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)

The thymus gland, which plays a key role in the maturation and functioning of the lymphoid system, is implicated in the acquired immune deficiency syndrome (AIDS). The observation that the thymic hormone, thymosin α1, is elevated in individuals at risk for AIDS (as opposed to being depressed in other immunodeficient states) has provided the first direct evidence that the thymus is malfunctioning early in the course of this deadly disease. These observations have been valuable in screening for the (...) syndrome with a rapid radioimmunoassay and in the initiation of the first clinical trials with thymosin in high risk homosexuals and hemophiliacs. If the progressive immune paralysis in AIDS is due to a dying thymus, the early identification of asymptomatic carriers of AIDS or individuals with modest AIDS‐related dysfunction may lead to therapy with thymosin or other thymomimetic agents that can restore immune function and prevent the onset of frank AIDS. (shrink)

The thymus has been an enigmatic organ for centuries. Its true function was revealed only in 1961 when it was shown to be responsible for the proper development of the immune system. This finding has revolutionized the science of immunology and has led to a better understanding of the mechanisms involved in resistance to infections and of the pathogenesis of autoimmune and immunodeficiency diseases.

The differentiation of T Lymphocytes within the thymus is an important biological phenomenon during wich these cell acquire their functions to further control the immune system. Numerous experiments under various conditions have been devised to understand the different mechanisms involved in this complex process. Nevertheless, interpretation of these experiments lead to still contradictory debatable hypotheses. Modelisation of this process through classical simulation methods cannot be envisaged because they are not adapted to modifications of the model structure, which is the (...) point of interest. For these reasons, we proposed a new approach of automatic search for model. The program consists of four independent connected modules : The generator produces model, based on the rationale of formal grammars. Protocol and experimental data are stored in a set of experiments. The simulator using a protocol and a model provides simulated results. Finally, the supervisor by comparing simulated results and experimental data, adapts the model parameters to increase their fit and either chooses a new experiment to explore, or modifies the model structure. Change of the model structure is performed among still unexplored models according to their promise level, which is iteratively evaluated relatively to previously explored models through a proposed model distance. The generator is written in Prolog and the other modules in C++. The architecture of the program allows us to modify or complete a module without changing anything in the other modules. As a consequence, the proposed modeling approach conceived to study T lymphocyte differentiation within the thymus remains independent of this biological phenomenon and can be applied to other biological problems. (shrink)

The differentiation of T lymphocytes, the cells that are responsible for cell‐mediated immunity, takes place within the thymus, but details of the developmental pathway have long been obscure. Although distinct subpopulations of thymocytes had been characterized, they acted like separate developmental streams rather than sequential differentiation stages. Recently, a minor subgroup of thymocytes representing an earlier blast population has been identified, offering the hope that the key developmental events will be discerned by focus on this new population of precursor (...) cells. (shrink)

In lieu of an abstract, here is a brief excerpt of the content:Fetal Tissue ResearchMary Carrington Coutts (bio)I. IntroductionThe use of tissue from fetal remains for transplantation and biomedical research has become a controversial issue in recent years, involving scientists, doctors, patients, and the federal government. Fetal tissue is potentially useful in a wide range of treatments for a number of serious diseases, some of them affecting millions of people. Despite the promise, transplantation research using fetal tissue from induced abortion (...) slowed dramatically in the U.S. in 1988, when a moratorium was declared on federal funding for such research involving humans. That moratorium was lifted by President Clinton on January 21, 1993. Though the future of fetal tissue transplantation research is brighter, public debate on the issue is likely to continue, exacerbated by the "acrimonious abortion debate" (VI, Post 1991, p. 14).Using fetal tissue in biomedical research and in transplantation is not a new practice. As early as 1928 unsuccessful attempts were made to transplant fetal pancreas cells into diabetics (VII, Fichera 1928). Fetal tissue was used effectively in biomedical research during the 1950s, and was instrumental in the culture of the polio virus, which led to the development of the polio vaccine. Fetal tissue cultures were also essential in the development of the rubella vaccine, and continue to be used in virology research. Transplantation of fetal thymus cells into patients with DiGeorge Syndrome has been recognized as effective therapy since the late 1960s.Many of the therapeutic applications involving fetal tissue are still experimental, so it is difficult to pinpoint fetal tissue transplantation's therapeutic potential. One promising application is the transplantation of human fetal brain cells into the substantia nigra of patients with Parkinson's disease to restore motor function. Fetal neural transplants have also shown promise for patients suffering from Alzheimer's disease, spinal cord and other neural tissue injuries, and possibly some forms of cortical blindness. Fetal liver cells may be useful for treatment of some kinds of bone marrow disease seen in leukemia and aplastic anemia patients. [End Page 81] Fetal tissue transplantation may also help those suffering from blood clotting disorders, such as sickle cell anemia, thalassemia, and hemophilia. Fetal pancreatic tissue has potential applications in the treatment of diabetes, especially juvenile onset diabetes. Human gene therapy may also employ embryonic and early fetal cells.The Center for Biomedical Ethics at the University of Minnesota reports that more than 1,000 patients have received transplanted fetal tissue worldwide. Countries where fetal tissue transplantation has occurred include: Australia, Canada, China, the Commonwealth of Independent States (formerly the U.S.S.R.), Cuba, Czechoslovakia, Finland, France, Germany, Great Britain, Hungary, India, Italy, Mexico, Norway, Spain, Sweden, and Yugoslavia (IV, Vawter 1992, p. 2; I, Spain 1988; VII, Reinikainen 1989).Fetal tissue has unique characteristics that make it especially valuable in some treatments. Fetal cells develop much faster than adult cells, hastening the therapeutic effect—a potentially significant benefit for gravely ill patients. They are also less likely to be rejected by transplant recipients because they are less antigenic than adult cells. This reduces the need for the exact tissue matches that can be so difficult to obtain. Fetal tissue is also easier to culture and proliferates more readily than comparable adult tissue. Furthermore, fetal tissue is in greater supply, due to the number of elective abortions.Questions about the use of fetuses and fetal tissue in biomedical research were raised in the United States in the early 1970s. Between 1969 and 1973, all 50 states enacted the Uniform Anatomical Gift Act, allowing for the donation of all or part of the body of a dead fetus for research or therapeutic research. Prospects for the use of fetal tissue increased after the Supreme Court decision in Roe v. Wade legalized abortion. As the availability of fetal tissue increased so did the concern over the potential for controversial research on living, soon-to-be-aborted fetuses, and anxiety over maltreatment of dead abortuses. Vivid examples include Geoffrey Chamberlain's 1968 report of an experiment on a fetus of 26 weeks gestational age. Delivered by hysterotomy from a 14-year-old patient, the fetus was attached to an "artificial placenta" and kept alive for more than... (shrink)

This study provides an integrated analysis of ϑυμός. A psychosomatic concept, found in Greek epics and medicine, θυμός designates courage as a “vital force around the chest”. Later, its meaning has been specified in two fields: 1) ϑυμός, thymós, the irascible soul, parallel to the concupiscible soul and opposite to the rational one, according to Plato’s tripartition; 2) ϑύμος, thymus, a cardiac gland of the vascular system. Today, the idea that θυμός, courage, and ϑύμος, cardiac gland, could have a (...) common semantic root – θύειν “to sacrifice by blowing and burning” – seems almost impossible. Our aim is to reconstitute the concept of ϑυμός, demonstrating how it has been reduced to a polarisation rational/irrational, and marginalised. We will examine the notion of ϑυμός in Greek tradition and describe one of its widespread manifestations, tattooing, both as a painful solicitation of interiority and for how the tattooed pictures reflect the personality of their wearers. (shrink)

T cells, which are derived from hematopoietic stem cells (HSCs), are the most important components of adaptive immune system. Based on the expression of αβ and γδ receptors, T cells are mainly divided into αβ and γδ T cells. In the thymus, they share common progenitor cells, while undergoing a series of well‐characterized and different developmental processes. N6‐Methyladenosine (m6A), one of the most abundant modifications in mRNAs, plays critical roles in cell development and maintenance of function. Recently, we have (...) demonstrated that the depletion of m6A demethylase ALKBH5 in lymphocytes specifically induces an expansion of γδ T cells through the regulation of Jag1/Notch2 signaling, but not αβ T cells, indicating a checkpoint role of ALKBH5 and m6A modification in the early development of γδ T cells. Based on previous studies, many key pathway molecules, which exert dominant roles in γδ T cell fate determination, have been identified as the targets regulated by m6A modification. In this review, we mainly summarize the potential regulation between m6A modification and these key signaling molecules in the γδ T cell lineage commitment, to provide new perspectives in the checkpoint of γδ T cell development. (shrink)

During the 1890s, animal development became associated with glandular activity, with profound implications for pediatric nosology and treatment. The significance of this endocrinological turn of developmental physiology and pathophysiology in part hinges on an often-overlooked continuity with ubiquitous early modern medical thought concerning semen as a recrementitious (reabsorbed) nutrient or stimulant. Mid-19th-century interests in adult sexual physiology were increasingly nerve-centered and antihumoral. Scattered empirical, particularly veterinarian, interests in gonadal developmental functions failed to moderate these explanatory trends. While Brown-Séquard’s rejuvenation experiments (...) still offered no clear starting point for a developmental endocrinology, in 1892 Gaston Variot and Paul Bezançon more explicitly deduced a testicular developmental endocrinological function from various observations on testicular ectopy and a local form of animal “demi-castration.” Ensuing interest in the thyroid, the thymus and in the testicles led to various working conceptions of their respective and putatively reciprocal developmental properties, including the idea of a thyroid–testis axis. From 1896, the pubertal affliction of chlorosis became the subject of multiple opotherapeutic approaches, providing an experimental basis for theories of ovarian internal secretion. Polyglandular therapy, piloted for divergent developmental conditions, remained routine until the 1930s despite the biological inefficacy of many endocrine products. (shrink)

Establishment of cell lineage identity from multipotent progenitors is controlled by cooperative actions of lineage‐specific and stably expressed transcription factors, combined with input from environmental signals. Lineage‐specific master transcription factors activate and repress gene expression by recruiting consistently expressed transcription factors and chromatin modifiers to their target loci. Recent technical advances in genome‐wide and multi‐omics analysis have shed light on unexpected mechanisms that underlie more complicated actions of transcription factors in cell fate decisions. In this review, we discuss functional dynamics (...) of stably expressed and continuously required factors, Notch and Runx family members, throughout developmental stages of early T cell development in the thymus. Pre‐ and post‐commitment stage‐specific transcription factors induce dynamic redeployment of Notch and Runx binding genomic regions. Thus, together with stage‐specific transcription factors, shared transcription factors across distinct developmental stages regulate acquisition of T lineage identity. (shrink)

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