The thyroid-pituitary homeostatic mechanism

The paper develops a mathematical theory of thyroid-pituitary interaction. It is assumed that the pituitary gland produces thyrotropin, which activates an enzyme of the thyroid gland. The rate of production of thyroid hormone is considered to be proportional to the concentration of that enzyme. It is further assumed that in the absence of the thyroid hormone the rate of production of thyrotropin is constant, but, in general, it is a linear function of the concentration of the thyroid hormone. This picture leads to a system of non-linear differential equations, which present great difficulties. This system, however, may be conveniently “linearized”, by considering that the relations between different variables are linear, but that within different ranges of the variables the coefficients are different. Using this approximation, it is possible to show that the system admits periodic solutions of the nature of relaxation oscillations. Such oscillations are actually observed in some mental disorders, such as periodic catatonia. The study of the effects of different parameters of the system suggests different possible approaches to clinical treatment. In the light of this theory, the experimental determination of the parameters of the system becomes desirable and important.     

Decline in excision circles requires homeostatic renewal or homeostatic death of naive T cells

When the TCR is formed in the thymus, fragments of DNA are excised from the T cell progenitor chromosome. These TCR rearrangement excision circles (TRECs) are stable, are not replicated in cell division and are therefore most frequent in naive T cells that have recently left the thymus. During life, the average TREC content of peripheral naive T cells decreases between one and two orders of magnitude in humans. It is generally believed that the age-dependent decrease in the production of naive T cells by the thymus is sufficient to explain the decrease in the TREC content. Here, we demonstrate that this decrease in thymic production is required, but it is not sufficient to explain the TREC data. Only if the decrease in thymic output is compensated by homeostasis can one explain the decrease in the TREC content. The homeostatic response can take two forms: when the total number of naive T cells declines, there could be an increase in the renewal rate or an increase of the average cellular lifespan.     

Apoptotic cells induce a phosphatidylserine-dependent homeostatic response from phagocytes

Engulfment of apoptotic cells by phagocytes is important throughout development and adult life. When phagocytes engulf apoptotic cells, they increase their cellular contents including cholesterol and phospholipids, but how the phagocytes respond to this increased load is poorly understood. Here, we identify one type of a phagocyte response, wherein the recognition of apoptotic cells triggers enhanced cholesterol efflux (to apolipoprotein A-I) from macrophages. Phosphatidylserine (PS) exposed on apoptotic cells was necessary and sufficient to stimulate the efflux response. A major mechanism for this enhanced efflux by macrophages was the upregulation of the mRNA and protein for ABCA1, a membrane transporter independently linked to cholesterol efflux as well as engulfment of apoptotic cells. This increase in phagocyte ABCA1 levels required the function of nuclear receptor LXRalpha/beta, a known regulator of cholesterol homeostasis in humans and mice. Taken together, these data reveal a "homeostatic program" initiated in phagocytes that include a proximal membrane signaling event initiated by PS recognition, a downstream signaling event acting through nuclear receptors, and an effector arm involving upregulation of ABCA1, in turn promoting reverse cholesterol transport from the phagocytes. These data also have implications for macrophage handling of contents derived from apoptotic versus necrotic cells in atherosclerotic lesions.     

Bone marrow is a preferred site for homeostatic proliferation of memory CD8 T cells

Proliferative renewal of memory CD8 T cells is essential for maintaining long-term immunity. In this study, we examined the contributions that various tissue microenvironments make toward the homeostatic proliferation of Ag-specific memory CD8 T cells. We found that dividing memory T cells were present in both lymphoid and nonlymphoid tissues. However, the bone marrow was the preferred site for proliferation and contained a major pool of the most actively dividing memory CD8 T cells. Adoptive transfer studies indicated that memory cells migrated through the bone marrow and divided there preferentially. These results show that the bone marrow is not only the source of stem cells for generating naive T cells but also provides the necessary signals for the self-renewal of memory T cells.     

The role of IL-5 for mature B-1 cells in homeostatic proliferation, cell survival, and Ig production

B-1 cells, distinguishable from conventional B-2 cells by their cell surface marker, anatomical location, and self-replenishing activity, play an important role in innate immune responses. B-1 cells constitutively express the IL-5R alpha-chain (IL-5Ralpha) and give rise to Ab-producing cells in response to various stimuli, including IL-5 and LPS. Here we report that the IL-5/IL-5R system plays an important role in maintaining the number and the cell size as well as the functions of mature B-1 cells. The administration of anti-IL-5 mAb into wild-type mice, T cell-depleted mice, or mast cell-depleted mice resulted in reduction in the total number and cell size of B-1 cells to an extent similar to that of IL-5Ralpha-deficient (IL-5Ralpha(-/-)) mice. Cell transfer experiments have demonstrated that B-1 cell survival in wild-type mice and homeostatic proliferation in recombination-activating gene 2-deficient mice are impaired in the absence of IL-5Ralpha. IL-5 stimulation of wild-type B-1 cells, but not IL-5Ralpha(-/-) B-1 cells, enhances CD40 expression and augments IgM and IgG production after stimulation with anti-CD40 mAb. Enhanced IgA production in feces induced by the oral administration of LPS was not observed in IL-5Ralpha(-/-) mice. Our results illuminate the role of IL-5 in the homeostatic proliferation and survival of mature B-1 cells and in IgA production in the mucosal tissues.     

Anti-inflammatory intravenous immunoglobulin (IVIg) suppresses homeostatic proliferation of B cells

An intravenous injection of plasma-derived immunoglobulins is used for the treatment of severe infectious and autoimmune disorders. Despite of its clinical efficacy, precise mechanisms by which intravenous immunoglobulin (IVIg) suppresses proinflammatory immune response are still enigmatic. Here, we provide in vitro evidence that IVIg inhibits homeostatic proliferation of B cells accompanied by induction of their cell aggregation. The IVIg-driven suppression of B cell proliferation and induction of cell aggregation are both unaffected by treatment with a neutralizing antibody against low-affinity Fc receptors for IgG (CD16/FcγRIII and CD32/FcγRII), known cell surface ligands for IVIg. Our observations propose a new immunosuppressive action of IVIg, which directly acts on steady-state B cells to suppress their homeostatic expansion.     

Protein energy malnutrition impairs homeostatic proliferation of memory CD8 T cells

Nutrition is a critical but poorly understood determinant of immunity. There is abundant epidemiological evidence linking protein malnutrition to impaired vaccine efficacy and increased susceptibility to infections; yet, the role of dietary protein in immune memory homeostasis remains poorly understood. In this study, we show that protein-energy malnutrition induced in mice by low-protein (LP) feeding has a detrimental impact on CD8 memory. Relative to adequate protein (AP)-fed controls, LP feeding in lymphocytic choriomeningitis virus (LCMV)-immune mice resulted in a 2-fold decrease in LCMV-specific CD8 memory T cells. Adoptive transfer of memory cells, labeled with a division tracking dye, from AP mice into naive LP or AP mice demonstrated that protein-energy malnutrition caused profound defects in homeostatic proliferation. Remarkably, this defect occurred despite the lymphopenic environment in LP hosts. Whereas Ag-specific memory cells in LP and AP hosts were phenotypically similar, memory cells in LP hosts were markedly less responsive to polyinosinic-polycytidylic acid-induced acute proliferative signals. Furthermore, upon recall, memory cells in LP hosts displayed reduced proliferation and protection from challenge with LCMV-clone 13, resulting in impaired viral clearance in the liver. The findings show a metabolic requirement of dietary protein in sustaining functional CD8 memory and suggest that interventions to optimize dietary protein intake may improve vaccine efficacy in malnourished individuals.     

The role of alpha beta+ T cells and homeostatic T cell proliferation in Y-chromosome-associated murine lupus

Male BXSB mice develop an early life, severe lupus-like disease largely attributed to an undefined Y-chromosome-associated autoimmunity accelerator, termed YAA: Although the exact disease pathogenesis is uncertain, indirect evidence suggests that T cells play an important role in the male BXSB disease. We have developed TCR alpha-chain gene-deleted BXSB mice to directly examine the role of alphabeta+ T cells and the mode by which Yaa promotes disease in this strain. All disease parameters, including hypergammaglobulinemia, autoantibody production, glomerulonephritis, and the unique monocytosis of BXSB males, were severely reduced or absent in the alphabeta+ T cell-deficient mice. Adoptively transferred CD4+ T cells of either male or female BXSB origin showed equal homeostatic proliferation in alphabeta+ T cell-deficient male recipients. Moreover, deficient male mice eventually developed equally severe lupus-like disease after adoptive transfer and homeostatic expansion of T cells from wild-type BXSB males or females. The results directly demonstrate that the Yaa-mediated disease requires alphabeta+ T cells that are not, in themselves, abnormal in either composition or properties, but are engaged by a Yaa-encoded abnormality in a non-T cell component. In addition, homeostatic anti-self proliferation of mature T cells derived from a small number of precursors can induce systemic autoimmunity in an appropriate background.     

The elusive short gene--an ensemble method for recognition for prokaryotic genome

Glucagon-like peptide-1 (GLP-1) and leptin are anorectic hormones produced in the small intestine and white adipose tissue, respectively. Investigating how these hormones act together as an integrated anorectic signal is important to elucidate a mechanism to maintain energy balance. In the present study, coadministration of subthreshold GLP-1 and leptin dramatically reduced feeding in rats. Although coadministration of GLP-1 with leptin did not enhance leptin signal transduction in the hypothalamus, it significantly decreased phosphorylation of AMP-activated protein kinase (AMPK). In addition, coadministration of GLP-1 with leptin significantly increased proopiomelanocortin (POMC) mRNA levels. Considering that α-melanocortin stimulating hormone (α-MSH) is derived from POMC and functions through the melanocortin-4-receptor (MC4-R) as a key molecule involved in feeding reduction, the interaction of GLP-1 and leptin on feeding reduction may be mediated through the α-MSH/MC4-R system. As expected, the interaction of GLP-1 and leptin was abolished by intracerebroventricular preadministration of the MC4-R antagonists agouti-related peptide and SHU9119. Taken together, GLP-1 and leptin cooperatively reduce feeding at least in part via inhibition of AMPK following binding of α-MSH to MC4-R.     

A role for retinoic acid in homeostatic plasticity

Prolonged changes in neuronal activity trigger compensatory modifications in synaptic function to restore firing rates to normal levels. In this issue of Neuron, Aoto et al. demonstrate that synthesis of retinoic acid offsets chronic network inactivity by increasing synaptic strength through upregulation of GluR1 receptors.     

Illuminating synapse-specific homeostatic plasticity

Homeostatic plasticity can globally scale the strength of all synapses on a neuron, but whether a similar bidirectional homeostatic scaling can also operate independently at individual synapses was unknown until now. Here, Man and colleagues demonstrate that single synapses show an input-specific homeostatic downregulation of synaptic efficacy in response to increased activity.     

A polarised population of dynamic microtubules mediates homeostatic length control in animal cells

Because physical form and function are intimately linked, mechanisms that maintain cell shape and size within strict limits are likely to be important for a wide variety of biological processes. However, while intrinsic controls have been found to contribute to the relatively well-defined shape of bacteria and yeast cells, the extent to which individual cells from a multicellular animal control their plastic form remains unclear. Here, using micropatterned lines to limit cell extension to one dimension, we show that cells spread to a characteristic steady-state length that is independent of cell size, pattern width, and cortical actin. Instead, homeostatic length control on lines depends on a population of dynamic microtubules that lead during cell extension, and that are aligned along the long cell axis as the result of interactions of microtubule plus ends with the lateral cell cortex. Similarly, during the development of the zebrafish neural tube, elongated neuroepithelial cells maintain a relatively well-defined length that is independent of cell size but dependent upon oriented microtubules. A simple, quantitative model of cellular extension driven by microtubules recapitulates cell elongation on lines, the steady-state distribution of microtubules, and cell length homeostasis, and predicts the effects of microtubule inhibitors on cell length. Together this experimental and theoretical analysis suggests that microtubule dynamics impose unexpected limits on cell geometry that enable cells to regulate their length. Since cells are the building blocks and architects of tissue morphogenesis, such intrinsically defined limits may be important for development and homeostasis in multicellular organisms.     

Mechanisms for managing cellular and homeostatic stress in vitro

The ability to maintain embryo development in culture depends upon the ability of the embryo to maintain cellular homeostasis. Disruptions in the ability to regulate cellular homeostasis such as pH, calcium levels and osmotic pressure result in perturbed development and a reduced ability to establish and maintain a pregnancy following transfer. Therefore, it is important that in vitro conditions are designed to minimize stress on the embryo and maximize the ability of the embryo to maintain cellular homeostasis. While embryos do exhibit a degree of plasticity and can adapt to their environment, this requires expenditures of extra energy which negatively impacts viability. Therefore, reducing stress by taking into account the physiology of the embryo is essential for the maintenance of developmental competence in vitro.     

Alternative mechanisms for homeostatic regulation of mammalian cell populations

A model for homeostatic regulation in mammalian tissues is analyzed. The model treats resting and active dividing cells, immature and mature non-dividing cells as separate populations. In the model, regulation is accomplished through control of the proportion of newly-formed cells that will become non-dividers. Four possible regulating substances, produced by dividing cells, non-dividing cells, mature non-dividing cells, and newly-formed cells respectively, are considered. Stability theorems are provided. System behavior in each instance depends on the relative values of the rate at which cells divide and the rate at which non-dividers die.     

Mouse CD24 is required for homeostatic cell renewal

Under physiological conditions, some adult tissues retain a capacity for self-renewal. This property is attributable to the proliferation and differentiation of stem, transit-amplifying, and differentiating cells, which are regulated by cell-cell or cell-matrix interactions or by secreted factors. By gain and loss of function experiments, we demonstrate the involvement of mouse CD24 (mouse cluster of differentiation 24), which is a glycosyl phosphatidylinositol (GPI)-anchored cell-surface glycoprotein, in the regulation of homeostatic cell renewal. BrdU incorporation observations, at optical and electron-microscopic levels, have revealed increased cell proliferation in the developing brain and in the epithelia of mCD24-deleted mice. We have observed ectopic proliferative cells in the suprabasal layers of the mutant skin leading to a general disruption of basal and suprabasal layers. By contrast, ectopic mCD24 expression mediated by retroviral infection of the embryonic brain leads to a decreased number of clusters of cells generated in the progeny. Together, these results and our previous published data indicate that mCD24 contributes to the regulation of the production of differentiated cells by controlling the proliferation/differentiation balance between transit-amplifying and committed differentiated cells.