Our paper is a comparative analysis of Alexander Dugin's The Fourth Way and Karl Popper's The Open Society. Both works of the two thinkers are viewed as completely concrete (and real) conceptual frameworks, offering two radically different models of perception of the world, the individual and community relations, of the international relations. Our analysis takes into consideration both the internal, that is the “intimate enemies of democracy”, and the new (old) enemies of the open society that “relapse” through the Fourth (...) Way. Our theoretical research is focused on the parallel between the negative starting premises for the functioning of the Open Society – historicism, utopian social engineering, collectivism and chieftainism – studied in relation to the same principles, which, respectively, are the foundation of the Fourth Political Theory. The article also considers another important problem: the thesis, that the internal, autoimmune diseases of the Open Society, are in fact the preconditions, on which the doctrines of its external opponents are based. (shrink)

The molecular components of complement are a major part of the armoury of the mammalian immune system, being required for the lysis of antibody‐targeted cells. Several of the complement proteins are known to be encoded by genes within the major histocompatibility complex (MHC). Molecular analysis of these genes is providing new information on the basis of complement action and the possible roles of this system in autoimmune disease.

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)

Traditionally, autoimmune disease has been considered to be a case of false recognition; the immune system mistakenly identifies 'self' tissues as foreign, attacking them thus causing damage and malady. Accordingly, the history of autoimmunity is usually told as part ot the history of immunology, that is, of theories and experiments relating to the ability of the immune system to discriminate between self and nonself. This paper challenges this view, claiming that the emergence of the notion of autoimmunity in (...) the 1950s must be considered as part of a long develolpment in thought about pathology throughout the twentieth century, namely the conceptualisaiton of disease as a reactive and self-destructive process. During the first part of the twentieth century this notion became one of the cornerstones of pathology and was increasingly employed for the explanation of the non-infections, slow-burning diseases. Thus, the category of chronic disease had been defined anew, now encompassing all those diseases characterised by a persistent inflammatory process. Inflammation, in turn, was conceived as double-eged physiological mechanism, which was usually the direct mediator of damage, of the essence of disease. The paper also shows how this kind of analysis could emable a unified historical discussion of autoimmunity and allergy, hitherto considered to have distinct conceptual origins. (shrink)

Systemic autoimmune diseases are characterized by the production of antibodies against a broad range of self-antigens. Recent evidence indicates that the majority of these autoantigens are modified in various ways during cell death. This has led to the hypothesis that the primary immune response in the development of autoimmunity is directed to components of the dying cell. In this article, we summarize data on the modification of autoantigens during cell death and the possible consequences of this for autoimmunity. BioEssays (...) 22:627–636, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Here we discuss the hypothesis that the RNA components of the Ro ribonucleoproteins (RNPs), the Y RNAs, can be processed into microRNAs (miRNAs). Although Ro RNPs, whose main protein components Ro60 and La are targeted by the immune system in several autoimmune diseases, were discovered many years ago, their function is still poorly understood. Indeed, recent data show that miRNA-sized small RNAs can be generated from Y RNAs. This hypothesis leads also to a model in which Ro60 acts as (...) a modulator in the Y RNA-derived miRNA biogenesis pathway. The implications of these Y RNA-derived miRNAs, which may be specifically produced under pathological circumstances such as in autoimmunity or during viral infections, for the enigmatic function of Ro RNPs are discussed. (shrink)

This article analyses the biochemical object of tnf inhibitors from the perspective of living with an autoimmune disease. The author tries to tease out how the concept of immune inhibition is used in tandem with the biochemical object of tnf inhibitors to dominate in defining and narrating what health and disease, normal and pathological, cure and healing can mean in the context of autoimmune bodies. Specifically, and within the ‘pathological’ framework of autoimmune diseases, the pharmacological (...) treatment of tnf inhibition is designed to suppress the ‘overly’ active immune system, thus acting as a negative or suppressing biochemical agent aimed at putting the ‘malfunctioning’ immune system back in balance. As can be seen in the current conjuncture, tnf inhibitors officially —and governmentally— place those taking them in a risk group, as they 'lower' their overall bodily immunity and make them more vulnerable to infectious diseases, while stabilizing their patho-logical, ‘over’-immune uninhibited condition. Part personal narrative of being diagnosed with an autoimmune condition, part speculative autoimmune theory inspired by such a diagnosis, the article ultimately calls for a different form of embodiment that is neither negative nor affirmative, and yet is resistant even to itself. (shrink)

The nonobese diabetic (NOD) mouse spontaneously develops an autoimmune diabetes that shares many immunogenetic features with human insulin-dependent diabetes mellitus (IDDM), type 1 diabetes. The mononuclear cell infiltrates in the islet, which results in the development of insulitis (a prerequisite step for the development of diabetes) are primarily composed of T cells. It is now well accepted that these T cells play important roles in initiating and propagating an autoimmune process, which in turn destroys insulin-producing islet β cells (...) in the pancreas. T cells are subdivided into CD4+ helper T cells and CD8+ cytotoxic T cells. CD4+ T cells are further subdivided into Th1 and Th2 cells based on profiles of cytokine production, and these two T-cell populations counterregulate each other. Because many autoimmune diseases are Th1 T-cell mediated, current studies have focused on manipulating the Th1/Th2 imbalance to suppress the autoimmune process in the NOD model. Furthermore, the incidence of disease is much higher in females than that in males, suggesting an involvement of sex-steroid hormones in the development of diabetes. Understanding insights of the mechanism of immune-mediated islet cell destruction and the interaction between the immune and the neuroendocrine system may, therefore, provide new therapeutic means of preventing this chronic debilitating disease. BioEssays 20:750–757, 1998. © 1998 John Wiley & Sons, Inc. (shrink)

The pregnancy compensation hypothesis provides a mechanistic explanation for the evolution of sex differences in immune system functioning, the excess of women experiencing autoimmune disease, and why this is observed only in industrialized nations; none of which can be explained by the staying alive theory, as proposed by the authors of the target article.

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)

Physico-chemical sciences are dominated by the deterministic interpretation. Scientific medicine has generally been assigned to the area of functional biology and thence to the physico-chemical sciences. In as much as diseases are alterations of physiological processes, they share the ontological status of the latter. However, many diseases cannot be accommodated within a deterministic interpretation. First, many diseases are initiated by errors in transmission of information and followed by natural selection. These diseases, such as tumoural transformations and autoimmune processes, behave (...) as evolutionary processes. Second, physiological processes do not cause irreversible changes while diseases may do so when not followed by restitutio ad integrum. The tendency of living organisms to maintain stationary states of great stability and minimum energy dissipation is largely due to intermolecular forces-stabilized structures, the information for which is selected during phylogenesis and decodified during ontogenesis. Diseases cause alterations of the biological structures, thereby shifting living organisms toward stationary states of lower stability and increased dissipation. The shift, reversible or irreversible, to less stable and efficient stationary states is a common thermodynamic feature of diseases. In spite of the uniqueness of their genotype, living organisms, during ontogenetic development, form spatio-temporal unrestricted classes of infinite membership. Neither stationarity nor environment-induced perturbations and consequent adaptations are sources of historicity because of the genomic programme constraint. Historicity is conferred, however, to each organism by the permanent record of such unique events as: a) the variation-selection processes occurring in the brain-mind and immunological systems; and b) irreversible alterations induced by diseases. The disease-induced changes have ontological and epistemological consequences. Since biological structures and functions are transformed into individual, historical entities, the laws of scientific medicine must be applied in clinical practice to higher levels of organization, namely to the ensembles or groups of individuals affected by the diseases. (shrink)

Few topics in contemporary science hold the wide interest commanded by immunology, so this graceful and timely account of the development of this science is a welcomed addition to the literature. Succinct, well-written, and informed, Intolerant Bodies narrates the history of immunology through the lens of autoimmune disease. In what the authors call “a biography” , they have focused on four central illnesses: multiple sclerosis, systemic lupus erythematosus, rheumatoid arthritis, and type 1 diabetes mellitus. However, the story told (...) here extends far beyond the topic of “attack against self” to provide perhaps the best overview of immunity available for the general reader. The specialist will also appreciate the rich anecdotal material and benefit from the historical insights scattered throughout the text. So the book is, in fact, more than a history of autoimmunity and offers a compact history for those who need not consult more comprehensive accounts (e .. (shrink)

The common autoimmune disease type 1 diabetes provides a paradigm for the genetic analysis of multifactorial disease. Disease occurrence is attributable to the interaction with the environment of alleles at many loci interspersed throughout the genome. Their mapping and identification is difficult because the disease-associated alleles occur almost as commonly in patients as in healthy individuals; even the highest-risk genotypes bestow only modest risks of disease. The identification of common quantitative trait loci (QTL) in (...) autoimmune disease and in other common disorders, therefore,requires a very close marriage of genetics and biology. Two QTLs have been identified in human type 1 diabetes: the major histocompatibility complex HLA class II loci and a promoter polymorphism of the insulin gene. The evidence for their primary roles in disease aetiology demonstrates the necessity of combined studies of genetics and biology. Their functions and interaction underpin an emerging picture of the basic causes of the disease and direct analyses towards other candidate genes and pathways. The genetic tools used for QTL identification include transgenesis and gene knockouts, whole genome scanning for linkage, mouse congenic strains, linkage disequilibrium mapping, and the establishment of ancestral haplotypes among disease-associated chromosomes. BioEssays 1999;21:164–174. © 1999 John Wiley & Sons, Inc. (shrink)

Leishmania major infection of inbred mice leads to a major dichotomous response—death or survival—that depends on the strain of mice. This finding has motivated efforts to locate genetic determinants of disease susceptibility. Genotyping studies have confirmed a complex multilocus trait, but studies directed at the biology of the response suggest identifiable components of susceptibility that may direct the genetic investigations. A confluence of parasite variables—residence in macrophages, class II-dependent immunity, and avoidance of early IL-12 induction—with host factors—a prominent helper (...) T-cell precursor frequency to a dominant parasite epitope and a bias in IL-4 gene activation—conspires to drive an aberrant immune response in animals that suffer fatal disease. These insights may lead to an understanding of factors that focus responses on dominant antigens and that mold the naive T-cell repertoire. Collectively, such factors might contribute to the pathogenesis of other infectious and autoimmune diseases. BioEssays 21:510–518, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Applying a necessary condition communication theory formalism roughly similar to that of Dretske, but focused entirely on the statistical properties of long sequences of signals emitted by the interacting cognitive modules of human biology, we explore the regularities apparent in comorbid psychiatric and chronic physical disorders using an extension of recent perspectives on autoimmune disease. We find that structured psychosocial stress can literally write a distorted image of itself onto child development, resulting in a life course trajectory to (...) characteristic forms of comorbid mind/body dysfunction affecting both dominant and subordinate populations within a pathogenic social hierarchy. (shrink)

Ubiquitin is the most phylogenetically conserved protein known. This 8,500 Da polypeptide can be covalently attached to cellular proteins as a posttranslational modification. In most cases, the addition of multiple ubiquitin adducts to a protein targets it for rapid degradation by a multisubunit protease known as the 26S proteasome. While the ubiquitin/26S proteasome pathway is responsible for the degradation of the bulk of cellular proteins during homeostasis, it may also be responsible for the rapid loss of protein during the programmed (...) death of certain cells, such as skeletal muscle during insect metamorphosis. In addition, alterations in the expression and regulation of ubiquitin may play significant roles in pathological disorders. For example, dramatic increases in ubiquitin and ubiquitin‐protein conjugates are observed in a wide variety of neurodegenerative disorders, including Alzheimer's disease. Patients suffering from the autoimmune disease systemic lupus erythematosus generate antibodies reacting with ubiquitin and ubiquitinated histones. At present, it is not known whether these changes in ubiquitin expression and regulation initiate pathological changes in these diseases or if they are altered as a consequence of these disorders. (shrink)

Epidemiological data suggest that previous infections can alter an individual's susceptibility to unrelated diseases. Nevertheless, the underlying mechanisms are not completely understood. Substantial research efforts have expanded the classical concept of immune memory to also include long‐lasting changes in innate immunity and antigen‐independent reactivation of adaptive immunity. Collectively, these processes provide possible explanations on how acute infections might induce long‐term changes that also affect immunity to unrelated diseases. Here, we review lasting changes the immune compartment undergoes upon infection and how (...) infection experience alters the responsiveness of immune cells towards universal signals. This heightened state of alert enhances the ability of the immune system to combat even unrelated infections but may also increase susceptibility to autoimmunity. At the same time, infection‐induced changes in the regulatory compartment may dampen subsequent immune responses and promote pathogen persistence. The concepts presented here outline how infection‐induced changes in the immune system may affect human health. (shrink)

In the past decade, the availability of genetically modified animals has enabled the discovery of interesting roles for phosphatidylinositol 3‐kinase‐γ (PI3Kγ) and ‐δ (PI3Kδ) in different cell types orchestrating innate and adaptive immune responses. Therefore, these PI3K isoforms appear to be attractive drug targets for the treatment of diseases caused by unrestrained immune reactions. Currently, pharmacological targeting of PI3Kγ and/or PI3Kδ represents one of the most promising challenges for companies interested in the development of novel safe treatments for inflammatory diseases. (...) In this review we provide a general outline of PI3Kγ‐ and PI3Kδ‐specific functions in distinct subsets of inflammatory cells. We also discuss the therapeutic impact of novel compounds targeting PI3Kγ, PI3Kδ or both, in mouse models of autoimmune disorders (systemic lupus erythematosus (SLE) and rheumatoid arthritis), respiratory diseases (allergic asthma and chronic obstructive pulmonary disease) and cardiovascular dysfunctions (atherosclerosis and myocardial infarction). (shrink)

The presence of fetal cells has been associated with both positive and negative effects on maternal health. These paradoxical effects may be due to the fact that maternal and offspring fitness interests are aligned in certain domains and conflicting in others, which may have led to the evolution of fetal microchimeric phenotypes that can manipulate maternal tissues. We use cooperation and conflict theory to generate testable predictions about domains in which fetal microchimerism may enhance maternal health and those in which (...) it may be detrimental. This framework suggests that fetal cells may function both to contribute to maternal somatic maintenance (e.g. wound healing) and to manipulate maternal physiology to enhance resource transmission to offspring (e.g. enhancing milk production). In this review, we use an evolutionary framework to make testable predictions about the role of fetal microchimerism in lactation, thyroid function, autoimmune disease, cancer and maternal emotional, and psychological health.Also watch the Video Abstract. (shrink)

Autoimmune diseases such as rheumatoid arthritis and gastrointestinal disorders such as stomach ulcers are often treated with drugs. NSAIDs, a common treatment in rheumatoid arthritis, may cause stomach ulcers which call for additional medications, notably antacids in the sense of drugs that suppress acid secretion by the stomach. Infection with Helicobacter pylori also plays a role in the ulcers. The infection is typically treated with antibiotics added to antacids. Considering NSAIDs and antacids, we suspect that overmedication is common to (...) the extent that particular diets are a better option. Current research and current treatments with these drugs are also problematic since circadian rhythms are mostly disregarded. All the processes involved in the disorders treated show marked variations in the course of the day. Hence experiments conforming to the guidelines of evidence-based medicine, and treatments in line with them, have outcomes strongly depending on the time factor. This calls for reforms in medicine with fresh inputs from biology. (shrink)

Autoimmune diseases such as rheumatoid arthritis and gastrointestinal disorders such as stomach ulcers are often treated with drugs. NSAIDs, a common treatment in rheumatoid arthritis, may cause stomach ulcers which call for additional medications, notably antacids in the sense of drugs that suppress acid secretion by the stomach. Infection with Helicobacter pylori also plays a role in the ulcers. The infection is typically treated with antibiotics added to antacids. Considering NSAIDs and antacids, we suspect that overmedication is common to (...) the extent that particular diets are a better option. Current research and current treatments with these drugs are also problematic since circadian rhythms are mostly disregarded. All the processes involved in the disorders treated show marked variations in the course of the day. Hence experiments conforming to the guidelines of evidence-based medicine, and treatments in line with them, have outcomes strongly depending on the time factor. This calls for reforms in medicine with fresh inputs from biology. (shrink)

The immunoglobulin molecule is a perfect template for the de novo generation of biocatalytic functions. Catalytic antibodies, or abzymes, obtained by the structural mimicking of enzyme active sites have been shown to catalyze numerous chemical reactions. Natural enzyme analogs for some of these reactions have not yet been found or possibly do not exist at all. Nowadays, the dramatic breakthrough in antibody engineering and expression technologies has promoted a considerable expansion of immunoglobulin's medical applications and is offering abzymes a unique (...) chance to become a promising source of high‐precision “catalytic vaccines.” At the same time, the discovery of natural abzymes on the background of autoimmune disease revealed their beneficial and pathogenic roles in the disease progression. Thus, the conflicting Dr. Jekyll and Mr. Hyde protective and destructive essences of catalytic antibodies should be carefully considered in the development of therapeutic abzyme applications. (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)

The random nature of immunoglobulin gene segment rearrangement inevitably leads to the generation of self‐reactive B cells. Avoidance of destructive autoimmune reactions is necessary in order to maintain physiological homeostasis. However, current central and peripheral tolerance concepts fail to explain the massive number of autoantibody‐borne autoimmune diseases. Moreover, recent studies have shown that in physiological mouse models autoreactive B cells were neither clonally deleted nor kept in an anergic state, but were instead able to mount autoantibody responses. We (...) propose that activation of autoreactive B cells is induced by polyvalent autoantigen complexes that can occur under physiological conditions. Repeated encounter of autoantigen complexes leads to the production of affinity‐matured autoreactive IgM that protects its respective self‐targets from degradation. We refer to this novel mechanism as adaptive tolerance. This article discusses the discovery of adaptive tolerance and the unexpected role of high affinity IgM autoantibodies. (shrink)

In an instant classic paper ; 2002: 179–182) biologist Yuri Lazebnik deplores the poor effectiveness of the approach adopted by biologists to understand and “fix” biological systems. Lazebnik suggests that to remedy this state of things biologist should take inspiration from the approach used by engineers to design, understand, and troubleshoot technological systems. In the present paper I substantiate Lazebnik’s analysis by concretely showing how to apply the engineering approach to biological problems. I use an actual example of electronic circuit (...) troubleshooting to ground the thesis that, in engineering, the crucial phases of any non-trivial troubleshooting process are aimed at generating a mechanistic explanation of the functioning of the system, which makes extensive recourse to problem-driven qualitative reasoning possibly based on cognitive artifacts applied to systems that are known to have been designed for function. To show how to translate these findings into biological practice I consider a concrete example of biological model building and “troubleshooting”, aimed at the identification of a “fix” for the human immune system in presence of progressing cancer, autoimmune disease, and transplant rejection. The result is a novel immune system model—the danger model with regulatory cells— and new, original hypotheses concerning the development, prophylaxis, and therapy of these unwanted biological processes. Based on the manifest efficacy of the proposed approach, I suggest a refocusing of the activity of theoretical biologists along the engineering-inspired lines illustrated in the paper. (shrink)

During the 1940s and 1950s, the Australian microbiologist F. Macfarlane Burnet sought a biologically plausible explanation of antibody production. In this essay, we seek to recover the conceptual pathways that Burnet followed in his immunological theorizing. In so doing, we emphasize the influence of speculations on individuality, especially those of philosopher Alfred North Whitehead; the impact of cybernetics and information theory; and the contributions of clinical research into autoimmune disease that took place in Melbourne. We point to the (...) influence of local experimental and intellectual currents on Burnet’s work. Accordingly, this essay describes an arc distinct from most other tracings of Burnet’s conceptual development, which focus on his early bacteriophage research, his fascination with the work of Julian Huxley and other biologists in the 1920s, and his interest in North Atlantic experimental investigations in the life sciences. No doubt these too were potent influences, but they seem insufficient to explain, for example, Burnet’s sudden enthusiasm in the 1940s for immunological definitions of self and not-self. We want to demonstrate here how Burnet’s deep involvement in philosophical biology – along with attention to local clinical research – provided him with additional theoretic tools and conceptual equipment, with which to explain immune function. (shrink)

While gender and race often are considered socially constructed, this book argues that they are physiologically constituted through the biopsychosocial effects of sexism and racism. This means that to be fully successful, critical philosophy of race and feminist philosophy need to examine not only the financial, legal, political and other forms of racist and sexism oppression, but also their physiological operations. Examining a complex tangle of affects, emotions, knowledge, and privilege, The Physiology of Sexist and Racist Oppression develops an understanding (...) of the human body whose unconscious habits are biological. On this account, affect and emotion are thoroughly somatic, not something "mental" or extra-biological layered on top of the body. They also are interpersonal, social, and can be transactionally transmitted between people.Ranging from the stomach and the gut to the hips and the heart, from autoimmune diseases to epigenetic markers, Sullivan demonstrates the gastrointestinal effects of sexual abuse that disproportionately affect women, often manifesting as IBS, Crohn's disease, or similar functional disorders. She also explores the transgenerational effects of racism via epigenetic changes in African American women, who experience much higher pre-term birth rates than white women do, and she reveals the unjust benefits for heart health experienced by white people as a result of their racial privilege. Finally, developing the notion of a physiological therapy that doesn't prioritize bringing unconscious habits to conscious awareness, Sullivan closes with a double-barreled approach for both working for institutional change and transforming biologically unconscious habits. The Physiology of Sexist and Racist Oppression skillfully combines feminist and critical philosophy of race with the biological and health sciences. The result is a critical physiology of race and gender that offers new strategies for fighting male and white privilege. (shrink)

RNA modifications have recently emerged as an important regulatory layer of gene expression. The most prevalent and reversible modification on messenger RNA (mRNA), N6‐methyladenosine, regulates most steps of RNA metabolism and its dysregulation has been associated with numerous diseases. Other modifications such as 5‐methylcytosine and N1‐methyladenosine have also been detected on mRNA but their abundance is lower and still debated. Adenosine to inosine RNA editing is widespread on coding and non‐coding RNA and can alter mRNA decoding as well as protect (...) against autoimmune diseases. 2′‐O‐methylation of the ribose and pseudouridine are widespread on ribosomal and transfer RNA and contribute to proper RNA folding and stability. While the understanding of the individual role of RNA modifications has now reached an unprecedented stage, still little is known about their interplay in the control of gene expression. In this review we discuss the examples where such interplay has been observed and speculate that with the progress of mapping technologies more of those will rapidly accumulate. (shrink)

As the number of infections and mortalities from the SARS‐CoV‐2 pandemic continues to rise, the development of an effective therapy against COVID‐19 becomes ever more urgent. A few reports showing a positive correlation between BCG vaccination and reduced COVID‐19 mortality have ushered in some hope. BCG has been suggested to confer a broad level of nonspecific protection against several pathogens, mainly via eliciting “trained immunity” in innate immune cells. Secondly, BCG has also been proven to provide benefits in autoimmune (...) diseases by inducing tolerogenicity. Being an acute inflammatory disease, COVID‐19 requires a therapy that induces early priming of anti‐viral immune responses and regulates aberrant hyperactivity of innate‐immune cells. Here, we hypothesize that BCG can offer reliable spatiotemporal protection from COVID‐19 by triggering trained immunity and tolerogenesis, through multiple cellular pathways. We propose further research on BCG‐mediated immunoprotection, especially in vulnerable individuals, as a strategy to halt the progress of the SARS‐CoV‐2 pandemic. Also see the video abstract here https://youtu.be/P2D2RXfq6Vg. (shrink)

The c‐Jun N‐terminal kinases (JNKs) are members of the mitogen‐activated protein kinase (MAPK) family. In mammalian genomes, three genes encode the JNK family. To evaluate JNK function, mice have been created with deletions in one or more of three Jnk genes. Initial studies on jnk1−/− or jnk2−/− mice have shown roles for these JNKs in the immune system whereas studies on jnk3−/− mice have highlighted roles for JNK3 in the nervous system. Further studies have highlighted the contributions of JNK1 and/or (...) JNK2 to a range of biological and pathological processes. These include bone remodelling and joint disease, inflammatory and autoimmune diseases, obesity, diabetes, cardiovascular disease, liver disease and tumorigenesis in addition to effects in neurons. These results emphasise the differences in the roles played by JNK isoforms in vivo and suggest that the design of JNK inhibitors for subsequent therapeutic uses may benefit from selective inhibition of individual JNK isoforms. BioEssays 28: 923–934, 2006. © 2006 Wiley periodicals, Inc. (shrink)

Systemic lupus erythematosus is an inflammatory autoimmune disease with depression as one of its most common symptoms. The aim of this study is to establish a nomogram prediction model to assess the occurrence of depression in patients with SLE. Based on the Hospital Anxiety and Depression Scale cutoff of 8, 341 patients with SLE, recruited between June 2017 and December 2019, were divided into depressive and non-depressive groups. Data on socio-demographic characteristics, medical history, sociopsychological factors, and other risk (...) factors were collected. Between-group differences in clinical characteristics were assessed with depression as the dependent variable and the variables selected by logistic multiple regression as predictors. The model was established using R language. Marital status, education, social support, coping, and anxiety predicted depression. The nomogram prediction model showed that the risk rate was from 0.01 to 0.80, and the receiver operating characteristic curve analysis showed that the area under the curve was 0.891. The calibration curve can intuitively show that the probability of depression predicted by the nomogram model is consistent with the actual comparison. The designed nomogram provides a highly predictive assessment of depression in patients with SLE, facilitating more comprehensive depression evaluation in usual clinical care. (shrink)

The US FDA currently encourages the addition of vitamin D to milk and cereals, with the aim of reducing rickets in children and osteoporosis in adults. However, vitamin D not only regulates the expression of genes associated with calcium homeostasis, but also genes associated with cancers, autoimmune disease, and infection. It does this by controlling the activation of the vitamin D receptor (VDR), a type 1 nuclear receptor and DNA transcription factor. Molecular biology is rapidly coming to an (...) understanding of the multiplicity of roles played by the VDR, but clinical medicine is having difficulty keeping up with the pace of change. For example, the FDA recently proposed a rule change that will encourage high levels of vitamin D to be added to even more foods, so that the manufacturers can claim those foods “reduce the risk of osteoporosis”. The FDA docket does not review one single paper detailing the transcriptional activity of vitamin D, even though, on average, one new paper a day is being published on that topic. Nor do they review whether widespread supplementation with vitamin D, an immunomodulatory secosteroid, might predispose the population to immune dysfunction. This BioEssay explores how lifelong supplementation of the food chain with vitamin D might well be contributing to the current epidemics of obesity and chronic disease. BioEssays 30:173–182, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Where does my body begin? Where does it end? What is inside my body? What is outside? What is primary? What is secondary? What is natural? What is artificial? Science fiction has long imagined a future fusion of humanity with technology. Today, many of us—especially people with health issues such as autoimmune diseases—have functionally become hybrids connected to other machines and to other bodies. The combination of artificial intelligence with implants, transplants, prostheses, and genetic reprogramming is transforming medical research (...) and treatment, and it is now also transforming what we thought was human nature. Mark C. Taylor identifies this process as “intervolution” and explores how it is weaving together smart things and smart bodies to create new forms of life. Our wired bodies are no longer freestanding individuals, but interconnected nodes in worldwide networks. Recognizing this transformation overturns deeply entrenched distinctions and oppositions between minds and bodies. Intervolution reveals that we are already cyborgs, integral cogs in what will become a superorganism of bodies and things. (shrink)

Insulin‐dependent diabetes mellitus (IDDM) is an autoimmune disease whose etiology is complex. Both genetic susceptibility, which is polygenic, and environmental factors, including virus infections, appear to be involved in the development of IDDM. In this review, we have tried to balance the discussion of diabetes by examining both immunological and virological perspectives. Several mouse models, including viral and non‐viral models, have been used to study diabetes. For this review, we include lessons gleaned from the non‐obese diabetic (NOD) mouse (...) and from mouse models of coxsackievirus‐ and encephalomyocarditis‐virus‐induced diabetes. Finally, we present a multi‐stage model in which several viral infections, including the coxsackieviruses, are postulated to play a role in the autoimmune destruction of pancreatic beta cells. (shrink)

Ten years ago, I was diagnosed with a rare illness called Myasthenia Gravis. Myasthenia Gravis is a long-term neuromuscular autoimmune disease where antibodies block or destroy specific receptors at the junction between nerve and muscle; hence, nerve impulses fail to trigger muscle contractions. The disease leads to varying degrees of muscle weakness. Currently, I have only minor symptoms, I am not seriously impaired, and I do not suffer from any social disadvantage because of my illness. Yet, my (...) life and my body since my diagnosis feel different than before. In this paper I aim to make this feeling intelligible and propose that it is a state of what I call ‘latent impairment’. Latent impairment is a state of being ‘in between’, different from being actually impaired and also different from being abled-bodied. The theory takes its cues both from social constructionist theories of disability as well as theories of (chronic) illness and their focus on the importance of subjectivity. Furthermore, I suggest that a phenomenological understanding of latent impairment can show possible ways of becoming an ally to the DRM. (shrink)

Over the past two decades, the understanding of the roles of vitamin D has expanded to include many nonskeletal effects such as reduced risk of acute respiratory tract infections, autoimmune diseases, cancer, cardiovascular disease, diabetes mellitus, neurological diseases, and adverse pregnancy and birth outcomes. The role of vitamin D for optimal health is well known in Western developed countries but less so in Central Asian countries. This narrative review compares the status of vitamin D between Central Asian countries (...) and Northern European countries. The analysis also summarizes the evidence for the beneficial effects of vitamin D and recommendations for Central Asian countries. (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)

Human B cell stimulatory factor 2 (originally designated BSF2) was initially characterized and isolated as a T cell‐derived factor that caused the terminal maturation of activated B cells to immunoglobulin producing cells. Molecular cloning of the cDNA has revealed that BSF2 is identical with 26 kD protein, interferon β2, plasmacytoma growth factor and hepatocyte stimulating factor and the designation “IL‐6” has been proposed for this molecule. It is now known that BSF2/IL‐6 has a wide variety of biological functions and that (...) abnormal regulation of BSF2/IL‐6 expression may be related to the pathogenesis of certain autoimmune diseases such as rheumatoid arthritis and multiple myeloma. (shrink)

Significant associations have been found between specific human leukocyte antigen (HLA) alleles and organ transplant rejection, autoimmune disease development, and the response to infection. Traditional searches for disease associations have conventionally measured risk associated with the presence of individual HLA alleles. However, given the high level of HLA polymorphism, the pattern of amino acid variability, and the fact that most of the HLA variation occurs at functionally important sites, it may be that a combination of variable amino (...) acid sites shared by several alleles (shared epitopes) are better descriptors of the actual causative genetic variants. Here we describe a novel approach to genetic association analysis in which genes/proteins are broken down into smaller sequence features and then variant types defined for each feature, allowing for independent analysis of disease association with each sequence feature variant type. We have used this approach to analyze a cohort of systemic sclerosis patients and show that a sequence feature composed of specific amino acid residues in peptide binding pockets 4 and 7 of HLA-DRB1 explains much of the molecular determinant of risk for systemic sclerosis. (shrink)

Graphical AbstractMuller found halving gene dosage, as in males with one X chromosome, did not affect specific gene function. Why then was dosage “compensated?” This paradox was solved by invoking collective gene functions such as self/not self discrimination afforded by protein aggregation pressure. This predicts female susceptibility to autoimmune disease.

Multiple Sclerosis is a debilitating chronic autoimmune disease of the central nervous system that results in lower quality of life. Medication adherence is important for reducing relapse, disease progression, and MS-related symptoms, particularly during the early stages of MS. However, adherence may be impacted by negative emotional states. Therefore, it is important to identify protective factors. Past research suggests that the ability to discriminate between negative emotional states, also known as negative emotion differentiation, may be protective against (...) enactment of maladaptive risk-related behaviors. However, less is known as to how NED may promote adaptive health behaviors such as medication adherence. Utilizing weekly diaries, we investigated whether NED moderates the association between negative affect and medication adherence rates across 58 weeks among patients newly diagnosed with MS. Results revealed that NED significantly moderated the relationship between negative affect and medication adherence. Specifically, greater negative affect was associated with lower adherence only for individuals reporting low NED. However, this link disappeared for those reporting moderate to high NED. Building upon past research, our findings suggest that NED may promote adaptive health behaviors and have important clinical implications for the treatment and management of chronic illness. (shrink)

What are the implications of microchimerism in sociocultural and ethico-legal contexts, particularly as they relate to the destabilization of genetic origins? Conventional biomedicine and related law have been reluctant to acknowledge microchimerism—the existence of unassimilated traces of genetic material that result in some cells in the body coding differently from the dominant DNA—despite it becoming increasingly evident that microchimerism is ubiquitous in the human population. One exception is maternal–fetal microchimerism which has long been recognized, albeit with little consideration of the (...) nonmedical implications. Most immediate issues concern the ongoing biomedical debate around whether microchimerism is beneficial in terms of enhancing the body’s range of immunological responses, harmful in provoking autoimmune diseases, or simply neutral with respect to subsequent health. That controversy remains unresolved, but whichever way it develops, I want to extend consideration by insisting that changing biological concerns cannot be separated from sociocultural and ethico-legal effects. Once the diversity of DNA coding in a singular body has been established, relations of kinship, the identification of legal parenthood, and the operation of surrogacy laws are of direct interest. The overriding problematic asks whether our ethical and legal apparatus is able to address such newly emerging questions. (shrink)

Although we are likely unaware of it, in one troubling respect nearly all of us today wear the ring of Gyges. Because we are “invisible,” we use the ring to harm others with impunity. What is our ring of Gyges? It is our use/release of epigenetically toxic environmental pollutants (ETEP), such as endocrine disruptors, metals, and some pesticides. For developmentally/pre- and-postnatally-exposed children, ETEP often cause heritable gene-expression changes, developmental toxicity (DT) that increases later-life disease/dysfunction/death, including asthma/allergy, cancer, cardiovascular (...) class='Hi'>disease, depression, diabetes, hypertension, immune/precocious autoimmune diseases, infertility, neuro-developmental/neuro-degenerative diseases, obesity, osteoporosis, puberty, and schizophrenia.Yet, like Gyges, we offenders are “invisible” in at least two senses: (i) invisible before the law, because current regulations do not prohibit ETEP exposures able to cause DT; (ii) invisible as perpetrators, because most child-DT harms appear later in life. This paper (1) uses ETEP and DT to explain how we cause severe, hidden, pollution harms to children and future generations, (2) argues that no major ethical theory can justify allowing avoidable ETEP, and (3) shows that we have justice-based duties to help stop avoidable ETEP exposures, because, to varying degrees, we help cause ETEP and profit from them. Finally, the paper (4) answers objections to (3). (shrink)

Through her stories and mine, my sister and I allow the outside world to see the ways in which we grapple with a critical health incident along her journey of living with lupus. Lupus is a chronic, autoimmune disease that is difficult to recognize and to diagnose. The ambiguous nature of the disease creates considerable confusion for the ill person as well as her support system. Using an illness narrative, I analyze a real life event linked to (...) chronic illness, invisibility, living loss, liminality and family—and more specifically, to social support within the sibling relationship. (shrink)

An innovative approach to the production of anti‐receptor antibodies is now being fully exploited for a number of different cell receptors. This approach employs the concept that antibodies directed against pharmacologically active ligands have a three‐dimensional binding site which is somewhat analogous to the natural receptor. Consequently, when anti‐idiotype antibodies are produced against these anti‐ligand antibodies, some of the anti‐idiotypes will comprise a positive three‐dimensional shape which mimics the original ligand. The anti‐idiotypic antibodies generated in this fashion are able to (...) bind to cell surface receptors. This approach has now been successfully applied to peptide hormones, small bio‐active peptides, interferon, viral hemagglutinins, and a number of small neurotransmitter ligands. So far, the boundaries for this working ‘molecular engineering’ concept have not been reached. This concept may also shed light on the processes which take place in the generation of anti‐receptor antibodies in several autoimmune diseases. (shrink)