Precommitment in the Immune System

Lefkovits, Ivan

doi:10.1007/978-3-642-65875-4_2

Cited by 8 publications

(3 citation statements)

References 113 publications

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“…This allowed to obtain the first round of quantitative information on the frequency of precursor cells, that is, for obtaining data on how many cells were able to respond to a certain stimulus . In Table , such data are compiled, showing the spread of the findings depending on the condition of stimulation and, of course to large extent, depending on the type of antigen used (multiple epitopes, tertiary structure).…”

Section: Resultsmentioning

confidence: 99%

Alacrity of Cells Engaged in the Immune Response

Lefkovits

2012

Scand J Immunol

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A hypothesis is postulated and experimental findings are given that a special kind of cell heterogeneity exists that renders cells differentially sensitive to the epitopal stimulus with the consequence that only a portion of ligand‐specific cells engages in the response. The differential sensitivity is based on epigenetically driven cell‐to‐cell variations in the expressed gene products, such that every cell becomes unique in its molecular profile, and will preserve its individuality in ‘sensing’ the boundary conditions of the response milieu. The readiness of cells to engage in the response will be termed alacrity. High‐alacrity cells are ready to respond under given conditions because their molecular expression pattern – both in qualitative and in quantitative terms – matches the response milieu. This heterogeneity has little to do with the BCR and TCR specificity, that is, not all antigen‐specific cells respond to a stimulus, and cells failing to respond do so because their overall molecular pattern is inadequate to the conditions of the response milieu. The corollary to this proposition is that whatever physiological conditions prevail, some ligand‐specific cells will likely be ready to engage in the response, because their uniqueness makes them differentially reactive to external signals. Although the pool of cells available for any response is restricted under any given boundary condition, some idle cells are saved to be ‘in reserve’. Experiments are described that are compatible with this proposition, and approaches are suggested to elucidate the mechanism of developing and maintaining alacrity. This paper is a contribution to the Centennial conference in honour of Niels Kaj Jerne, held in Lisbon November 2011.

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Section: Resultsmentioning

confidence: 99%

Alacrity of Cells Engaged in the Immune Response

Lefkovits

2012

Scand J Immunol

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“…Cells loose the ability to divide and become specialized in monotonous tasks; for example, they become involved in a "high-throughput" protein production of some sort, or maybe they have to fuel the machinery for release of mechanical energy needed for some mechanical function. As an example of the former task can serve the plasma cell originating from a precommitted lymphocyte 12 that at the end-stage is specialized toward production of a single molecular species of antibody, while the representative of the latter kind is a cardiomyocyte that provides synchronized mechanical activity for the coordinated cardiac pump function. Plasma cells have a large protein-synthetic machinery enabling a high-throughput synthesis of some 2000 IgM or 10 000 IgG antibody molecules per second per cell, 13 while cardiomyocytes maintain an efficient transport system for the uptake of molecules needed for energy conversion (mainly fatty acids and glucose) 14 and for an efficient mitochondrial network engaged in the appropriate energy supply.…”

Section: Discussionmentioning

confidence: 99%

“Turnover Proteome” of Human Atrial Trabeculae

et al. 2007

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Most of the biologically relevant data on cardiomyocytes are derived from isolated cells under conditions that are, to some extent, altered compared to the natural milieu of the functional heart. The handling procedure of the dissection, isolation, and short-term culturing induces changes in the cells such that the subsequently measured parameters (among others, the protein synthesis) reflect the actual experimental conduct rather than the intrinsic properties of these terminally differentiated cells. Although it is known that the protein synthetic machinery of isolated cardiomyocytes is operational and functional, the biosynthetic yield of human cardiomyocytes in the natural milieu of the trabeculae remains to be established, with a special emphasis to clarify whether the protein synthesis includes just a limited set of polypeptides or it encompasses all cellular constituents. Knowledge on this issue is a prerequisite for achieving further advances in our understanding of heart remodeling related to hypertrophy in particular, and for attempting interventions leading to repair of damaged heart in general. The experimental system of "organ bath" enables simultaneous registration of contractile forces of portions of cardiac muscle tissue (and other myocyte-containing tissues) and biosynthetic labeling of newly synthesized cellular constituents. The organ bath methodology was adapted for this project such as enabling to measure molecular changes in response to in vitro applied stimuli. Instead of Krebs-Henseleit-solution, as used in classical protocols of organ bath studies, we utilized cell culture media suitable to experimental conditions related to metabolic labeling. Proteome patterns established by performing two-dimensional gel electrophoresis of the extracts from biosynthetically labeled trabeculae revealed that cardiomyocytes synthesize the full spectrum of cellular proteins. Proteomic silver-stain readout was used to obtain samples for spot excisions, as material suitable for mass spectrometric analysis. Protein spots were identified both from the excised spots and also by matching with the in-house- and www-databases (Swiss-Prot/High-Performance Heart). From our findings that protein synthesis in terminally differentiated cardiomyocytes is not confined just to the synthesis of those structures needed for the post-mitotic house-keeping functions, we conclude that this model might serve as a valid experimental system to study and elucidate the effects of various pharmacological compounds under conditions where physiology (contractile forces) and biochemistry (protein synthesis) of intact human heart tissue are monitored simultaneously.

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“…Meanwhile, Ivan was continuing to perform his influential limiting dilution experiments and provide strong support for clonal selection theory [4]. It seemed a good guess that a mouse could make perhaps a million various types of antibody molecule, but it was not clear to what extent the antibodies made by individual mice against a single hapten were different.…”

Section: Counting Lymphocytes and Antibodiesmentioning

confidence: 99%

Importance of Counting in Biology

Pink

2005

Scand J Immunol

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In this study, analysis of biological problems through structural and quantitative approaches is described. Classical genetics on major histocompatibility complex in avian species has been evaluated. Experiments showing that antibodies from various individuals were generally distinct have led to further analysis of immunoglobulin light chain diversity by means of O'Farrell's 2D gel technique. The transition of the research towards vaccine development has been described. 'It's not the voting that's democracy, it's the counting.' -Tom Stoppard (Czech-born dramatist), Jumpers (1972) act 1.

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Precommitment in the Immune System

Cited by 8 publications

References 113 publications

Alacrity of Cells Engaged in the Immune Response

Alacrity of Cells Engaged in the Immune Response

“Turnover Proteome” of Human Atrial Trabeculae

Importance of Counting in Biology

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