suppressed can be ‘boosted’ through exposure to active chickenpox (...) infections. We argue that even if this hypothesis were true, immunization policies that discourage routine childhood varicella vaccination in order to prevent shingles for other people are unethical. Such policies harm children and treat them as mere means for the benefit of others, and are inconsistent with how parents should treat their children and physicians should treat their patients. These policies also seem incompatible with institutional transparency. (shrink)

Cancer is generally defined as uncontrollable growth of cells caused by genetic aberrations and/or environmental factors. Yet contagious cancers also occur. The recent emergence of a contagious cancer in Tasmanian devils has reignited interest in transmissible cancers. Two naturally occurring transmissible cancers are known: devil facial tumour disease and canine transmissible venereal tumour. Both cancers evolved once and have then been transmitted from one individual to another as clonal cell lines. The dog cancer is ancient; having evolved more than 6,000 (...) years ago, while the devil disease was first seen in 1996. In this review I will compare and contrast the two diseases focusing on the life histories of the clonal cell lines, their evolutionary trajectories and the mechanisms by which they have achieved immune tolerance. A greater understanding of these contagious cancers will provide unique insights into the role of the immune system in shaping tumour evolution and may uncover novel approaches for treating human cancer. (shrink)

Given immunity’s general role in the organism’s economy—both in terms of its internal environment as well as mediating its external relations—immune theory has expanded its traditional formulation of preserving individual autonomy to one that includes accounting for nutritional processes and symbiotic relationships that require immune tolerance. When such a full ecological alignment is adopted, the immune system becomes the mediator of both defensive and assimilative environmental intercourse, where a balance of immune rejection and tolerance (...) governs the complex interactions of the organism’s ecological relationships. Accordingly, immunology, which historically had affiliated with the biology of individuals, now becomes a science concerned with the biology of communities. With this translocation, the ontological basis of the organism is undergoing a profound change. Indeed, the recent recognition of the ubiquity of symbiosis has challenged the traditional notions of biological individuality and requires a shift in the metaphysics undergirding biology, in which a philosophy of the organism must be characterized by ecological dialectics “all-the-way-down.”. (shrink)

Why do some invertebrates store so much carotenoids in their tissues? Storage of carotenoids may not simply be passive and dependent on their environmental availability, as storage variation exists at various taxonomic scales, including among individuals within species. While the strong antioxidant and sometimes immune-stimulating properties of carotenoids may be beneficial enough to cause the evolution of features improving their assimilation and storage, they may also have fitness downsides explaining why massive carotenoid storage is not universal. Here, the functional (...) and ecological implications of carotenoid storage for the evolution of invertebrate innate immune defenses are examined, especially in crustaceans, which massively store carotenoids for unclear reasons. Three testable hypotheses about the role of carotenoid storage in immunological (resistance and tolerance) and life-history strategies (with a focus on aging) are proposed, which may ultimately explain the storage of large amounts of these pigments in a context of host–pathogen interactions. (shrink)

Many male traits are well explained by sexual selection theory as adaptations to mating competition and mate choice, whereas no unifying theory explains traits expressed more in females. Anne Campbell's “staying alive” theory proposed that human females produce stronger self-protective reactions than males to aggressive threats because self-protection tends to have higher fitness value for females than males. We examined whether Campbell's theory has more general applicability by considering whether human females respond with greater self-protectiveness than males to other threats (...) beyond aggression. We searched the literature for physiological, behavioral, and emotional responses to major physical and social threats, and found consistent support for females' responding with greater self-protectiveness than males. Females mount stronger immune responses to many pathogens; experience a lower threshold to detect, and lesser tolerance of, pain; awaken more frequently at night; express greater concern about physically dangerous stimuli; exert more effort to avoid social conflicts; exhibit a personality style more focused on life's dangers; react to threats with greater fear, disgust, and sadness; and develop more threat-based clinical conditions than males. Our findings suggest that in relation to threat, human females have relatively heightened protective reactions compared to males. The pervasiveness of this result across multiple domains suggests that general mechanisms might exist underlying females' unique adaptations. An understanding of such processes would enhance knowledge of female health and well-being. (shrink)

The mammalian blastocyst exhibits a high capacity for aerobic glycolysis, a metabolic characteristic of tumours. It has been considered that aerobic glycolysis is a means to ensure a high carbon flux to fulfil biosynthetic demands. Here, alternative explanations for this pattern of metabolism are considered. Lactate creates a microenvironment of low pH around the embryo to assist the disaggregation of uterine tissues to facilitate trophoblast invasion. Further it is proposed that lactate acts as a signalling molecule (especially at the reduced (...) oxygen tension present at implantation) to elicit bioactive VEGF recruitment from uterine cells, to promote angiogenesis. Finally it is suggested that the region of high lactate/low pH created by the blastocyst modulates the activity of the local immune response, helping to create immune tolerance. Consequently, the mammalian blastocyst offers a model to study the role of microenvironments, and how metabolites and pH are used in signalling. (shrink)

Commensal and pathogenic organisms employ camouflage and mimicry to mediate mutualistic interactions and predator escape. However, the immune mechanisms accounting for the establishment and maintenance of symbiotic bacterial populations are poorly understood. A promising hypothesis suggests that molecular mimicry, a condition in which different organisms share common antigens, is a mechanism of establishing tolerance between commensals and their hosts. On this view, certain bacteria may mimic the structural features of some of their host’s T-cell receptors (TCRs), namely those (...) that survive thymic selection due to their lack of complementarity to self-antigens. With such “holoimmunity” the mimicking micro-organisms avoid immune recognition as the copied TCRs become mirror images of an extended super-organismal self, consisting of symbiotic and host antigens. Accordingly, analysis of genomic and metagenomic data suggests a tripartite mimicry between TCRs, self-antigens, and commensal antigens that would serve as the basis for immune tolerance between these populations. And conversely, in an autoimmune scenario, both symbiotic microbes and the mimicked host tissue would be targeted for immune destruction. (shrink)

The main thesis of this article is that Western societies risk becoming Balkanized if they confront the superdiversity issue without sound management of intolerance. The Balkanization process has some essential features that allow the use of this term outside the area of origin (namely the Balkan Peninsula). Thus: It always affects a diverse political unit that comprises an inextricable medley of racial, ethnocultural, religious, ideological, or gender identities. It emerges only where neither the hegemony principle nor the confederacy principle can (...) sustain a divided population’s peaceful coexistence. It entails “antagonistic and conflict-oriented relationships resistant to resolution” between the groups or classes dissociated from a diverse political unit. It increases the density of physical and psychological boundaries between the formerly associated parts. It is perpetuated by the great sponsors of the dissociated parts. Any diverse political unit can enter a process of Balkanization, regardless of its degree of culture and civilization. Balkanization does not have a fatal course. Just as there is no society immune to Balkanization, there is no diverse society doomed to Balkanization. Balkanization can be prevented, checked, stopped, or reversed, depending on society members’ individual and collective actions. To survive, the superdiverse liberal democracies from the Euro-Atlantic area need an agonistic public sphere, where actionable truths emerge from a genuine clash of educated opinions. If intolerance management is the first step in preventing the Balkanization of a superdiverse political unit, promoting social and political tolerance towards all people who express educated opinions is the best starting point to genuine tolerance. The return to Enlightenment rationalism values that underpinned our freedom of thought and expression will help us meet the challenges inherent in current and future superdiversity. By feeding enlightened conversations and debates with genuine, educated opinions, people learn to have tolerance for “unpleasant” pieces of knowledge. Then, they spread general tolerance – as a by-product – across the entire society. (shrink)

Staphylococcus aureus is an opportunistic pathogen capable of causing a variety of diseases including osteomyelitis, endocarditis, infections of indwelling devices and wound infections. These infections are often chronic and highly recalcitrant to antibiotic treatment. Persister cells appear to be central to this recalcitrance. A multitude of factors contribute to S. aureus virulence and high levels of treatment failure. These include its ability to colonize the skin and nares of the host, its ability to evade the host immune system and (...) its development of resistance to a variety of antibiotics. Less understood is the phenomenon of persister cells and their role in S. aureus infections and treatment outcome. Persister cells occur as a sub‐population of phenotypic variants that are tolerant to antibiotic treatment. This review examines the importance of persisters in chronic and relapsing S. aureus infections and proposes methods for their eradication. (shrink)

Stress associated proteins (SAPs), novel A20/AN1 zinc‐finger domain‐containing proteins, are fast emerging as potential candidates for biotechnological approaches in order to improve abiotic stress tolerance in plants – the ultimate aim of which is crop‐yield protection. Until relatively recently, such proteins had only been identified in humans, where they had been shown to be key regulators of innate immunity. Their phylogenetic relationship and recruitment of diverse protein domains reflect an architectural and mechanistic diversity. Emerging evidence suggests that SAPs may (...) act as ubiquitin ligase, redox sensor, and regulator of gene expression during stress. Here, we evaluate the new knowledge on SAPs with a view to understand their mechanism of action. Furthermore, we set an agenda for investigating hitherto unexplored roles of these proteins. (shrink)

A pathogenic connection between autoreactive T cells, fungal infection, and carcinogenesis has been demonstrated in studies of human autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy as well as in a mouse model in which kinase-dead Ikkα knock-in mice develop impaired central tolerance, autoreactive T cell–mediated autoimmunity, chronic fungal infection, and esophageal squamous cell carcinoma, which recapitulates APECED. IκB kinase α is one subunit of the IKK complex required for NF-κB activation. IKK/NF-κB is essential for central tolerance establishment by regulating the development of (...) medullary thymic epithelial cells that facilitate the deletion of autoreactive T cells in the thymus. In this review, we extensively discuss the pathogenic roles of inborn errors in the IKK/NF-κB loci in the phenotypically related diseases APECED, immune deficiency syndrome, and severe combined immunodeficiency; differentiate how IKK/NF-κB components, through mTEC, T cells/leukocytes, or epithelial cells, contribute to the pathogenesis of infectious diseases, autoimmunity, and cancer; and highlight the medical significance of IKK/NF-κB in these diseases. IKK/NF-κB regulates the expression of many genes that encode proteins involved in many crucial biological functions, such as immunity, tissue homeostasis, and fungal/bacterial/viral infections. Also, IKKα plays anti-tumor activities in many organs independently of NF-κB pathways. Thus, an inborn error in one of these gene loci can cause severe human diseases through these complicated mechanisms. (shrink)

Immunity has established itself as one of the most exciting and productive conceptual lenses being used in contemporary social theory. Ulbricht’s first book demonstrates why this is the case, through using the imaginary of immunity to explicate a selection of the features of liberal multicultural theory. Influenced by the work of Italian philosopher Robert Esposito, the book traces ideas of tolerance, consensus and rights as they appear across a selection of liberal theoretical interventions. After engaging with an impressive swathe (...) of literature throughout his book, Ulbricht’s critical arrival point is an exciting use of Lefebvrian rhythmanalysis in a bid to supplant universal theories of multiculturalism with a recognition of multiculturalism as an intensely local and ad hoc human experience. (shrink)

A recent American Academy of Pediatrics (AAP) clinical report states that it is an acceptable option for pediatric care clinicians to dismiss families who refuse vaccines. This is a clear shift in guidance from the AAP, which previously advised clinicians to “endeavor not to discharge” patients solely because of parental vaccine refusal. While this new policy might be interpreted as encouraging or recommending dismissal of vaccine-refusing families, it instead expresses tolerance for diverse professional approaches. This is unlike the earlier (...) guidance, which promoted a unified response to vaccine refusal. In fact, the resolution (which was presented at the AAP’s Annual Leadership Forum) that led to this clinical report also calls on the AAP “to continue to support pediatricians who continue to provide health care to children of parents who refuse to immunize their children.” However, the shift toward embracing dismissal as an acceptable response to vaccine refusal may erode professional solidarity. Pediatricians are clearly divided on this question; most do not dismiss vaccine-refusing families. By declaring that dismissal is an acceptable option, the AAP has sanctioned a practice that may be unfair to the many clinicians who do not dismiss these families. Clinicians who adopt a policy of dismissal toward families who refuse vaccines might impose burdens on colleagues who remain willing to offer care to those families, and their actions might show insufficient commitment to the efforts of their profession to promote health for all children. (shrink)

The logics of formal inconsistency are logics tolerant to some amount of contradiction, but in which some versions of explosion still hold. The main result of this paper is a reconstruction of two such logics in the dialogical framework. By doing so, we achieve two things. On the one hand, we provide a formal approach to argumentative situations where some contradictions may occur while keeping the idea that there may still be situations in which some propositions are ‘safe’ in the (...) sense of immunity to the contradictions. On the other hand, we open a new line of study on these logics, in the context of the game-theoretical approach to semantics born in the 1960s, with various interesting perspectives, some of which are discussed at the end of this article. (shrink)

Marshall and O’Leary’s thoughtful response to our article suggests that dismissal policies are ethically justifiable because they might induce parents to immunize their children. This outcome is conceivable, but we have only anecdotes about how often it occurs. Such evidence became the thin reed on which the American Academy of Pediatrics rested its new policy of tolerating the practice of dismissing vaccine-hesitant parents. It seems likely that relatively few parents would agree to vaccinate because they were threatened with dismissal. Other (...) heavy-handed interventions have failed to move most such parents. When Washington state made nonmedical exemptions more difficult to obtain, nearly two-thirds of vaccine refusers were unmoved and their children remained unvaccinated. Even if dismissal threats led some parents to accept vaccines, this alone would not justify a dismissal policy. The benefits would still have to be weighed against the risks of dismissing those families who do not change their minds. (shrink)

Narrow Band-pass filtering techniques have been a challenging task since the inception of audio and telecommunication applications. The challenge involves keeping quality factor, gain and mid-frequency of the filter independent of each other. The critical applications require a design that ensures mid-frequency immune to the circuit component tolerances. It becomes increasingly difficult for low-frequency applications where the shift in few Hz in mid-frequency would cause desired frequencies to fall outside the filter’s bandwidth and go undetected. The selection of right (...) topology of the filter for the best performance is the key to successful design. This book objectively compares the relative performance of none popular narrow band-pass filter topologies. The filter topologies are evaluated using a real-world practical example of designing an extremely narrow band-pass filter. The book provides guidelines for selecting the right topology for the low-frequency narrow band-pass filter. (shrink)

Vaccine hesitancy persists despite vaccination’s important role in global health. As many vaccines provide social benefits through herd immunity, vaccination decisions can raise moral concerns. Two studies explored the role of moral convictions in vaccination decisions. Study 1 (N = 485) revealed higher vaccination intentions when individuals thought about vaccination in moral terms. Emotions and moral piggybacking positively predicted moral convictions. In Study 2 (N = 1,111), we evaluated the effects of emotional, moral, and scientific pro-vaccination arguments on moral convictions, (...) support for mandatory vaccination, and tolerance of dissenting views. While no group differences were observed, moral convictions were correlated with increased support for mandatory vaccination but also with a reduced tolerance of dissenting opinions. Overall, moral convictions play a small but significant role in vaccination-related decisions. While moral convictions have beneficial effects on compliance, it is crucial not to overlook the adverse consequences, which may lead to a growing societal divide. (shrink)

In this commentary of Koonin’s target paper, we defend an extended view of CRISPR-Cas immunity by arguing that CRISPR-Cas includes, but cannot be reduced to, defence against nonself. CRISPR-Cas systems can target endogenous elements and tolerate exogenous elements. We conclude that the vocabulary of “defence” and “nonself” might be misleading when describing CRISPR-Cas systems.

The naive theory of vagueness holds that the vagueness of an expression consists in its failure to draw a sharp boundary between positive and negative cases. The naive theory is contrasted with the nowadays dominant approach to vagueness, holding that the vagueness of an expression consists in its presenting borderline cases of application. The two approaches are briefly compared in their respective explanations of a paramount phenomenon of vagueness: our ignorance of any sharp boundary between positive and negative cases. These (...) explanations clearly do not provide any ground for choosing the dominant approach against the naive theory. The decisive advantage of the former over the latter is rather supposed to consist in its immunity to any form of sorites paradox. But another paramount phenomenon of vagueness is higher-order vagueness: the expressions introduced in order to express in the object language the vagueness of the object language are themselves vague. Two highly plausible claims about higher-order vagueness are articulated and defended: the existence of “definitely ω ” positive and negative cases and the “radical” character of higher-order vagueness itself. Using very weak logical principles concerning vague expressions and the ‘definitely’-operator, it is then shown that, in the presence of higher-order vagueness as just described, the dominant approach is subject to higher-order sorites paradoxes analogous to the original ones besetting the naive theory, and therefore that, against the communis opinio, it does not fare substantially better with respect to immunity to any form of sorites paradox. (shrink)

Maintaining intestinal homeostasis is a key prerequisite for a healthy gut. Recent evidence points out that microRNAs (miRNAs) act at the epicenter of the signaling networks regulating this process. The fine balance in the interaction between gut microbiota, intestinal epithelial cells, and the host immune system is achieved by constant transmission of signals and their precise regulation. Gut microbes extensively communicate with the host immune system and modulate host gene expression. On the other hand, sensing of gut microbiota (...) by the immune cells provides appropriate tolerant responses that facilitate the symbiotic relationships. While the role of many regulatory proteins, receptors and their signaling pathways in the regulation of the intestinal homeostasis is well documented, the involvement of non‐coding RNA molecules in this process has just emerged. This review discusses the most recent knowledge about the contribution of miRNAs in the regulation of the intestinal homeostasis. (shrink)

The best way to divide control over children’s education between private and state authorities is unclear. This task has ethical implications that this thesis explores—in the context of a pluralist liberal democracy. In cases where authority over children’s education is granted to private groups, like ethnic or religious minorities, rights are often part of the default vocabulary adopted by politically liberal commentaries. These rights are often viewed as a shield that offers the group immunity from state interference. Some illiberal minority (...) groups argue that they need to be shielded from state interference because the persistence of their cultural or religious identity depends on it. For example, the Amish community in Wisconsin argued in Wisconsin v. Yoder that the future of their community would be jeopardized if they were forced to send their children to school beyond the age of fourteen. While a rights-based approach does explain many of the variables connected with cases like these, the explanation is incomplete. I will offer two clarifications to the rights-based view. First, in the event that a minority group is shielded from state interference, it is not clear that it would be morally legitimate for the group to take over the authority of the state. I will, then, offer a plausible theory that could justify the self-governing authority of minority groups in these situations. My second clarification is that the concept of individual autonomy, often the central liberal value protected by rights, is too broad to support a zero-tolerance approach toward illiberal groups. This indicates that illiberal minority groups might still have a claim to self-governing authority even though they arguably interfere with the autonomy of their children. Some interference with minor elements of individual autonomy should arguably be tolerated in cases where the ruination or assimilation of the group’s unique culture or religion is at stake. (shrink)

Over-enthusiastic newborn screening has often caused substantial harm and has been imposed on the public without adequate information on benefits and risks and without parental consent. This problem will become worse when genomic screening is implemented. For the past 40 years, there has been broad agreement about the criteria for ethically responsible screening, but the criteria have been systematically ignored by policy makers and practitioners. Claims of high benefit and low risk are common, but they require precise definition and documentation, (...) which has often not occurred, undermining claims that involuntary testing is justified. Even when the benefits and risks are well established, it does not automatically follow that involuntary testing is justified, a position supported by the widespread tolerance for parental refusal of immunizations and newborn screening. (shrink)

The world awaits a SARS-CoV-2 virus vaccine to keep the populace healthy, fully reopen their economies, and return their social and healthcare systems to “normal.” Vaccine safety and efficacy requires meticulous testing and oversight; this paper describes how despite grandiose public statements, the current vaccine development, testing, and production methods may prove to be ethically dubious, medically dangerous, and socially volatile. The basic moral concern is the potential danger to the health of human test subjects and, eventually, many vaccine recipients. (...) This is further complicated by economic and political pressures to reduce government oversight on rushed vaccine testing and production, nationalistic distribution goals, and failure to plan for the widespread immunization needed to produce global herd immunity. As this paper asserts, the public must be better informed to assess promises about the novel vaccines being produced and to tolerate delays and uncertainty. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Human Rights, China, and Cross-Cultural Inquiry:Philosophy, History, and Power PoliticsRandall PeerenboomStephen Angle's Human Rights and Chinese Thought: A Cross-Cultural Inquiry (Cambridge: Cambridge University Press, 2002) is a wonderful book that combines philosophically sophisticated discussions of controversial human-rights issues with a detailed intellectual history of the evolution of human-rights discourse in China over the last several hundred years. I will use Angle's book as a platform for consideration of a (...) number of issues regarding the role of philosophy, history, and power politics in relation to human rights in China and elsewhere.Angle focuses his discussion on two claims: first, that countries have different concepts of human rights, and second, that we ought not demand that countries comply with human-rights concepts different from their own.1 These two claims (or something similar) are central to China's official position on rights and to humanrights debates more generally, including the debate about values in Asia.2Angle's response, in short, is that there are distinctive concepts of human rights in China, and that "there have been both continuities and changes in the ways that rights have been conceptualized over the course of China's rich and distinctive rights discourse" (p. 250). However, the only way a community can unilaterally declare its values and practices immune from the scrutiny of others is through "parochialism," which, according to Angle, cuts off that community from making legitimate demands on others. Rather, he suggests, we "should seek an accommodation of differences with one another in the spirit of toleration, and on that basis engage one another on as many levels as possible" (pp. 250-251).One of the many great strengths of this book is that Angle grounds his responses in an interesting and insightful discussion of contemporary philosophers, assessing along the way the contributions and limits of MacIntrye, Rawls, Dworkin, Raz, Walzer, and especially Brandom, among others, to this cross-cultural inquiry of human rights. It might seem, given this list of luminaries, Angle's own training in Western analytic philosophy, and his position in the philosophy department of an American university, that Western philosophy is driving the debate and dictating the fundamental terms and parameters of the inquiry.3 This, of course, is precisely one of the complaints of non-Westerners such as Liu Huaqiu, who argue that they are being measured by Western standards, that rights are concepts grounded in historically contingent modern Western philosophical traditions, and that the rights movement is biased in favor of secular liberalism, which is at odds with and may preclude states based on religious worldviews and communitarian or collectivist [End Page 283] points of view that do not privilege autonomy, choice, and individual interests to the extent that liberals do.Angle's response is twofold. First, he argues, sensibly enough, that we cannot and need not set aside or escape our traditions and value systems. Cross-cultural inquiry must begin from somewhere. But we must remain open-minded and willing to continue the conversation, at least for a considerable while and in most cases indefinitely, even if in some cases we simultaneously must rely on coercion and repression.4 As discussed below, Angle endorses a limited moral pluralism that tolerates some differences while not providing an excuse for appeasing dictators or turning a blind eye to genocide and other atrocities.Second, Angle is not out simply to measure China by the standards of contemporary Western philosophers. Rather, he wants to show that China has its own distinctive discourse on rights, and that this discourse is multifaceted and constantly evolving. According to Angle, "Chinese rights discourse should be seen as an ongoing creative achievement, rather than a reaction to or misunderstanding of Western ideas and institutions" (p. 2).5 He shows this by providing a detailed intellectual history of Chinese rights discourse, another great strength of the book. His primary focus is on several prominent Neo-Confucians and pre-1949 debates, although he also considers some contemporary debates.6 Angle is clearly successful at demonstrating that Chinese thinkers have advanced a number of different views and that rights discourse over the last century and a half has been... (shrink)

At The paper analyzes the problems of cultural diversity and universality as elaborated in the concepts of “intercultural philosophy” (Ra 1 Fornet-Betancourt), “transculture” (Mikhail Epstein), and “discourse ethics” (Jürgen Habermas, Karl-Otto Apel, and Seyla Benhabib). In the postmodern theories of culture, there is an internal tension between multiculturalism and deconstruction. Multiculturalism implies an essentialist connection between cultural production and ethnic or physical origin. In contrast, the paper argues for a concept of cultural diversity free from determinism and representation. The paper (...) articulates a criticalphilosophical-methodological approach at the heart of which is Mikhail Bakhtin’s dialogical philosophy and the idea of “vnenakhodimost” (“outsidedness”). According to Mikhail Epstein’s concept of “transculture,” each culture is incomplete, thus needs to transcend its borders in dialogue with other cultures. Transculture is a path of liberation of the individual from the symbolic dependencies of culture itself and self-imposed identities. It is a state of virtual belonging of one individual to many cultures. Critical universality means diversity as a property of a single individual or a single culture insofar as they can include the diversity of others. It is viewed as an internal diversity of individuals, their dialogical openness to others and self-identification primarily as members of humanity. The paper focuses on Jürgen Habermas’s analysis of the problem of cultural identity and diversity in terms of the liberal conception of equality and cultural rights. Multiculturalism itself is not immune from knowledge/power relations. Its paradox is that individual basic liberties are restricted in the name of the securing collective rights of culture groups. Habermas argues that these problems can be solved only from the perspective of “the difference-sensitive egalitarian universalism of equal rights.” Mutual recognition requires a transformation of interpersonal relations through discourse and public debates over identity politics. Attention is paid to David Rasmussen’s analyses of conflict and toleration within the confines of a post-secular society. (shrink)

In the past few years in the Netherlands and other multi-ethnic democratic states we hear sharp political and intellectual criticism on the philosophical idea of a ‘multicultural society’. In this article, the author questions the criticism of several liberal and conservative political philosophers, who in their approach give attention to the genealogy of multiculturalism. While a liberal as Brian Barry sees multiculturalism as a regression, the conservative Roger Scruton on the other hand considers this political and intellectual phenomenon as a (...) bridge too far, a symptom of the disintegration of the modern nation. The author argues that these criticisms are forcing us to abandon a form of multiculturalism that considers ‘toleration’ as the highest principle. The ‘toleration-multiculturalist’ gets entangled in inconsistencies and moral paradoxes, as soon as he wants to determine his position towards intolerant and immodest variations of the Volksgeist, the cultural homogeneity and identity. The underlying problem in the discussion among liberals, conservatives and multiculturalists is the ontological vulnerability of cultures. This vulnerability has to do with the fact that cultures, traditions and identities are dependant on the constructive work of autonomous interpreters. Therefore a permanent dialogue with the past is necessary. While nationalists and multiculturalists are inclined to eliminate this vulnerability by fixating and immunizing the cultural and national identity, the liberals are neutralizing the cultural loyalties of people through the privatisation of identities. In contrast to these positions the author pleads for a form of democracy in which the rituals of democracy mediate the permanent dissensus about the meaning of nevertheless being a national community. (shrink)

In the past few years in the Netherlands and other multi-ethnic democratic states we hear sharp political and intellectual criticism on the philosophical idea of a ‘multicultural society’. In this article, the author questions the criticism of several liberal and conservative political philosophers, who in their approach give attention to the genealogy of multiculturalism. While a liberal as Brian Barry sees multiculturalism as a regression, the conservative Roger Scruton on the other hand considers this political and intellectual phenomenon as a (...) bridge too far, a symptom of the disintegration of the modern nation. The author argues that these criticisms are forcing us to abandon a form of multiculturalism that considers ‘toleration’ as the highest principle. The ‘toleration-multiculturalist’ gets entangled in inconsistencies and moral paradoxes, as soon as he wants to determine his position towards intolerant and immodest variations of the Volksgeist, the cultural homogeneity and identity. The underlying problem in the discussion among liberals, conservatives and multiculturalists is the ontological vulnerability of cultures. This vulnerability has to do with the fact that cultures, traditions and identities are dependant on the constructive work of autonomous interpreters. Therefore a permanent dialogue with the past is necessary. While nationalists and multiculturalists are inclined to eliminate this vulnerability by fixating and immunizing the cultural and national identity, the liberals are neutralizing the cultural loyalties of people through the privatisation of identities. In contrast to these positions the author pleads for a form of democracy in which the rituals of democracy mediate the permanent dissensus about the meaning of nevertheless being a national community. (shrink)

If an ethical theory sometimes requires that agents be motivated by features other than those it advances as justifications for the rightness or wrongness of actions, some consider this type of self-effacement to be a defeater from which no theory can recover. Most famously, Michael Stocker argues that requiring a divided moral psychology in which reasons are partitioned from motives would trigger a “malady of the spirit” for any agent attempting to live according to the prescriptions of modern ethical theories. (...) Stocker’s argument is tremendously influential, and the fact that he specifically links modern ethical theories to self-effacement leads advocates of virtue ethics to presume that their view is immune to the problem of self-effacement and that this immunity gives virtue ethics an advantage over its contemporary rivals. This immunity has been challenged by Thomas Hurka and Simon Keller, who maintain that virtue ethics is equally as vulnerable to the charge of self-effacement as its modern counterparts. I argue in this paper that recent attempts to reply to Hurka and Keller are not successful. Specifically, I argue that recent attempts to immunize virtue ethics from self-effacement do not adequately address the challenge from Keller that virtue ethics can only escape from self-effacement via measures that are also available to modern theories. Thus, even if virtue ethics can avoid self-effacement, one must give up the claim that virtue ethics is uniquely immune to self-effacement compared to its modern rivals. I close by noting that my aim is not to argue that virtue ethics is deficient in this respect. Instead, I suggest that advocates of virtue ethics ought to consider the possibility that self-effacement is a tolerable psychological challenge for any ethical theory that requires agents to reflect on the substantive normative guidance it provides. (shrink)

The thymus is a unique primary lymphoid organ that supports the production of self‐tolerant T‐cells essential for adaptive immunity. Intrathymic microenvironments are microanatomically compartmentalised, forming defined cortical, and medullary regions each differentially supporting critical aspects of thymus‐dependent T‐cell maturation. Importantly, the specific functional properties of thymic cortical and medullary compartments are defined by highly specialised thymic epithelial cells (TEC). For example, in the medulla heterogenous medullary TEC (mTEC) contribute to the enforcement of central tolerance by supporting deletion of autoreactive (...) T‐cell clones, thereby counterbalancing the potential for random T‐cell receptor generation to contribute to autoimmune disease. Recent advances have further shed light on the pathways and mechanisms that control heterogeneous mTEC development and how differential mTEC functionality contributes to control self‐tolerant T‐cell development. Here we discuss recent findings in relation to mTEC development and highlight examples of how mTEC diversity contribute to thymus medulla function. (shrink)