Immunological Self Research Articles

Establishment of the immunological self in juvenile Patiria pectinifera post-metamorphosis.

Ontogeny of the immune system is a fundamental immunology issue. One indicator of immune system maturation is the establishment of the immunological self, which describes the ability of the immune system to distinguish allogeneic individuals (allorecognition ability). However, the timing of immune system maturation during invertebrate ontogeny is poorly understood. In the sea star Patiria pectinifera, cells that have dissociated from the embryos and larvae are able to reconstruct larvae. This reconstruction phenomenon is possible because of a lack of allorecognition capability in the larval immune system, which facilitates the formation of an allogeneic chimera. In this study, we revealed that the adult immune cells of P. pectinifera (coelomocytes) have allorecognition ability. Based on a hypothesis that allorecognition ability is acquired before and after metamorphosis, we conducted detailed morphological observations and survival time analysis of metamorphosis-induced chimeric larvae. The results showed that all allogeneic chimeras died within approximately two weeks to one month of reaching the juvenile stage. In these chimeras, the majority of the epidermal cell layer was lost and the mesenchymal region expanded, but cell death appeared enhanced in the digestive tract. These results indicate that the immunological self of P. pectinifera is established post-metamorphosis during the juvenile stage. This is the first study to identify the timing of immune system maturation during echinodermal ontogenesis. As well as establishing P. pectinifera as an excellent model for studies on self- and non-self-recognition, this study enhances our understanding of the ontogeny of the immune system in invertebrates.

Speciation of Genes and Genomes: Conservation of DNA Polymorphism by Barriers to Recombination Raised by Mismatch Repair System

Some basic aspects of human and animal biology and evolution involve the establishment of biological uniqueness of species and individuals within their huge variety. The discrimination among closely related species occurs in their offspring at the level of chromosomal DNA sequence homology, which is required for fertility as the hallmark of species. Biological identification of individuals, i.e., of their biological “self”, occurs at the level of protein sequences presented by the MHC/HLA complex as part of the immune system that discriminates non-self from self. Here, a mechanistic molecular model is presented that can explain how DNA sequence divergence and the activity of key mismatch repair proteins, MutS and MutL, lead to 1) genetic separation of closely related species (sympatric speciation) (Fitch and Ayala, Proceedings of the National Academy of Sciences, 1994, 91, 6717–6720), 2) the stability of genomes riddled by diverged repeated sequences, and 3) conservation of highly polymorphic DNA sequence blocks that constitute the immunological self. All three phenomena involve suppression of recombination between diverged homologies, resulting in prevention of gene sharing between closely related genomes (evolution of new species) as well as sequence sharing between closely related genes within a genome (e.g., evolution of immunoglobulin, MHC, and other gene families bearing conserved polymorphisms).

The transcription factor Sox4 is required for thymic tuft cell development.

Medullary thymic epithelial cells (mTECs) help shape the thymic microenvironment for T-cell development by expressing a variety of peripheral tissue-restricted antigens (TRAs). The self-tolerance of T cells is established by negative selection of autoreactive T cells that bind to TRAs. To increase the diversity of TRAs, a fraction of mTECs terminally differentiates into distinct subsets resembling atypical types of epithelial cells in specific peripheral tissues. As such, thymic tuft cells that express peripheral tuft cell genes have recently emerged. Here, we show that the transcription factor SRY-box transcription factor 4 (Sox4) is highly expressed in mTECs and is essential for the development of thymic tuft cells. Mice lacking Sox4 specifically in TECs had a significantly reduced number of thymic tuft cells with no effect on the differentiation of other mTEC subsets, including autoimmune regulator (Aire)+ and Ccl21a+ mTECs. Furthermore, Sox4 expression was diminished in mice deficient in TEC-specific lymphotoxin β receptor (LTβR), indicating a role for the LTβR-Sox4 axis in the differentiation of thymic tuft cells. Given that Sox4 promotes differentiation of peripheral tuft cells, our findings suggest that mTECs employ the same transcriptional program as peripheral epithelial cells. This mechanism may explain how mTECs diversify peripheral antigen expression to project an immunological self within the thymic medulla.

Thymoproteasome and peptidic self.

Positive selection of T cells in the thymus is induced by low-affinity TCR recognition of self-peptide-MHC complexes expressed by cortical thymic epithelial cells (cTECs). cTECs express a specialized type of proteasomes, the thymoproteasome, which generates a unique spectrum of MHC class I-associated peptides and plays a critical role in thymic positive selection of CD8+ T cells. However, it remains unclear how the thymoproteasome contributes to the thymic positive selection. More than 30years ago, the "peptidic self" hypothesis proposed that TCRs recognize MHC-presented peptides only, without interacting with MHC molecules, which turned out to be incorrect. Interestingly, however, by implying that a set of MHC-associated peptides forms immunological self, this hypothesis also predicted that positive selection in the thymus is the primary immune response to "foreign epitope" peptides during T cell development. The thymoproteasome-dependent unique self-peptides may create those foreign epitope peptides displayed in the thymus for positive selection of T cells.

T cell responses to tumor: how dominant assumptions on immune activity led to a neglect of pathological functions, and how evolutionary considerations can help identify testable hypotheses for improving immunotherapy.

Cancer immunotherapy is based on the premise that activated, pro-inflammatory T cell responses to tumor will mostly combat tumor growth. Nowadays accepted as largely valid, this hypothesis has been formed as a result of extensive theoretical and experimental argumentation on the inherent function of the immune system and the nature of the immunological self, dating back to the foundations of immunology. These arguments have also been affected by how current working hypotheses were set by researchers, an issue that has been the focus of study by medical anthropologists. As a result of these processes, cancer immunotherapy has developed into a truly promising anti-cancer strategy, with very substantial benefits in clinical outcomes. However, as immunotherapy still has large margins for improvement, a more thorough examination of both the historical background and evolutionary context of current assumptions for how the immune system responds to cancer can help reveal novel, testable questions. We describe how attempting to answer some of these questions experimentally, such as identifying the contributors of tumor-associated fibrosis, has led to potentially useful insights on how to improve immunotherapy.

Major histocompatibility complex and its importance towards controlling infection

It is well documented that infectious pathogen burden and infected cell mass determine the clinical severity of infectious diseases, however, the ability of the host to recognize and process antigens to produce antibodies or the cellular immune response during infection could be under genetic control. The Major Histocompatibility Complex (MHC) or Human Leukocyte Antigen (HLA) system is the most intensively studied of all genetic systems because of its influence to many important traits, including resistance to infectious diseases, autoimmunity and immunological self or nonself compatibility. This is understandable in the light of the evolutionary pressure so that we are equipped to face the multitude of infectious challenges. Infectious diseases are a major selective pressure;and genes involved in the immune response are the most numerous and diverse in the human genome; reflecting the evolutionary advantages of a diverse immunological response to a wide range of infectious pathogens.Asian Journal of Medical Sciences Vol.8(2) 2017 1-13

A generalized quantitative antibody homeostasis model: antigen saturation, natural antibodies and a quantitative antibody network.

In a pair of articles, we present a generalized quantitative model for the homeostatic function of clonal humoral immune system. In this second paper, we describe how antibody production controls the saturation of antigens and the network of antibody interactions that emerges in the epitome space with the establishment of the immune system. Efficient control of antigens, be it self or foreign, requires the maintenance of antibody concentrations that saturate antigen to relevant levels. Simple calculations suggest that the observed diverse recognition of antigens by natural antibodies is only possible by cross-reactivity whereby particular clones of antibodies bind to diverse targets and shared recognition of particular antigens by multiple antibody clones contribute to the maintenance of antigen control. We also argue that natural antibodies are none else than the result of thymus-independent responses against immunological self. We interpret and explain antibody production and function in a virtual molecular interaction space and as a network of interactions. Indeed, the general quantitative (GQM) model we propose is in agreement with earlier models, confirms some assumptions and presumably provides the theoretical basis for the construction of a real antibody network using the sequence and interaction database data.

The Old One-Two: Solving the Mystery of Cognate Help.

The pivotal findings reported by Noelle et al. ([1][1]) in 1992 resolved a puzzle that had been 40 years in the making. In the mid-20th century, seminal studies from Owen ([2][2]), Medawar and colleagues ([3][3], [4][4]) and Burnet ([5][5]) established the concept of an immunological self, forcing

Induction of autoimmune disease by deletion of CTLA-4 in mice in adulthood

Cytotoxic T lymphocyte antigen-4 (CTLA-4) is essential for immunological (self-) tolerance, but due to the early fatality of CTLA-4 KO mice, its specific function in central and peripheral tolerance and in different systemic diseases remains to be determined. Here, we further examined the role of CTLA-4 by abrogating CTLA-4 expression in adult mice and compared the resulting autoimmunity that follows with that produced by congenital CTLA-4 deficiency. We found that conditional deletion of CTLA-4 in adult mice resulted in spontaneous lymphoproliferation, hypergammaglobulinemia, and histologically evident pneumonitis, gastritis, insulitis, and sialadenitis, accompanied by organ-specific autoantibodies. However, in contrast to congenital deficiency, this was not fatal. CTLA-4 deletion induced preferential expansion of CD4(+)Foxp3(+) Treg cells. However, T cells from CTLA-4-deficient inducible KO mice were able to adoptively transfer the diseases into T cell-deficient mice. Notably, cell transfer of thymocytes de novo produced myocarditis, otherwise not observed in donor mice depleted in adulthood. Moreover, CTLA-4 deletion in adult mice had opposing impacts on induced autoimmune models. Thus, although CTLA-4-deficient mice had more severe collagen-induced arthritis (CIA), they were protected against peptide-induced experimental autoimmune encephalomyelitis (EAE); however, onset of protein-induced EAE was only delayed. Collectively, this indicates that CTLA-4 deficiency affects both central and peripheral tolerance and Treg cell-mediated suppression.

Intronic regulation of Aire expression by Jmjd6 for self-tolerance induction in the thymus.

The thymus has spatially distinct microenvironments, the cortex and the medulla, where the developing T-cells are selected to mature or die through the interaction with thymic stromal cells. To establish the immunological self in the thymus, medullary thymic epithelial cells (mTECs) express diverse sets of tissue-specific self-antigens (TSAs). This ectopic expression of TSAs largely depends on the transcriptional regulator Aire, yet the mechanism controlling Aire expression itself remains unknown. Here, we show that Jmjd6, a dioxygenase that catalyses lysyl hydroxylation of splicing regulatory proteins, is critical for Aire expression. Although Jmjd6 deficiency does not affect abundance of Aire transcript, the intron 2 of Aire gene is not effectively spliced out in the absence of Jmjd6, resulting in marked reduction of mature Aire protein in mTECs and spontaneous development of multi-organ autoimmunity in mice. These results highlight the importance of intronic regulation in controlling Aire protein expression.

Single-cell transcriptome analysis reveals coordinated ectopic gene-expression patterns in medullary thymic epithelial cells.

Expression of tissue-restricted self-antigens (TRAs) in medullary thymic epithelial cells (mTECs) is essential for self-tolerance induction and prevents autoimmunity, with each TRA being expressed in only a few mTECs. How this process is regulated in single mTECs and coordinated at the population level, such that the varied single-cell patterns add up to faithfully represent TRAs, is poorly understood. Here we used single-cell RNA-sequencing and provide evidence for numerous recurring TRA co-expression patterns, each present in only a subset of mTECs. Co-expressed genes clustered in the genome and showed enhanced chromatin accessibility. Our findings characterize TRA expression in mTECs as a coordinated process, which might involve local re-modeling of chromatin and thus ensures a comprehensive representation of the immunological self.

Towards a Liquid Self: How Time, Geography, and Life Experiences Reshape the Biological Identity

The conceptualization of immunological self is amongst the most important theories of modern biology, representing a sort of theoretical guideline for experimental immunologists, in order to understand how host constituents are ignored by the immune system (IS). A consistent advancement in this field has been represented by the danger/damage theory and its subsequent refinements, which at present represents the most comprehensive conceptualization of immunological self. Here, we present the new hypothesis of “liquid self,” which integrates and extends the danger/damage theory. The main novelty of the liquid self hypothesis lies in the full integration of the immune response mechanisms into the host body’s ecosystems, i.e., in adding the temporal, as well as the geographical/evolutionary and environmental, dimensions, which we suggested to call “immunological biography.” Our hypothesis takes into account the important biological changes occurring with time (age) in the IS (including immunosenescence and inflammaging), as well as changes in the organismal context related to nutrition, lifestyle, and geography (populations). We argue that such temporal and geographical dimensions impinge upon, and continuously reshape, the antigenicity of physical entities (molecules, cells, bacteria, viruses), making them switching between “self” and “non-self” states in a dynamical, “liquid” fashion. Particular attention is devoted to oral tolerance and gut microbiota, as well as to a new potential source of unexpected self epitopes produced by proteasome splicing. Finally, our framework allows the set up of a variety of testable predictions, the most straightforward suggesting that the immune responses to defined molecules representing potentials antigens will be quantitatively and qualitatively quite different according to the immuno-biographical background of the host.

Therapeutic Effect of Human Amniotic Membrane–Derived Cells on Experimental Arthritis and Other Inflammatory Disorders

Rheumatoid arthritis (RA) is an autoimmune disease caused by loss of immunologic self tolerance and characterized by chronic joint inflammation. Cells isolated from human amniotic membrane (HAMCs) were recently found to display immunosuppressive properties. The aim of this study was to characterize the effect of HAMCs on antigen-specific T cell responses in RA patients and to evaluate their therapeutic potential in a preclinical experimental model of RA. We investigated the effects of HAMCs on collagen-reactive T cell proliferation and cytokine production, on the production of mediators of inflammation by synoviocytes, and on the generation of Treg cells in peripheral blood mononuclear cells and synovial membrane cells isolated from RA patients. Mice with collagen-induced arthritis (CIA) were treated with HAMCs after disease onset, and clinical scores and joint levels of mediators of inflammation were evaluated. We determined Th1/Th17-mediated autoreactive responses in the mice by measuring the proliferation and the cytokine profile of lymph node cells restimulated with collagen. Treatment with HAMCs suppressed synovial inflammatory responses and antigen-specific Th1/Th17 activation in cells isolated from RA patients. Moreover, HAMCs stimulated the generation of human CD4+CD25+FoxP3+ Treg cells with a capacity to suppress collagen-specific T cell responses. Systemic infusion of HAMCs significantly reduced the incidence and severity of CIA by down-regulating the 2 deleterious components of disease: Th1-driven autoimmunity and inflammation. In mice with CIA, HAMC treatment decreased the production of various inflammatory cytokines and chemokines in the joints, impaired antigen-specific Th1/Th17 cell expansion in the lymph nodes, and generated peripheral antigen-specific Treg cells. HAMCs also protected the mice from experimental sepsis, inflammatory bowel disease, and autoimmune encephalomyelitis. HAMCs have emerged as attractive candidates for a cell-based therapy for RA.

Overlapping gene coexpression patterns in human medullary thymic epithelial cells generate self-antigen diversity

Promiscuous expression of numerous tissue-restricted self-antigens (TRAs) in medullary thymic epithelial cells (mTECs) is essential to safeguard self-tolerance. A distinct feature of promiscuous gene expression is its mosaic pattern (i.e., at a given time, each self-antigen is expressed only in 1-3% of mTECs). How this mosaic pattern is generated at the single-cell level is currently not understood. Here, we show that subsets of human mTECs expressing a particular TRA coexpress distinct sets of genes. We identified three coexpression groups comprising overlapping and complementary gene sets, which preferentially mapped to certain chromosomes and intrachromosomal gene clusters. Coexpressed gene loci tended to colocalize to the same nuclear subdomain. The TRA subsets aligned along progressive differentiation stages within the mature mTEC subset and, in vitro, interconverted along this sequence. Our data suggest that single mTECs shift through distinct gene pools, thus scanning a sizeable fraction of the overall repertoire of promiscuously expressed self-antigens. These findings have implications for the temporal and spatial (re)presentation of self-antigens in the medulla in the context of tolerance induction.

T-regulatory cell-mediated immune tolerance as a potential immunotherapeutic strategy to facilitate graft survival.

T-regulatory cell-mediated immune tolerance as a potential immunotherapeutic strategy to facilitate graft survival.

The Immunologic Self

Immunology has been referred to as the science of self/non-self discrimination. Who or what is the "I" of which we often speak? It has been identified with body, brain, soul, and memories. There has been a diversity of ways to characterize the self, including denying its importance and existence, and to date no satisfactory conceptualization has been achieved. This article addresses the concept of self from an immunological perspective, a perspective that offers insights into the philosophic issues associated with the concept of self and personal identity. The article proposes that the immunological and the psychological are two aspects of one and the same self, offers criteria for an adequate conceptualization of the self, and discusses the philosophical and psychological implications of the immunological views of self. It concludes that we must move away from a simplistic, exclusively inward or mentalistic conception of the self.

Immune self-reactivity triggered by drug-modified HLA-peptide repertoire

Human leukocyte antigens (HLAs) are highly polymorphic proteins that initiate immunity by presenting pathogen-derived peptides to T cells. HLA polymorphisms mostly map to the antigen-binding cleft, thereby diversifying the repertoire of self-derived and pathogen-derived peptide antigens selected by different HLA allotypes. A growing number of immunologically based drug reactions, including abacavir hypersensitivity syndrome (AHS) and carbamazepine-induced Stevens-Johnson syndrome (SJS), are associated with specific HLA alleles. However, little is known about the underlying mechanisms of these associations, including AHS, a prototypical HLA-associated drug reaction occurring exclusively in individuals with the common histocompatibility allele HLA-B*57:01, and with a relative risk of more than 1,000 (refs 6, 7). We show that unmodified abacavir binds non-covalently to HLA-B*57:01, lying across the bottom of the antigen-binding cleft and reaching into the F-pocket, where a carboxy-terminal tryptophan typically anchors peptides bound to HLA-B*57:01. Abacavir binds with exquisite specificity to HLA-B*57:01, changing the shape and chemistry of the antigen-binding cleft, thereby altering the repertoire of endogenous peptides that can bind HLA-B*57:01. In this way, abacavir guides the selection of new endogenous peptides, inducing a marked alteration in 'immunological self'. The resultant peptide-centric 'altered self' activates abacavir-specific T-cells, thereby driving polyclonal CD8 T-cell activation and a systemic reaction manifesting as AHS. We also show that carbamazepine, a widely used anti-epileptic drug associated with hypersensitivity reactions in HLA-B*15:02 individuals, binds to this allotype, producing alterations in the repertoire of presented self peptides. Our findings simultaneously highlight the importance of HLA polymorphism in the evolution of pharmacogenomics and provide a general mechanism for some of the growing number of HLA-linked hypersensitivities that involve small-molecule drugs.

Francisco Varela and the Immunological Self

Francisco Varela, a leading neurobiologist and cognitive scientist, made a 10‐year‐long incursion into immunology. His in‐depth contributions aimed to develop a systemic description to replace the standard stimulus/response/regulation scaffold that has governed immunology since its inception in the 19th century. Many of these efforts involved expansions of the notions introduced by Niels Jerne in his idiotypic network theory (Jerne, 1974a, 1974b) with the added notion of organizational closure, derived from the autopoietic theory. However, today, just like yesterday, the immunological community remains inclined to neglect these efforts and instead rests satisfied with half‐a‐century old clonal selection concepts (Burnet, 1959). Copyright © 2011 John Wiley & Sons, Ltd.

Systemic lupus erythematosus, regulatory T cells and pregnancy

Systemic lupus erythematosus (SLE) is the most common autoimmune disease affecting women of reproductive age and is associated with poor maternal and fetal outcomes. CD4+CD25+ Treg cells are a subset of T lymphocytes with potent immunosuppressive activity that play crucial roles in controlling immunological self tolerance. Evidence suggests that they are augmented in pregnancy, especially in the first trimester, suggesting an important role in early placental development. The literature describing Treg cells in SLE is conflicting, but SLE is associated with reduced numbers and functionally defective Treg cells, which may predispose pregnant women with the disease to pregnancy complications. This article discusses the role of Treg cells in SLE and pregnancy, and how these cells may contribute to poor pregnancy outcome in SLE-affected women.

CD4+CD25+ regulatory T cells in systemic sclerosis and other rheumatic diseases

Systemic sclerosis (SSc) is a generalized connective tissue disorder, characterized by a wide spectrum of microvascular and immunological abnormalities, leading to a progressive thickening and fibrosis of the skin and other organs, such as the lungs, GI tract, heart and kidneys. SSc is thought to be an autoimmune disease owing to the presence of high affinity antibodies and possible clinical overlap with other autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. Autoimmune diseases arise because of a breakdown in immunological self tolerance. Self tolerance is maintained via multiple regulatory mechanisms within the immune system, including the thymic deletion of self-reactive T cells and mechanisms of peripheral tolerance. In recent years, the presence of CD4+CD25+FOXP3+ Tregs has been identified as a major mechanism of peripheral tolerance, and accumulating evidence indicates that alterations in Treg frequencies and/or function may contribute to autoimmune diseases. Here, we will review recent data on the percentage, function and phenotype of CD4+CD25+ Tregs in rheumatic disease, and discuss how recent developments may guide research in this area in SSc.