Estrogen receptor alpha is necessary in thymic development and estradiol-induced thymic alterations.

Estrogens affect the development, maturation, and function of multiple organ systems, including the immune system. One of the main targets of estrogens in the immune system is the thymus, which undergoes atrophy and phenotypic alterations when exposed to elevated levels of estrogen. To determine how estrogens influence the thymus and affect T cell development, estrogen receptor alpha (ERalpha) knockout (ERKO) mice were examined. ERKO mice have significantly smaller thymi than their wild-type (WT) littermates. Construction of ER radiation bone marrow chimeras indicated that the smaller thymi were due to a lack of ERalpha in radiation-resistant tissues rather than hemopoietic elements. ERKO mice were also susceptible to estradiol-induced thymic atrophy, but the extent of their atrophy was less than what was seen in WT mice. The estradiol-treated ERKO mice failed, however, to manifest alterations in their thymic CD4/CD8 phenotypes compared with WT mice. Therefore, ERalpha is essential in nonhemopoietic cells to obtain a full-sized thymus, and ERalpha also mediates some of the response of the thymus to elevated estrogen levels. Finally, these results suggest that in addition to ERalpha, another receptor pathway is involved in estradiol-induced thymic atrophy.     

Athyreotic cretinism associated with thymic hypoplasia and amyloidosis of lymphoid tissue

A child presenting at 5 months of age with Hemophilus influenzae meningitis was also found to be severely hypothyroid. The child died two years later from the complications of measles pneumonia. At autopsy, no thyroid tissue was found and the thymus was hypoplastic. Most of the lymphoid tissues were infiltrated by amyloid.It is possible that there was a combined developmental defect involving thyroid and thymus. The alternatives are that the association occurred purely by chance or that the severe hypothyroid state led to thymic insufficiency.     

p73 is expressed in human thymic epithelial cells.

The thymus is a heterogeneous immune organ in which immature T-cells develop and eventually specialize to make certain immune responses of their own. Among various types of stromal cells in the thymus, thymic epithelial cells (TECs) have a crucially important function for presenting self-antigens and secreting cytokines to thymocytes for their maturation into T-cells. In this study we show that the p73 gene, a homologue of the tumor suppressor gene p53, was expressed in the nucleus of the human TEC in vivo and in TEC lines in vitro. Because p73 has the capacity to be a transactivator like p53, it may contribute to T-cell development in the context of TEC biology as regulated in the cell cycle and apoptosis.     

Morphine-induced mu-opioid receptor rapid desensitization is independent of receptor phosphorylation and beta-arrestins

Receptor desensitization involving receptor phosphorylation and subsequent betaArrestin (betaArr) recruitment has been implicated in the tolerance development mediated by mu-opioid receptor (OPRM1). However, the roles of receptor phosphorylation and betaArr on morphine-induced OPRM1 desensitization remain to be demonstrated. Using OPRM1-induced intracellular Ca(2+) ([Ca(2+)](i))release to monitor receptor activation, as predicted, [D-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin (DAMGO), induced OPRM1 desensitization in a receptor phosphorylation- and betaArr-dependent manner. The DAMGO-induced OPRM1 desensitization was attenuated significantly when phosphorylation deficient OPRM1 mutants or Mouse Embryonic Fibroblast (MEF) cells from betaArr1 and 2 knockout mice were used in the studies. Specifically, DAMGO-induced desensitization was blunted in HEK293 cells expressing the OPRM1S375A mutant and was eliminated in MEF cells isolated from betaArr2 knockout mice expressing the wild type OPRM1. However, although morphine also could induce a rapid desensitization on [Ca(2+)](i) release to a greater extent than that of DAMGO and could induce the phosphorylation of Ser(375) residue, morphine-induced desensitization was not influenced by mutating the phosphorylation sites or in MEF cells lacking betaArr1 and 2. Hence, morphine could induce OPRM1 desensitization via pathway independent of betaArr, thus suggesting the in vivo tolerance development to morphine can occur in the absence of betaArr.     

The human thymic microenvironment: cortical thymic epithelium is an antigenically distinct region of the thymic microenvironment

The thymic microenvironment is a complex tissue essential for normal T cell maturation. Prothymocytes in the subcapsular cortical (SCC) region of the thymus undergo cell division and migrate to the inner cortex. The majority of cortical thymocytes cease dividing and die, but a minority are exported to the periphery. We have previously shown thymic hormones in SCC and medullary thymic epithelium and have identified a monoclonal antibody (TE-4) that defines human endocrine thymic epithelium. However, no marker that selectively defines cortical thymic epithelium has been available. In this study, we have produced two monoclonal antibodies, TE-3A and TE-3B, raised against human thymic stroma that bind to an intracellular antigen in cortical but not medullary thymic epithelium. In double immunofluorescence assays in which we used anti-keratin, anti-thymosin alpha 1, and anti-endocrine thymic epithelium antibodies (TE-4, A2B5), TE-3+ SCC epithelium was TE-4+ and contained keratin and thymosin. alpha 1. In contrast, TE-3+ inner cortical epithelium was TE-4/A2B5 nonreactive and did not contain thymosin alpha 1. An ontogeny study of seven fetal and five neonatal thymuses demonstrated that expression of the TE-3 antigen was acquired at 10 wk fetal gestation. Using TE-3 antibody, we observed sequential stages of separation of cortical and medullary epithelium from 12 to 20 wk fetal gestation. In dysplastic (severe combined immunodeficiency disease) thymuses, strands of TE-3+ nonendocrine cells encircled nests of TE-4+ endocrine epithelium. Thus, human cortical thymic epithelium is antigenically distinct from endocrine medullary epithelium. Antibodies against the TE-3 antigen define an intracellular molecule that may reflect a specialized function of cortical thymic epithelium.     

In vivo administration of IL-1 induces thymic hypoplasia and increased levels of serum corticosterone

Administration of IL-1 alpha or IL-1 beta to normal mice induces a decrease in thymic cellularity, the magnitude of which depends on the number of injections and dose of IL-1. Twice daily injections of 200 ng of IL-1 alpha or -beta for 4 days results in a 90% decrease in thymic cellularity, which regenerated after cessation of treatment. Study of thymocyte subpopulations revealed that the number of CD4+/CD8+ thymocytes was dramatically decreased in IL-1-treated mice. Functional assessment of the CD4-/CD8- population from treated animals showed that these cells had adequate mitogenic responses in vitro and that the proportion of these cells in cycle was not different from control CD4-/CD8- cells. IL-1 treatment also prevented the regeneration of thymic cellularity after irradiation. The use of strains of mice differing genetically at the Ly 1 locus to construct radiation bone marrow chimeras demonstrated that bone marrow-derived thymocyte precursors were able to seed the thymus in the IL-1-treated animals. Again, however, the CD4+/CD8+ thymocyte population was significantly decreased. Thymic repopulation occurred upon cessation of IL-1 therapy. Finally, we determined that a single i.p. injection of IL-1 caused a three-fold increase in serum corticosterone levels, which peaked approximately 3 h after IL-1 administration. Thus, an IL-1-dependent increase in serum corticosterone levels may be responsible for the observed thymic hypoplasia.     

Morphine-induced immune alterations in vivo

The high incidence of human immunodeficiency virus (HIV) seropositivity among drug abusers prompted us to examine in an animal model the effects of morphine on aspects of the immune system that may be specifically related to HIV infection. We now report a robust, sustained elevation in the ratio of CD4+/CD8+ cells in the spleen and thymus of mice chronically treated with morphine. Since CD4+ cells have been reported to be target cells for HIV, these alterations, in concert with a marked cellular atrophy that appears to be restricted to organs of the immune system, suggest that opiates may serve as cofactors in altering the immune status of the host and thus contribute to the increased susceptibility to HIV infection and eventual development of AIDS in opiate abusers.     

Early hominid enamel hypoplasia.

Enamel hypoplasia in the South African Plio-Pleistocene fossil hominid sample is examined. The Swartkrans hominids are shown to have a higher incidence of hypoplasia than the Sterkfontein hominids. Within the Swartkrans sample, individuals with hypoplasia of the first upper molar have lower-than-expected ages of death. Possible taphonomic explanations for these observations are discussed.     

Avian thymic hormone (ATH) is a parvalbumin

Amino acid sequence analysis of a protein from chicken thymus tissue which promotes immunological maturity in chicken bone marrow cells in culture has established sequences of a 45-residue fragment, a 24-residue fragment and a 9-residue and an 8-residue peptide. Independent comparison of the 45- and 24-residue fragments with known amino acid sequences by computer search has unequivocally identified avian thymic hormone as a parvalbumin. This is the first demonstration that a protein previously identified by a biological function is a parvalbumin.     

Questionable thymic nurse cell.

Since their discovery in 1980, thymic nurse cells (TNCs) have been controversial. Questions pertaining to the existence of the TNC as a "unit" cell with thymocytes completely enclosed within its cytoplasm were the focus of initial debates. Early skeptics proposed the multicellular complex to be an artifact of the procedures used to isolate TNCs from the thymus. Since that time, TNCs have been found in fish, frogs, tadpoles, chickens, sheep, pigs, rats, mice, and humans. Their evolutionary conservation throughout the animal kingdom relieved most speculations about the existence of TNCs and at the same time demonstrated their apparent importance to the thymus and T-cell development. In this review we will discuss and debate reports that describe (i) the organization or structure of TNCs, (ii) the thymocyte subset(s) found within the cytoplasm of TNCs and their uptake and release, and (iii) the function of this fascinating multicellular interaction that occurs during the process of T-cell development. Discussions about the future of the field and experimental approaches that will lead to answers to remaining questions are also presented.     

Membrane immunoglobulin is present on thymic and splenic lymphocytes of the trout Salmo gairdneri.

Three rabbit antisera raised to trout IgM showed positive immunofluorescent reactions with lymphocytes of trout spleen and thymus. These antisera showed no detectable cross-reactivity with keyhole limpet hemocyanin, as determined by direct radioimmune precipitation and adsorption, and did not appear to react significantly with carbohydrate moieties on trout IgM, as determined by the failure of proteolytic digests of trout IgM to inhibit in radioimmunoassay against intact trout IgM. Membrane immunoglobulin determinants were detectable on the membrane of both thymocytes and splenocytes with the lactoperoxidase-catalyzed iodination reaction. Radioimmunoassay of lysates of lymphocytes confirmed the association of immunoglobulin with trout thymocytes. By radioimmunoassay, lysates of thymic and splenic lymphocytes contained similar amounts of immunoglobulin, equivalent to approximately 8 X 10(4) molecules of IgM per cell (calculated as the monomer micro 2L2).     

Tolerance to proinsulin-2 is due to radioresistant thymic cells

Proinsulin is a key Ag in type 1 diabetes, but the mechanisms regulating proinsulin immune tolerance are unknown. We have shown that preproinsulin-2 gene-deficient mice (proins-2(-/-)) are intolerant to proinsulin-2. In this study, we analyzed the mechanisms underlying T cell-mediated tolerance to proinsulin-2 in 129/Sv nonautoimmune mice. The expression of one proinsulin-2 allele, whatever its parental origin, was sufficient to maintain tolerance. The site of proinsulin-2 expression relevant to tolerance was evaluated in thymus and bone marrow chimeras. CD4+ T cell reactivity to proinsulin-2 was independent of proinsulin-2 expression in radiation-sensitive bone marrow-derived cells. A wt thymus restored tolerance in proins-2(-/-) mice. Conversely, the absence of the preproinsulin-2 gene in radioresistant thymic cells was sufficient to break tolerance. Although chimeric animals had proinsulin-2-reactive CD4+ T cells in their peripheral repertoire, they displayed no insulitis or insulin Abs, suggesting additional protective mechanisms. In a model involving transfer to immunodeficient (CD3epsilon(-/-)) mice, naive and proinsulin-2-primed CD4+ T cells were not activated, but could be activated by immunization regardless of whether the recipient mice expressed proinsulin-2. Furthermore, we could not identify a role for putative specific T cells regulating proinsulin-2-reactive CD4+ T in transfer experiments. Thus, proinsulin-2 gene expression by radioresistant thymic epithelial cells is involved in the induction of self-tolerance, and additional factors are required to induce islet abnormalities.     

Hypothalamic control of thymic function.

Removal of the pituitary gland results in atrophy of the thymus. As the former is under the control of hypothalamus, destruction of anterior portion of the hypothalamus (AHTL) would be expected to negatively influence the thymic function. Contrary to our expectation, however, the thymus became hypertrophic and serum level of growth hormone (GH) markedly increased, when the anterior portion of the hypothalamus was destroyed in rats at 1 month of age and older. The results suggested that AHTL removed the cells secreting GHRIH (growth hormone release inhibitory hormone), but not GHRH (growth hormone releasing hormone), leading to increased pituitary secretion of GH. This high serum level of GH appeared to be responsible for the thymic hyperplasia occurring after AHTL. In other words, the development and aging of the thymus appear to be dependent on the serum level of GH which is under the balance of positive (GHRH) and negative (GHRIH) signals from the hypothalamus. In rats and mice, the serum level of GH is very high just after birth, quickly declines in young adults and does not change greatly thereafter. Thus, it is likely that the initial positive signal is high just after birth and decreasing thereafter with a concomitant increase of negative signal, leading to the onset ofthymic atrophy at around puberty, in association with sex steroid release.     

T-T interaction during thymic selection.

During thymic development, immature thymocytes are selected through the interaction with self peptides loaded on self MHC molecules. Although there is a great deal of debates on how specifically thymocytes recognize self peptides during thymic selection, recent data suggest an important role of peptide diversity in selecting an adequate T-cell repertoire in the thymus. The findings that human T-cells, unlike mouse T-cells, express MHC class II molecules on their surfaces and can play as antigen presenting cells suggesting possible peripheral T-T interaction network has not been intensively studied so far. However, the facts that human thymocytes have surface expression of MHC class II molecules and thymocytes can be selected by thymocytes in in vitro re-aggregation culture system led us to propose a novel hypothesis - "T-T interaction during thymic selection". Our proposition is that peripheral T-T interaction through TCR-derived peptides might reflect the selection process in the thymus and that T-T interaction also plays an important role in thymic selection. This review deals with our thymic T-T interaction hypothesis and its implications on human T-cell development.     

Multiple ophthalmic anomalies and digital hypoplasia.

Multiple congenital eye and hand anomalies occurred in a young female born to normal but consanguineous parents. Both eyes were microphthalmic with severe corneal, iris lens pathology. Ultrasonography revealed multiple echos from the vitreous. The ocular findings are suggestive of retinal dysplasia. A skeletal dysplasia, presenting as distal phalangeal hypoplasia, was found in both hands. There was no history of intrauterine exposure to drugs. This appears to be a unique association of congenital malformations, without other systemic involvement. Diagnostic and genetic implications are discussed.