Complex physical properties of an adaptive, self-organizing biological system

The physical interpretation of the functioning of the adaptive immune system, which has been thoroughly characterized on genetic and molecular levels, provides a unique opportunity to define an adaptive self-organizing biological system in its entirety. This paper describes a configuration space model of immune function, where directed chemical potentials of the system constitute a space of interactions. In the physical sense, the humoral adaptive immune system adjusts the chemical potential of all available antigenic molecules by tuning the chemical potential and organizing the network hierarchy of its sensor-effector molecules, antibodies. The coupling of sensors and effectors allows the system to adjust the thermodynamic activity of antigens and antibodies, while network organization helps minimize chemical potentials and maximize diversity. Mathematically the system couples the variance of Gaussian distributed interaction energies in its interaction space to the exponentially distributed chemical potentials of its effector molecules to maintain its stationary state. This process creates a scale-free network in interaction space, where absolute thermodynamic activity corresponds to node degree. In the thermodynamic interpretation, the system is an ensemble carrying out {mu}N work, adjusting chemical potentials according to the changes in the chemical potentials of the surroundings. The validity of the model is supported by identifying an interaction flexibility index, the corresponding variables in thermodynamics and network science, and by confirming its applicability to the humoral immune system. Overall, this statistical thermodynamics model of adaptive immunity describes how adaptive biological self-organization arises from the maintenance of a scale-free, directed interaction network with fractal topology.Comment: 22 pages, 8 figure

Statistical thermodynamics of self-organization in the adaptive immune system

The steady flow of energy can arrange matter and information in particular ways in a process we perceive as self-organization. Adaptive immunity is a phenomenon implemented by a complex adaptive biological system, whose self-organization can be understood as the maintenance of a steady state and can be modeled mathematically and physically. Using this approach, statistical distributions of thermodynamics can be shown to be applicable for the description of the organization and are in accordance with experimental observations of the immune system. Here I summarize arguments for such a statistical thermodynamic interpretation of immune function and highlight the interpretations of a key variable that characterizes self-organization in the context of chemical thermodynamics, networks and biochemical measurements.Comment: 14 pages, 4 figure

Dendritic Cells in Chronic Mycobacterial Granulomas Restrict Local Anti-Bacterial T Cell Response in a Murine Model

Background: Mycobacterium-induced granulomas are the interface between bacteria and host immune response. During acute infection dendritic cells (DCs) are critical for mycobacterial dissemination and activation of protective T cells. However, their role during chronic infection in the granuloma is poorly understood. Methodology/Principal Findings: We report that an inflammatory subset of murine DCs are present in granulomas induced by Mycobacteria bovis strain Bacillus Calmette-guerin (BCG), and both their location in granulomas and costimulatory molecule expression changes throughout infection. By flow cytometric analysis, we found that CD11c + cells in chronic granulomas had lower expression of MHCII and co-stimulatory molecules CD40, CD80 and CD86, and higher expression of inhibitory molecules PD-L1 and PD-L2 compared to CD11c + cells from acute granulomas. As a consequence of their phenotype, CD11c + cells from chronic lesions were unable to support the reactivation of newly-recruited, antigen 85Bspecific CD4 + IFNc + T cells or induce an IFNc response from naïve T cells in vivo and ex vivo. The mechanism of this inhibition involves the PD-1:PD-L signaling pathway, as ex vivo blockade of PD-L1 and PD-L2 restored the ability of isolated CD11c + cells from chronic lesions to stimulate a protective IFNc T cell response. Conclusions/Significance: Our data suggest that DCs in chronic lesions may facilitate latent infection by down-regulating protective T cell responses, ultimately acting as a shield that promotes mycobacterium survival. This DC shield may explai

Monovalent Fc receptor blockade by an anti-Fcγ receptor/albumin fusion protein ameliorates murine ITP with abrogated toxicity

Patients with immune thrombocytopenia (ITP) commonly have antiplatelet antibodies that cause thrombocytopenia through Fcγ receptors (FcγRs). Antibodies specific for FcγRs, designed to inhibit antibody-FcγR interaction, had been shown to improve ITP in refractory human patients. However, the development of such FcγR-specific antibodies has stalled because of adverse events, a phenomenon recapitulated in mouse models. One hypothesis behind these adverse events involved the function of the Fc region of the antibody, which engages FcγRs, leading to inflammatory responses. Unfortunately, inhibition of Fc function by deglycosylation failed to prevent this inflammatory response. In this work, we hypothesize that the bivalent antigen-binding fragment regions of immunoglobulin G are sufficient to trigger adverse events and have reasoned that designing a monovalent targeting strategy could circumvent the inflammatory response. To this end, we generated a fusion protein comprising a monovalent human FcγRIIIA-specific antibody linked in tandem to human serum albumin, which retained FcγR-binding activity in vitro. To evaluate clinically relevant in vivo FcγR-blocking function and inflammatory effects, we generated a murine version targeting the murine FcγRIII linked to murine albumin in a passive murine ITP model. Monovalent blocking of FcγR function dramatically inhibited antibody-dependent murine ITP and successfully circumvented the inflammatory response as assessed by changes in body temperature, basophil activation, and basophil depletion. Consistent with our hypothesis, in vivo cross-linking of the fusion protein induced these inflammatory effects, recapitulating the adverse events of the parent antibody. Thus, monovalent blocking of FcγR function demonstrates a proof of concept to successfully treat FcγR-mediated autoimmune diseases

Surface expression of activating and inhibitory costimulatory molecules and chemokine receptors is different on CD11c⁺ cells in acute and chronic granulomas.

<p>CD11c⁺ cells from granuloma single cell suspensions obtained from three, six and ten week systemically infected C57BL/6 mice were phenotyped using flow cytometry. A, Histograms represent fluorochrome surface staining with monoclonal antibodies against MHCII, activating costimulatory molecules (CD40, CD80 and CD86) and inhibitory costimulatory molecules (PD-L1 and PD-L2). Black-dashed histograms represent costimulatory molecule expression on naïve splenic CD11c⁺CD11b⁺ cells. Blacks arrows indicate directional shift in MHCII and costimulatory molecule expression compared to 3-week expression levels at time points where substantial change is observed. Histograms representative of 3 independent experiments with 3–7 mice per group. B, Average fold change between three and ten week time points in mean fluorescent intensity of MHCII and costimulatory molecules. Average generated from fold change in three independent experiments.</p

CD4⁺ T cells maintain contact with CD11c-EYFP⁺ cells in both acute and chronic granulomas.

<p>A, Quantitative analysis of CD4⁺ T cell contact with CD11c-EYFP⁺ cells in granulomas from three- and ten-week liver sections. All CD4⁺ T cells per granuloma section were determined to be in contact (green bars), or not in contact (white bars) with CD11c-EYFP⁺ cells. For each time point, liver sections from 3 independent mice were used, and 10–15 lesions per section were analyzed. Data are represented as mean +/− SEM, <i>P<0.0001</i>. B, Fluorescent images demonstrating CD11c-EYFP contact with CD4⁺ cells. Granulomas are outlined with white dashed lines at 1000× magnification and colors shown depict CD11c-EYFP (green cells), anti-CD4 Alexa 647 (red cells), and DAPI nuclear stain (blue).</p

Location of DCs in acute and chronic mycobacterium-granulomas is different.

<p>A, Schematic outline of DCs in the center, periphery or outside of the granuloma. B, Distribution of DC location from stained sections. 42, 43 and 17 lesions combined from three mice per time point were observed for CD11c⁺ location for three, six and ten weeks, respectively. C, CD11c-EYFP mice were systemically infected with dsRED BCG for three, six and ten weeks. EYFP expression (green cells) and DAPI nuclear stain (blue). Granulomas are outlined with white dashed lines and shown at 1000× magnification.</p

A portion of BCG is sustained within CD11c⁺ cells, both in acute and chronic granulomas.

<p>A, <i>Left</i>, Fluorescent images of CD11c-EYFP⁻ (left panels) and CD11c-EYFP⁺ cells (right panels) with dsRED BCG at three and ten weeks. Images magnified from 1000× images. DAPI nuclear stain (blue), dsRED BCG (red rods) and cytoplasmic CD11c-EYFP cells (green). <i>Right</i>, Average number of viable dsRED BCG rods per cell type (CD11c-EYFP+ or non-fluorescent) within the granuloma at three- and ten-weeks after infection. Data are represented as mean +/− SEM, <i>P<0.0001</i>. B, FACS plots generated from CD11c⁺ gate (left plot) and CD11b⁺CD11c⁻ gate (right plot). Boxed gate shows percentage of cells containing GFP-BCG. Gate placement was made from non-fluorescent-BCG infected CD11b+ and CD11c+ cells, <i>not shown</i>. Plots representative of 3- and 10-week time points with 3, 8 and 8 mice per group, respectively. C, Histograms generated from 10 week CD11c⁺ (1.17) and CD11b⁺CD11c⁻ (8.61) GFP BCG+ gates in (B).</p