Mice subcutaneously injected with bleomycin, an experimental model for human systemic sclerosis, develop skin and lung fibrosis, which is mediated by inflammatory cell infiltration. This process is highly regulated by multiple adhesion molecules. To assess the role of adhesion molecules in this pathogenetic process, the bleomycin-induced fibrosis was examined in mice lacking adhesion molecules. In addition, this model does not require antigen sensitization. Therefore, we can exclude the possible role of adhesion molecules on the sensitization phase. L-selectin and/or ICAM-1 deficiency inhibited skin and lung fibrosis with decreased Th2 and Th17 cytokines and increased Th1 cytokines. By contrast, P-selectin deficiency, E-selectin deficiency with or without P-selectin blockade, or PSGL-1 deficiency augmented the fibrosis in parallel with increased Th2 and Th17 cytokines and decreased Th1 cytokines. Furthermore, loss of L-selectin and/or ICAM-1 reduced Th2 and Th17 cell numbers in bronchoalveolar lavage fluid, whereas loss of P-selectin, E-selectin, or PSGL-1 reduced Th1 cell numbers. Moreover, Th1 cells exhibited higher PSGL-1 expression and lower expression of LFA-1, a ligand for ICAM-1, while Th2 and Th17 cells showed higher LFA-1 and lower PSGL-1 expression. This study suggests that L-selectin and ICAM-1 regulate Th2 and Th17 cell accumulation into the skin and lung, leading to the development of fibrosis, and that P-selectin, E-selectin, and PSGL-1 regulate Th1 cell infiltration, resulting in the inhibition of fibrosis.
Distributive justice concerns the moral principles by which we seek to allocate resources fairly among diverse members of a society. Although the concept of fair allocation is one of the fundamental building blocks for societies, there is no clear consensus on how to achieve "socially just" allocations. Here, we examine neurocognitive commonalities of distributive judgments and risky decisions. We explore the hypothesis that people's allocation decisions for others are closely related to economic decisions for oneself at behavioral, cognitive, and neural levels, via a concern about the minimum, worst-off position. In a series of experiments using attention-monitoring and brain-imaging techniques, we investigated this "maximin" concern (maximizing the minimum possible payoff) via responses in two seemingly disparate tasks: third-party distribution of rewards for others, and choosing gambles for self. The experiments revealed three robust results: (i) participants' distributive choices closely matched their risk preferences-"Rawlsians," who maximized the worst-off position in distributions for others, avoided riskier gambles for themselves, whereas "utilitarians," who favored the largesttotal distributions, preferred riskier but more profitable gambles; (ii) across such individual choice preferences, however, participants generally showed the greatest spontaneous attention to information about the worst possible outcomes in both tasks; and (iii) this robust concern about the minimum outcomes was correlated with activation of the right temporoparietal junction (RTPJ), the region associated with perspective taking. The results provide convergent evidence that social distribution for others is psychologically linked to risky decision making for self, drawing on common cognitive-neural processes with spontaneous perspective taking of the worst-off position.distributive justice | risky decisions | maximin rule | perspective taking | right temporoparietal junction T he "Occupy Wall Street" protests in New York garnered worldwide attention, highlighting growing concerns about wealth inequality. A remarkable feature of the protests was that not only the financially disadvantaged but middle-class citizens, who were relatively wealthy in the current economy, also joined the movement. Traditional economic models that assume utility only for self-related outcomes (1, 2) fail to explain such a mass phenomenon.However, there is one important psychological dimension that seems to characterize the wide civic involvement in the movement yet has been unaddressed in cognitive and social neuroscienceconcern about the lowest, worst-off outcomes. Notice that, in the "Occupy" protests, people were not just concerned about the inequality (variance) of wealth distribution generally, but specifically advocated increasing the incomes of society's most disadvantaged. John Rawls, an eminent modern social philosopher, similarly argued that the benefit to the least well-off should be maximized according to the "maximin principle" (maximizing th...
The posterior parietal cortex (PPC) features close anatomical and functional relationships with the prefrontal cortex. However, the necessity of the PPC in executive functions has been questioned. The present study used the stop-signal task to examine response inhibition, an executive function that inhibits prepotent response tendency. The brain activity and resting-state functional connectivity were measured to analyze a parcellation-based network that was aimed at identifying a candidate PPC region essential for response inhibition in humans. The intraparietal sulcus (IPS) was activated during response inhibition and connected with the inferior frontal cortex and the presupplementary motor area, the two frontal regions known to be necessary for response inhibition. Next, transcranial magnetic stimulation (TMS) was used to test the essential role of the IPS region for response inhibition. TMS over the IPS region prolonged the stop-signal reaction time (SSRT), the standard behavioral index used to evaluate stopping performance, when stimulation was applied 30 -0 ms before stopping. On the contrary, stimulation over the temporoparietal junction region, an area activated during response inhibition but lacking connectivity with the two frontal regions, did not show changes in SSRT. These results indicate that the IPS identified using the parcellation-based network plays an essential role in executive functions.
Objective. The presence of anti-DNA topoisomerase I (anti-topo I) antibody correlates positively with disease severity in patients with systemic sclerosis (SSc). However, the role of induction of anti-topo I antibody production and its potential contribution to the pathogenesis of SSc remain unclear. The aim of this study was to examine the role of anti-topo I antibody in the pathogenesis of SSc.Methods. To assess the contribution of anti-topo I antibody to the pathogenetic process, dermal sclerosis, pulmonary fibrosis, and cytokine production were examined in mice treated with topo I and either Freund's complete adjuvant (CFA) or Freund's incomplete adjuvant (IFA).Results. Treatment with topo I and CFA, in contrast to treatment with topo I and IFA, induced skin and lung fibrosis with increased interleukin-6 (IL-6), transforming growth factor 1, and IL-17 production and decreased IL-10 production. Anti-topo I antibody levels were greater in mice treated with topo I and CFA than in mice treated with topo I and IFA. Furthermore, treatment with topo I and CFA increased Th2 and Th17 cell frequencies in bronchoalveolar lavage fluid, whereas treatment with topo I and IFA increased Th1 and Treg cell frequencies. Moreover, loss of IL-6 expression ameliorated skin and lung fibrosis, decreased Th2 and Th17 cell frequencies, and increased Th1 and Treg cell frequencies.Conclusion. This study is the first to show that treatment with topo I and CFA induces SSc-like skin and lung fibrosis and autoimmune abnormalities. We also suggest that IL-6 plays important roles in the development of fibrosis and autoimmune abnormalities in this novel SSc model.
Objective To determine serum levels of interleukin 27 (IL-27) in patients with systemic sclerosis (SSc) and relate the results to the clinical features of SSc. Methods Serum levels of IL-27 in 91 patients with SSc and the production of IL-27 by isolated monocytes were examined by ELISA. The expression of IL-27 receptor in the skin fi broblasts, B cells and T cells was quantifi ed by real-time PCR. The effect of IL-27 on immunoglobulin G (IgG) production of B cells, IL-17 production of CD4 T cells and proliferation and collagen synthesis of fi broblasts was also analysed. Results Serum IL-27 levels were raised in patients with SSc compared with healthy controls and correlated positively with the extent of skin and pulmonary fi brosis and immunological abnormalities. IL-27 levels also correlated positively with serum levels of hyaluronan, recently identifi ed as an endogenous ligand for Toll-like receptors. The retrospective longitudinal analysis showed a tendency for serum IL-27 levels to be attenuated during the follow-up period. IL-27 production by cultured monocytes was increased by hyaluronan stimulation. IL-27 receptor expression was upregulated in the affected skin fi broblasts, B cells and CD4 T cells of patients with SSc. Moreover, IL-27 stimulation increased IgG production of B cells, IL-17 production of CD4 T cells and proliferation and collagen synthesis of fi broblasts in patients with SSc compared with those in healthy controls. Conclusion These results suggest that IL-27 and its signalling in B cells, T cells and fi broblasts contributes to disease development in patients with SSc.
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