Horror Autotoxicus Research Articles

How underappreciated autoinflammatory (innate immunity) mechanisms dominate disparate autoimmune disorders.

Historically inflammation against self was considered autoimmune which stems back to the seminal observations by Ehrlich who described serum factors, now known to be autoantibodies produced by B lineage cells that mediate "horror autotoxicus". The 20th century elucidation of B- and T-cell adaptive immune responses cemented the understanding of the key role of adaptive immune responses in mediating pathology against self. However, Mechnikov shared the Nobel Prize for the discovery of phagocytosis, the most rudimentary aspect of innate immunity. Fast forward some 100 years and an immunogenetic understanding of innate immunity led to the categorising of innate immunopathology under the umbrella term 'auto inflammation' and terminology such as "horror autoinflammaticus" to highlight the schism from the classical adaptive immune understanding of autoimmunity. These concepts lead to calls for a two-tiered classification of inflammation against self, but just as innate and adaptive immunity are functionally integrated, so is immunopathology in many settings and the concept of an autoimmune to autoinflammation continuum emerged with overlaps between both. Herein we describe several historically designated disorders of adaptive immunity where innate immunity is key, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD) where the immunopathology phenotype is strongly linked to major histocompatibility complex (MHC) class II associations and responds to drugs that target T-cells. We also consider MHC-I-opathies including psoriasis and Behcet's disease(BD) that are increasingly viewed as archetype CD8 T-cell related disorders. We also briefly review the key role of barrier dysfunction in eczema and ulcerative colitis (UC) where innate tissue permeability barrier dysfunction and microbial dysbiosis contributes to prominent adaptive immune pathological mechanisms. We also highlight the emerging roles of intermediate populations of lymphocytes including gamma delta (γδ) and mucosal-associated invariant T (MAIT) cells that represent a blend of adaptive immune plasticity and innate immune rapid responders that may also determine site specific patterns of inflammation.

Origins and history of autoimmunity—A brief review

AbstractIt was not widely recognized, until the 1950s, that an immune response could be developed not only against “foreign” but also “self” antigens from the studies of chronic thyroiditis leading to the acceptance of autoimmune diseases. Paul Ehrlich coined the term “horror autotoxicus” to emphasize the pathogenesis of autoimmunity and how the immune system distinguishes “foreign” from “self”. The process led to the concept of immune tolerance. The discoveries of allergy and anaphylaxis were the first signs that the immune system was capable of self‐damage. The first autoantibodies were discovered in the 1940s, when antinuclear antibodies and rheumatoid factors were described as serum factors that could bind nuclear antigens and immunoglobulins, respectively. It has now becoming increasingly understandable that autoantibodies play a pivotal role in the pathogenesis of several diseases and mediate systemic inflammation and tissue injury. The purpose of this review article is to elucidate, explain, and emphasize the origins and history of autoimmunity.

JAK1 signaling in dendritic cells promotes peripheral tolerance in autoimmunity through PD-L1-mediated regulatory Tcell induction.

Dendritic cells (DCs) induce peripheral Tcell tolerance, but cell-intrinsic signaling cascades governing their stable tolerogenesis remain poorly defined. Janus Kinase 1 (JAK1) transduces cytokine-receptor signaling, and JAK inhibitors (Jakinibs), including JAK1-specific filgotinib, break inflammatory cycles in autoimmunity. Here, we report in heterogeneous DC populations of multiple secondary lymphoid organs that JAK1 promotes peripheral Tcell tolerance during experimental autoimmune encephalomyelitis (EAE). Mice harboring DC-specific JAK1 deletion exhibit elevated peripheral CD4+ Tcell expansion, less regulatory Tcells (Tregs), and worse EAE outcomes, whereas adoptive DC transfer ameliorates EAE pathogenesis by inducing peripheral Tregs, programmed cell death ligand 1 (PD-L1) dependently. This tolerogenic program is substantially reduced upon the transfer of JAK1-deficient DCs. DC-intrinsic IFN-γ-JAK1-STAT1 signaling induces PD-L1, which is required for DCs to convert CD4+ Tcells into Tregs invitro and attenuated upon JAK1 deficiency and filgotinib treatment. Thus, DC-intrinsic JAK1 promotes peripheral tolerance, suggesting potential unwarranted DC-mediated effects of Jakinibs in autoimmune diseases.

A Comprehensive Review on Autoimmune Diseases

Abstract: Immunity refers to the inbuilt ability of the organism to resist a particular disease or to be able to protect itself from disease causing microorganisms by preventing its development. Immune system includes WBCs which includes all the neutrophils, lymphocytes including the T-cells, the B-cells & the natural killer cells, all together make up the lymphatic system, antibodies, the spleen, the thymus, the bone marrow; our skin, mucous glands, hair, tears etc. also protect our body. By autoimmunity we understand that it is misallocated response of our immune system when it releases autoantibodies to attack the healthy cells of the body. Scientists have studied a lot about autoimmunity and its disorders. By the end of the 19th century, it was first believed that our immune system has the inability to react against its own body tissue until in 20th century the concept of “horror autotoxicus” was proposed by the German immunologist Paul Ehrlich. The autoimmune disease occurs when the immune system reacts and attacks its own cells in the body as a result of breakdown of immunologic tolerance to auto reactive immune cells. Many times, genetic as well as environmental factors are the key reason for autoimmune diseases. Many kinds of research are going through as to find out the actual cause of autoimmunity; till now no actual or exact cause is known. There are at least 80 types of autoimmune diseases recognized by our scientists; some of the commonly known autoimmune diseases are: type 1 diabetes, systemic lupus erythematosus, scleroderma, thyroiditis, multiple sclerosis, autoimmune vasculitis, rheumatoid arthritis, and many more. With unusual autoimmune diseases, diagnosis may not be done instantly; the patients may suffer years before getting diagnosed properly. Most of the diseases don't have any cure; some even need lifelong treatment to ease the symptoms. The diseases will be discussed in detail in the further sections. Keywords: autoimmunity, immune system, cells, disease, disorder, diabetes, arthritis, lupus, ITP

The Trinity of cGAS, TLR9, and ALRs Guardians of the Cellular Galaxy Against Host-Derived Self-DNA.

The immune system has evolved to protect the host from the pathogens and allergens surrounding their environment. The immune system develops in such a way to recognize self and non-self and develops self-tolerance against self-proteins, nucleic acids, and other larger molecules. However, the broken immunological self-tolerance leads to the development of autoimmune or autoinflammatory diseases. Pattern-recognition receptors (PRRs) are expressed by immunological cells on their cell membrane and in the cytosol. Different Toll-like receptors (TLRs), Nod-like receptors (NLRs) and absent in melanoma-2 (AIM-2)-like receptors (ALRs) forming inflammasomes in the cytosol, RIG (retinoic acid-inducible gene)-1-like receptors (RLRs), and C-type lectin receptors (CLRs) are some of the PRRs. The DNA-sensing receptor cyclic GMP–AMP synthase (cGAS) is another PRR present in the cytosol and the nucleus. The present review describes the role of ALRs (AIM2), TLR9, and cGAS in recognizing the host cell DNA as a potent damage/danger-associated molecular pattern (DAMP), which moves out to the cytosol from its housing organelles (nucleus and mitochondria). The introduction opens with the concept that the immune system has evolved to recognize pathogens, the idea of horror autotoxicus, and its failure due to the emergence of autoimmune diseases (ADs), and the discovery of PRRs revolutionizing immunology. The second section describes the cGAS-STING signaling pathway mediated cytosolic self-DNA recognition, its evolution, characteristics of self-DNAs activating it, and its role in different inflammatory conditions. The third section describes the role of TLR9 in recognizing self-DNA in the endolysosomes during infections depending on the self-DNA characteristics and various inflammatory diseases. The fourth section discusses about AIM2 (an ALR), which also binds cytosolic self-DNA (with 80–300 base pairs or bp) that inhibits cGAS-STING-dependent type 1 IFN generation but induces inflammation and pyroptosis during different inflammatory conditions. Hence, this trinity of PRRs has evolved to recognize self-DNA as a potential DAMP and comes into action to guard the cellular galaxy. However, their dysregulation proves dangerous to the host and leads to several inflammatory conditions, including sterile-inflammatory conditions autoinflammatory and ADs.

Cosmic Topologies of Imitation: From the Horror of Digital Autotoxicus to the Auto-Toxicity of the Social

This article expands on an earlier concept of horror autotoxicus linked to digital contagions of spam and network Virality.1 It aims to present, as such, a broader conception of cosmic topologies of imitation (CTI) intended to better grasp the relatively new practices of social media marketing. Similar to digital autotoxicity, CTI provide the perfect medium for sharing while also spreading contagions that can potentially contaminate the medium itself. However, whereas digital contagions are perhaps limited to the toxicity of a technical layer of information viruses, the contagions of CTI are an all pervasive auto-toxicity which can infect human bodies and technologies increasingly in concert with each other. This is an exceptional autotoxicus that significantly blurs the immunological line of exemption between self and nonself, and potentially, the anthropomorphic distinction between individual self and collective others.

Glyco-Engineering of Human IgG-Fc to Modulate Biologic Activities.

Advances in genetic and protein engineering and the ability to maintain proliferating mammalian cells in vitro, has allowed reverse engineering of antibodies, i.e. generation of antibodies having specificity for self-antigens. Thus, the lethal consequence of horror autotoxicus, anti-self-responses as envisaged by Paul Ehrlich (1854-1915), has been turned to advantage for treatment of multiple disease states. In order to reap these benefits, it is essential that, in addition to target specificity, the antibody is customised to deliver appropriate downstream biologic effector activities. Genetic engineering allows the development of any chosen isotype; however, The IgG class predominates in human serum and the majority of monoclonal antibody (mAb) therapeutics are based on the IgG format. This review focuses on the structure and function of the four human IgG isotypes (subclasses) and the biologic functions that their immune complexes activate through interactions with cellular Fc receptors (FcγR & FcRn) and/or the C1q component of complement. The long catabolic half-life (~21 days) of IgG contributes to its efficacy as a therapeutic. Each human IgG subclass exhibits a unique profile of biologic activities that are dependent on the glycoform profile of the IgG-Fc. Our current understanding of IgG structure/function relationships allows protein and glycosylation engineering of the IgG-Fc to enhance or eliminate biologic activities and the generation of therapeutics optimal for a given disease indication.

Rare phenotypes in the understanding of autoimmunity.

The study of rare phenotypes has a long history in the description of autoimmune disorders. First Mendelian syndromes of idiopathic tissue destruction were defined more than 100 years ago and were later revealed to result from immune-mediated reactivity against self. In the past two decades, continuous advances in sequencing technology and particularly the advent of next-generation sequencing have allowed to define the genetic basis of an ever-growing number of Mendelian forms of autoimmunity. This has provided unique insight into the molecular pathways that govern immunological homeostasis and that are indispensable for the prevention of self-reactive immune-mediated tissue damage and 'horror autotoxicus'. Here we will discuss selected examples of past and recent investigations into rare phenotypes of autoimmunity that have delineated pathways critical for central and peripheral control of the adaptive immune system. We will outline the implications of these findings for rare and common forms of autoimmunity and will discuss the benefits and potential pitfalls of the integration of next-generation sequencing into algorithms for clinical diagnostics. Because of the concise nature of this review, we will focus on syndromes caused by defects in the control of adaptive immunity as innate immune-mediated autoinflammatory disorders have been covered in excellent recent reviews on Mendelian and polygenic forms of autoimmunity.

Autoantibodies: Focus on anti-DNA antibodies

Ever since the days of Ehrlich and the birth of humoral immunity, self-reactivity or 'horror autotoxicus' as referred to by Paul Ehrlich, has been of great concern. For instance, in patients with the autoimmune disease systemic lupus erythematosus (SLE), anti-nuclear and anti-DNA antibodies have been recognized for many years. Despite this, the exact mechanism as to how the immune system fails to protect the individual and allows these autoantibodies to develop in this and other systemic autoimmune diseases remains uncertain. So how can we explain their presence? Evidence suggests that B cells expressing autoreactive antibodies do not normally arise but rather undergo negative selection as they develop. In light of this, it might seem contradictory that not all autoreactive B cell clones are eliminated, although this may not even be the intention since autoantibodies are also found in healthy individuals and may even protect from autoimmunity. Here, we will discuss autoantibodies, in particular those recognizing DNA, with regard to their reactivity and their potentially pathogenic or protective properties.

It's Complicated: Inflammation from Metchnikoff to Meryl Streep

It's Complicated: Inflammation from Metchnikoff to Meryl Streep

The rise and fall of horror autotoxicus and forbidden clones

Cui and associates show that healthy individuals have natural autoantibodies (NAAs) specific for myeloperoxidase, proteinase 3, and glomerular basement membrane (GBM) with the same specificity as anti-neutrophil cytoplasmic antibodies and anti-GBM antibodies that are pathogenic. Although Ehrlich proposed horror autotoxicus and Burnet envisioned elimination of forbidden clones, NAAs are present in all healthy individuals and play beneficial homeostatic roles. Pathogenic autoimmunity is dysregulation of natural homeostatic autoimmunity rather than onset of a previously absent self-recognition.

The thymus as an obligatory intersection between the immune and neuroendocrine systems: pharmacological implications

Vincent Geenen received the MD (1982) and PhD (1987) degrees from the University of Liege Medical School in Belgium. He is currently Research Director for the National Fund of Scientific Research of Belgium (NFSR), Chairman of the Center of Immunology at University of Liege, Professor of Developmental Biology at Liege Faculty of Sciences, Professor of History of Biomedical Research at Liege Medical School, and Clinical Head in Endocrinology at Liege University Hospital. The recipient of several research awards in Belgium and Europe, he has given more than 90 invited lectures worldwide, authored or coauthored more than 140 papers and several book chapters, and coedited the book ‘Immunoendocrinology in Health and Disease’ (2004). He wrote the chapter ‘Thymus and T cells’ for the 2nd Edition of the Encyclopedia of Neuroscience on CD-ROM (Elsevier, 1998). His research focuses on thymus-dependent immunological self-tolerance, the role of a thymus dysfunction in the development of autoimmunity, the design of a thymus-based negative selfvaccine against type 1 diabetes, and immuneneuroendocrine interactions during embryo implantation and pregnancy. Dr. Vincent Geenen was the coordinator of the European FP6 Integrated Project Eurothymaide (2004–2008) entitled ‘Novel approaches in pathogenesis, diagnosis, and treatment of autoimmune diseases based on new insights into thymus-dependent self-tolerance, with special attention to type 1 diabetes’. Since 1995, his name is included in Who’s Who in the World, Who’s Who in Science and Engineering, and Who’s Who in Medicine and Health Care. Dr. Vincent Geenen holds memberships in the Endocrine Society, the American Association of Immunologists, the American Association of Diabetes, the International Federation of Neuroendocrinology, the European Association for the Study of Diabetes, the International Society of NeuroImmunoModulation and the European Neuroendocrine Association, among many organizations. Already in his famous side-chain theory (1900), P Ehrlich formulated the hypothesis that immune cells could express receptors susceptible to react against normal components of the body. In that case, however very improbable for him, he claimed that the organism should deploy specific mechanisms to escape from this difficulty (horror autotoxicus). In the second edition of ‘The Production of Antibodies’ (1949), F Macfarlane Burnet and F Fenner proposed the principle of self/nonself discrimination as the cardinal point of immune physiology, as well as the concept of self-markers for antigens encountered by precursors of immunocytes during embryonic life, to which thenceforth immunological tolerance could never be broken later in life. Autoimmunity, if this should occur, would then depend on ‘forbidden’ immune clones that later arose through somatic mutation. Since that time, self-tolerance has become a cornerstone of immune physiology, together with diversity, specificity and memory of the immune response. The absence or breakdown of self-tolerance is responsible for the progressive development of autoimmune diseases, either systemic (such as lupus erythematosus) or organ-specific (such as autoimmune endocrine diseases). All endocrine glands without exception may become deficient because of an autoimmune response directed against one or a few endocrine tissue-specific autoantigens. A legitimate question then is to understand why autoimmune pathogenic processes so frequently aggress endocrine tissues. The discovery of the intrathymic mechanisms responsible for the installation of central selftolerance has provided a number of answers to this important question. Among these answers, an important one concerns the true nature of self that is presented in the thymus to differentiating T cells during fetal life. Since its formulation some 60 years ago, self had been a seminal word coined in immunology’s language first as a fecund metaphor with some equivocal correlations to philosophy, psychology, and neurocognitive sciences. For unknown reasons, there were no serious attempts to elucidate the biochemical identity of self before a number of essential consecutive studies in the late 1980s and in the 1990s.

Restraining order for dendritic cells: all quiet on the fetal front

The paradoxical ability to launch effective immunity against pathogens while avoiding the horror autotoxicus of autoimmunity is one of the most remarkable features of the mammalian immune system. This assumes a particular evolutionary significance at the maternal/fetal interface, where avoidance of immune reactivity to the fetus is vital to the propagation of the species itself. Several mechanisms of suppressing maternal immunity against the fetus have been described. The article by Collins et al. in this issue of the JCI describes a novel mechanism of avoiding immune surveillance in which the migratory capacity of dendritic cells at the maternal/fetal interface is restrained (see the related article beginning on page 2062).

Human Autoantibodies Specific for Neurotrophin Receptors TrkA, TrkB, and TrkC Protect against Lethal Trypanosoma cruzi Infection in Mice

Patients with Chagas' disease remain asymptomatic for many years, presumably by keeping the etiological agent Trypanosoma cruzi in check through protective immunity against. Recently, we found that T. cruzi uses TrkA, a receptor tyrosine kinase responsive to neurotrophin nerve growth factor in vertebrate nervous systems, to invade cells. We also found that TrkA, TrkB, and TrkC, but not T. cruzi, are targets of specific autoantibodies present in the sera of patients with chronic Chagas' disease. Here we show that TrkA-, TrkB-, and TrkC-specific autoantibodies isolated from the sera of four individuals with chronic indeterminate (asymptomatic) Chagas' disease potently blocked invasion of Trk-bearing neuronal PC12 cells, neuroglial astrocytes, enteroglial cells, and Schwann cells and Trk-expressing non-neural smooth muscle and dendritic cells. However, these autoantibodies did not inhibit T. cruzi invasion of mutant PC12 cells lacking TrkA or of normal cells lacking Trk receptors, suggesting that autoantibodies interfered with parasite/Trk cross talk to access the intracellular milieu. Passive immunization of susceptible and resistant mouse strains with very small doses of these autoantibodies reduced parasitemia and transferred resistance to an otherwise lethal trypanosome infection. Hence, this exquisitely sensitive and unique regulatory immunity against the host (instead of parasite) could benefit infected individuals by blocking cellular invasion of the obligatory intracellular pathogen, resulting in attenuation of tissue infection and clinical manifestations. Such action is contrary to the horror autotoxicus frequently associated with microbe-related autoimmune responses.

Inflammation and oxidative stress in vertebrate host–parasite systems

Innate, inflammation-based immunity is the first line of vertebrate defence against micro-organisms. Inflammation relies on a number of cellular and molecular effectors that can strike invading pathogens very shortly after the encounter between inflammatory cells and the intruder, but in a non-specific way. Owing to this non-specific response, inflammation can generate substantial costs for the host if the inflammatory response, and the associated oxygen-based damage, get out of control. This imposes strong selection pressure that acts to optimize two key features of the inflammatory response: the timing of activation and resolution (the process of downregulation of the response). In this paper, we review the benefits and costs of inflammation-driven immunity. Our aim is to emphasize the importance of resolution of inflammation as a way of maintaining homeostasis against oxidative stress and to prevent the 'horror autotoxicus' of chronic inflammation. Nevertheless, host immune regulation also opens the way to pathogens to subvert host defences. Therefore, quantifying inflammatory costs requires assessing (i) short-term negative effects, (ii) delayed inflammation-driven diseases, and (iii) parasitic strategies to subvert inflammation.

Treg cells: guardians for life

Regulatory T cells expressing the transcription factor Foxp3 are known to control autoreactivity during and subsequent to the development of the peripheral immune system. New evidence emphasizes the fact that those cells are constant and powerful guardians against the state of 'horror autotoxicus'.

Thymus‐Dependent T Cell Tolerance of Neuroendocrine Functions

Under the evolutionary pressure exerted by the emergence of adaptive immunity and its inherent risk of horror autotoxicus, the thymus appeared some 500 million years ago as a novel lymphoid structure able to prevent autoimmunity and to orchestrate self-tolerance as a cornerstone in the physiology of the immune system. Also, the thymus plays a prominent role in T cell education to neuroendocrine principles. Some self-antigens (oxytocin, neurotensin, insulin-like growth factor 2 [IGF-2]) have been selected to be predominantly expressed in thymic epithelium and to be presented to thymus T cells for educating them to tolerate other antigens related to them. In the insulin family, IGF2 is dominantly transcribed in cortical (c) and medullary (m) thymic epithelial cells (TECs), whereas the insulin gene (INS) is expressed at low level by only a few subsets of mTECs. Intrathymic transcription of both IGF2 and INS is under the control of the autoimmune regulator (Aire) gene. The highest concentrations of IGF-2 in the thymus explain why this peptide is much more tolerated than insulin, and why tolerance to IGF-2 is so difficult to break by active immunization. The high level of tolerance to IGF-2 is correlated to the development of a tolerogenic/regulatory profile when the sequence B11-25 of IGF-2 (homologous to the autoantigen insulin B9-23) is presented to DQ8+ type 1 diabetic patients. Since subcutaneous and oral insulin does not exert any tolerogenic properties, IGF-2 and other thymus self-antigens related to type 1 diabetes (T1D) should be preferred to insulin for the design of novel specific antigen-based preventive approaches against T1D.

The Large Print Giveth and the Small Print Taketh Away: Preemptive treatment of serologically active, clinically quiet systemic lupus erythematosus

In this issue of Arthritis & Rheumatism, Tseng et al present the final results of an important clinical trial that was initially presented at the 2003 Annual Scientific Meeting of the American College of Rheumatology (1,2). Clinical trials in systemic lupus erythematosus (SLE) are difficult to do, and it is also difficult to recruit sufficient numbers of subjects. The best study designs and end point measures are evolving. Although new funding is available, clinical trials are still not adequately resourced. Tseng et al deserve our admiration and gratitude for their efforts. Their results have relevance for patient management and for experimental therapeutics in SLE. Their study addresses an important and longstanding clinical question in SLE, the roots of which are found in the history of the discovery of the molecular biology of SLE. From Ehrlich’s concept of horror autotoxicus, to the discovery of autoantibodies to nuclear constituents, to their application in the diagnosis and subsetting of phenotypes of SLE, and to the demonstration of autoantibodies and complement products in situ, the essential roles of autoantibodies and complement make a nice story of pathogenesis. This history has stimulated the widespread and often uncritical use of measurements of antibody and complement levels to diagnose and monitor the disease, as well as the idea that these immunologic measures can be used to decide when to initiate, taper, and stop therapy (3,4). These latter clinical conclusions have occurred despite disquieting observations that autoantibodies may be neither sufficiently specific nor sensitive for diagnosis, nor may they be necessarily correlated with clinically “active” disease or predictive of a flare (5–8). In clinical research there are no perfect studies, and good studies beget new questions. The present study illustrates both principles. The authors are appropriately circumspect about the generalizability of their findings. It is unclear which patients at the various centers were referred for screening and how representative these subjects are. The data indicate that the patients to which the study results apply are uncommon. The study accrued subjects over a 5-year period. The authors estimate that 50% of patients were neither eligible nor referred for formal screening for the study. Only 27% of the clinically stable patients were randomized, while nearly half of those who did not experience a serologic flare were censored. Although 40–80% of patients with SLE demonstrate antibodies to double-stranded DNA (anti-dsDNA) at some time during their disease course (7–11), the proportion of these patients who have clinically quiescent disease is uncertain; it is probably a small number of individuals (12,13). The landmark study by Bootsma et al (14), upon which Tseng and coworkers’ study builds, evaluated all available patients with SLE, but randomized those who had anti-dsDNA by blocks in order to balance the participants according to the presence or absence of a major or minor flare in the previous 2 years and by 2 immunosuppression maintenance regimens (stable treatment with corticosteroid and other immunosuppressive agents or decreasing corticosteroid dosage versus no immunosuppressive agents). The Dutch investigators showed that, compared with conventional treatment implemented after clinical relapse, early treatment of increases in the anti-dsDNA antibody titer with prednisone (30 mg/day over the maintenance dosage to a maximum 60 mg/day) reduced the incidence of major and minor flares. This first controlled study used only Supported by grants from the NIH (AR-47782) and Rheuminations, Inc. Ms Simard’s work was supported by a training grant from the NIH (T32-AI-07535). Matthew H. Liang, MD, MPH, Julia F. Simard, SM: Harvard School of Public Health, Robert B. Brigham Arthritis and Musculoskeletal Diseases Clinical Research Center, Brigham and Women’s Hospital, Boston VA Healthcare System, and the Massachusetts Veterans Epidemiology and Research Center, Boston. Address correspondence and reprint requests to Matthew H. Liang, MD, MPH, Division of Rheumatology, Immunology, and Allergy, Brigham and Women’s Hospital, 75 Francis Street, PBB-3, Boston, MA 02115. E-mail: mliang@partners.org. Submitted for publication May 5, 2006; accepted in revised form August 2, 2006.

Life amidst the contrivances

The established dogma of 'horror autotoxicus' was overturned 50 years ago with the publication of a paper showing that autoimmune thyroiditis could be induced in animals. Noel Rose recounts the events that led to the establishment of autoimmunity as a cause of disease.

Tissue Homeostasis and Immunity – More on Models

This article continues the ongoing debate around models of the immune system. Earlier contributors have paid much attention to the various processes that lead to adaptive immune system aggression or tolerance. They have often based their discussions around facts that have been established by experimental investigation. However, both the observation and interpretation of these facts have been influenced by the function--or system goal--that is believed to have generated them. The perception of this function (of all or part of the immune system) is influenced by long established theories in immunology (e.g. horror autotoxicus, clonal deletion in utero, pathogen elimination, clonal selection, auto-immunity and so on) which, for many, have become enshrined as facts. One function that has had less consideration and has not been extensively investigated is the maintenance of tissue homeostasis. When the immune system is viewed from this perspective, the facts invite alternative interpretations. Whilst this perspective may not necessarily be the only valid one, let alone a correct one, viewing things this way--at least briefly--might help to expose hidden assumptions. It also emphasizes that the immune system is a system and, as such, it can by analysed through the principles of general systems theory.