The autoimmunity of primary biliary cirrhosis and the clonal selection theory

Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease in which an immune-mediated injury targets the small intrahepatic bile ducts. PBC is further characterized by highly specific serum antimitochondrial autoantibodies (AMAs) and autoreactive T cells, a striking female predominance, a strong genetic susceptibility and a plethora of candidate environmental factors to trigger the disease onset. For these reasons, PBC appears ideal to represent the developments of the clonal selection theory over the past decades. First, a sufficiently potent autoimmunogenic stimulus in PBC would require the coexistence of numerous pre-existing conditions (mostly genetic, as recently illustrated by genome-wide association studies and animal models) to perpetuate the destruction of the biliary epithelium by the immune system via the persistence of forbidden clones. Second, the proposed modifications of mitochondrial autoantigens caused by infectious agents and/or xenobiotics well illustrate the possibility that peculiar changes in the antigen structure and flexibility may contribute to tolerance breakdown. Third, the unique apoptotic features shown for cholangiocytes are the ideal setting for the development of mitochondrial autoantigen presentation to the immune system through macrophages and AMA; thus, turning the non-traditional mitochondrial antigen into a traditional one. This article will review the current knowledge on PBC etiology and pathogenesis in light of the clonal selection theory developments.     

Autoimmunity since the 1957 clonal selection theory: a little acorn to a large oak

Knowledge on autoimmunity is examined from the launch of clonal selection theory 1957-1959. Crucial elements then were 'forbidden clones' of immunocytes as agents of tissue damage, somatic mutations that generated such clones and 'homeostatic mechanisms' that controlled them. The understanding of autoimmunity over the succeeding 50 years has expanded immensely, and many more diseases now come under this rubric. Examined here are current problems of definition including 'adaptive' and 'innate' types of autoimmunity, estimations of population burdens of autoimmune diseases, the nature of autoepitopes in the context of the diabetes autoantigen GAD65, and the complexities of immune tolerance and the genetic influences thereon, leading to the nomination of multiple 'tolerance/autoimmunity' genes as critical components of pathogenesis. Burnet's concept of mutagenesis as a basic feature of various pathologies including autoimmunity is given a contemporary focus, his views on deletional tolerance have been well vindicated, his 'forbidden clones' remain as unphysiological as before albeit phenotypically resembling normal lymphocytes, and his 'homeostatic mechanisms' can be now interpreted in terms of immunoregulatory networks.     

On the quantitative theory of reproductive effort in clonal plants: Refinements of theory,with evidence from goldenrods and mayapples

Summary Recently I proposed a quantitative theory which predicts the partition of resources between vegetative growth and seed production in highly rhizomatous clonal plants (Armstrong 1982, 1983). My basic premise was that this partition should be controlled by basic geometric properties of clonal growth. My conclusions were that the ratio of resources expended on seeds and rhizomes should be relatively constant in time and space, and that the value of this ratio should be predictable from a knowledge of the allometric relationships among certain morphological characters.In the present paper I first refine this theory to yield explicit ramet-level predictions directly applicable to clonal species with densely-packed canopies. These predictions are then tested using observations on goldenrods (Solidago altissima) and mayapples (Podophyllum peltatum). In the Solidago studies, the ratio of infructescence weight to total rhizome weight was found to be asymptotically constant for the larger ramets in a clone, confirming an important prediction of the theory. A second prediction of the theory, that the ratio of infructescence weight to total rhizome weight should be constant across clones, was not confirmed using the goldenrod data. This observation may simply be due to measurement biases. An alternative hypothesis is that the prediction of this theory constitute an r-limit strategy, and so are applicable only in the limit of density independent growth. Data from Sohn and Policansky (1977) on mayapples support this latter interpretation.     

Quantification of transformation efficiency using a new method for clonal growth and selection of axenic Dictyostelium cells

A new method for clonal growth of Dictyostelium axenic amoebae has been developed. Cells are plated in growth medium containing 1% ultra-low gelling temperature agarose. Cells grow normally in the agarose and form colonies up to several millimeters in diameter. When the colonies have grown to a sufficient size, they begin multicellular development. Pseudoplasmodia are formed, migrate to the surface of the agar, and then undergo fruiting body formation. Cells can be removed from the soft agarose colonies with a toothpick or by picking spores from the fruiting bodies. This method should be useful for drug, auxotrophic, and temperature selections where clonal maintenance of axenic colonies is important. This method has been used in combination with a selection for resistance to G418 to isolate independent colonies following DNA-mediated transformation. Several parameters in the calcium phosphate and electroporation transformation protocols have been optimized and the transformation frequency quantified. Independent transformed colonies are obtained at a frequency of 1 in 10(4) to 1 in 10(5) cells when integrating plasmids are introduced using calcium phosphate coprecipitation. The frequency is about tenfold higher when extrachromosomal shuttle vectors are introduced into cells.     

A model for follicular selection and ovulation: lessons from superovulation

A model for selection of the preovulatory follicle during the normal ovarian cycle is proposed. During menstruation the concentration of FSH rises to a level high enough to "activate" a single small antral follicle (2-4 mm dia.) so that it can produce large amounts of oestradiol. As the follicle develops, the concentration of FSH is suppressed below this threshold level by the secretion of oestradiol and inhibin. The dominant follicle becomes increasingly sensitive to FSH so that it continues to develop in an environment which inhibits development of other follicles. Multiple ovulation can be achieved by extending the period during which the level of FSH remains above this threshold level (e.g. during treatment with clomiphene or gonadotrophins). Although multiple ovulation occurs when the gate is widened in this way, the follicles are never completely synchronous as they continue to grow at approximately the same rate. Current evidence suggests that ovulation occurs at random between the two ovaries in successive cycles and that the corpus luteum exerts an inhibitory effect on folliculogenesis by suppressing the secretion of FSH and LH. These observations are compatible with the hypothesis that while small antral follicles are recruited continuously, at all stages of reproductive life, selection of the dominant follicle requires the unique gonadotrophic environment which is only present in the early follicular phase. The follicle of the month is, therefore, selected by chance because it is at the right place at the right time.     

Quantitative and qualitative approaches to GOD: the first 10 years of the clonal selection theory

Of the contentious issues surrounding the clonal selection theory, one of the most influential was that of the mechanism for the generation of diversity of antibody specificity. While Burnet's qualitative theory assumed a very large antibody repertoire, Talmage provided a detailed quantitative argument supporting only 5000 individual globulin patterns that provided an antiserum its specificity through combinatorial action. This methodological difference between the two men, and the mechanistic difference between their models, is key to the understanding of the clonal selection theory, its later acceptance and the proportion of credit paid to Burnet.     

Modeling of T-lymphocyte extravasation into a lymph node: The connection between the morphological basis of the process and the clonal selection theory

A model of the process of T-lymphocyte extravasation into a lymph node via the high endothelial venules in the course of the immune response has been developed. The histological structure and the morphometric parameters of the lymph node and its venules, as well as the presence of adhesion molecules on the endothelial cells and the speed of T-lymphocyte movement, were taken into account in the model and compared to the basic postulates of the clonal selection theory of immune surveillance. The inability of the venules of the lymph node to provide the passage of a sufficient number of T lymphocytes has been demonstrated; thus, the concept of immune surveillance formulated within the existing immunological theory has been proven inadequate. This finding points to the need for revision of the widely accepted concepts of the emergence of T-lymphocyte specificity and the very foundations of the clonal selection theory.     

Mechanisms of cohesin-mediated gene regulation and lessons learned from cohesinopathies

Cohesins are conserved and essential Structural Maintenance of Chromosomes (SMC) protein-containing complexes that physically interact with chromatin and modulate higher-order chromatin organization. Cohesins mediate sister chromatid cohesion and cellular long-distance chromatin interactions affecting genome maintenance and gene expression. Discoveries of mutations in cohesin's subunits and its regulator proteins in human developmental disorders, so-called “cohesinopathies,” reveal crucial roles for cohesins in development and cellular growth and differentiation. In this review, we discuss the latest findings concerning cohesin's functions in higher-order chromatin architecture organization and gene regulation and new insight gained from studies of cohesinopathies. This article is part of a Special Issue entitled: Chromatin and epigenetic regulation of animal development.     

Challenges of detecting directional selection after a bottleneck: lessons from Sorghum bicolor

Multilocus surveys of sequence variation can be used to identify targets of directional selection, which are expected to have reduced levels of variation. Following a population bottleneck, the signal of directional selection may be hard to detect because many loci may have low variation by chance and the frequency spectrum of variation may be perturbed in ways that resemble the effects of selection. Cultivated Sorghum bicolor contains a subset of the genetic diversity found in its wild ancestor(s) due to the combined effects of a domestication bottleneck and human selection on traits associated with agriculture. As a framework for distinguishing between the effects of demography and selection, we sequenced 204 loci in a diverse panel of 17 cultivated S. bicolor accessions. Genomewide patterns of diversity depart strongly from equilibrium expectations with regard to the variance of the number of segregating sites, the site frequency spectrum, and haplotype configuration. Furthermore, gene genealogies of most loci with an excess of low frequency variants and/or an excess of segregating sites do not show the characteristic signatures of directional and diversifying selection, respectively. A simple bottleneck model provides an improved but inadequate fit to the data, suggesting the action of other population-level factors, such as population structure and migration. Despite a known history of recent selection, we find little evidence for directional selection, likely due to low statistical power and lack of an appropriate null model.     

The development of a frame model for management strategies selection using fuzzy proximity

This research is to discuss management strategies selection and enterprise life cycle periods referencing fuzzy proximity from fuzzy set theory and based on the current development situation of enterprises in China. First, this paper measures the degree of proximity for eight kinds of management strategies and different enterprise life-cycle periods (the pioneering period, growth period, maturity period and recession period) using a fuzzy proximity vector. The eight management strategies include management idea innovation, management organization innovation, management method innovation, management culture innovation, management institution innovation, market innovation, business model innovation and performance management innovation. Second, this paper analyzes management innovation strategies in different enterprise life cycle periods, and verifies the consequences using an example of the developmental history of one engine manufacturing enterprise since 1997. Several conclusions can be drawn from this research: (1) The frame model of management innovation strategies in the enterprise’s life cycle is both reasonable and convincing as a reference for management innovation strategies selection when enterprises are developing. (2) The fuzzy proximity method can be applied to research where a management innovation strategy during a particular life cycle needs to be selected. Therefore, this research extends the application and scope of the fuzzy proximity method.     

Evidence for involvement of clonal anergy in MHC class I and class II disparate skin allograft tolerance after the termination of intrathymic clonal deletion

Mechanisms of cyclophosphamide (CP)-induced tolerance to class I (D) and class II (IE) alloantigens were studied. Transplantation tolerance across H-2D plus IE Ag-barriers has been achieved when B10.Thy-1.1 (Kb,IAb,IE-,Db; Thy-1.1) mice were primed i.v. with 9 x 10(7) spleen cells plus 3 x 10(7) bone marrow cells from B10.A(5R) mice (5R; kb,IAb,IEb,Dd; Thy-1.2) and treated i.p. with 200 mg/kg of CP 2 days later. The tolerant state in the early and the late stage was confirmed by prolonged acceptance of donor-type skin grafts, and in vitro unresponsiveness to donor Ag. In the tolerant B10.Thy-1.1 mice treated with 5R cells 28 days earlier and followed by CP, intrathymic clonal deletion of V beta 11+ T cells reactive to IE-encoded antigens was observed in association with intrathymic mixed chimerism. 5R skin survived, however, even after the clonal deletion of V beta 11+ T cells terminated by 180 days after tolerance induction. V beta 11+ T cells, which reappeared in the periphery of the recipient B10.Thy-1.1 mice bearing 5R skin at this stage, were not capable of proliferating in response to receptor cross-linking with V beta 11-specific mAb. Furthermore, the CTL activity against class I (Dd) alloantigens of spleen cells from these tolerant mice was restored by the addition of IL-2 to MLC. Thus, our experiments provide direct evidence that tolerance to both class I (Dd) and class II (IEb) alloantigens by clonal allergy occurs during the termination of intrathymic clonal deletion. These results clearly show practical hierarchy of the mechanisms of transplantation tolerance.     

The development of functional foods: lessons from the gut

Functional foods have resulted from the gradual recognition that healthy diets result from eating nutritious foods and from the identification of the mechanisms by which foods modulate metabolism and health. After initial successes with foods that reduce blood cholesterol level, probiotic bacteria and prebiotic carbohydrates have now also demonstrated added health benefits. As ingredients become more complex, the need to stabilize such ingredients in foods become increasingly important to the success of functional foods. Modern biotechnologies such as genomics, genetic expression and biomarkers of health and performance will be applied to this increasingly visible portion of human diets.