Glucocorticoid Regulation of Elastin Synthesis in Human Fibroblasts: Down-Regulation in Fibroblasts from Normal Dermis But Not From Keloids

Keloids arise as benign connective tissue masses at sites of injury in genetically predisposed individuals, In addition to excessive collagen accumulation, there is biochemical and histologic evidence of elastic tissue. Previous studies showed that glucocorticoid regulation of collagen synthesis differs in fibroblasts from normal adult dermis and keloids, To define further the abnormal regulation of matrix synthesis in keloid fibroblasts, we examined glucocorticoid regulation of elastin synthesis. The basal level of elastin synthesis was significantly higher in keloid than in normal cells, and hydrocortisone reduced synthesis of elastin and elastin mRNA in normal but not in keloid fibroblasts. We had shown previously that fibroblasts from fetal dermis resembled keloid fibroblasts in glucocorticoid regulation of growth and collagen synthesis. In this study, glucocorticoids failed to down-regulate elastin synthesis in fetal cells that had not differentiated to produce normal levels of elastin, whereas fetal cells with normal elastin production exhibited glucocorticoid down-regulation. Abnormal regulation in keloid cells was independent of cell density and was confined to fibroblasts cultured from the keloid nodule. These findings reinforce the conclusion that a matrix-regulatory pathway is deranged in these focal lesions. Coordinate down-regulation of collagen and elastin by hydrocortisone in normal adult denial fibroblasts and the failure of hydrocortisone to down-regulate synthesis of either protein in keloid cells support the existence of common elements in the regulatory pathways of these two matrix proteins

Socializing One Health: an innovative strategy to investigate social and behavioral risks of emerging viral threats

In an effort to strengthen global capacity to prevent, detect, and control infectious diseases in animals and people, the United States Agency for International Development’s (USAID) Emerging Pandemic Threats (EPT) PREDICT project funded development of regional, national, and local One Health capacities for early disease detection, rapid response, disease control, and risk reduction. From the outset, the EPT approach was inclusive of social science research methods designed to understand the contexts and behaviors of communities living and working at human-animal-environment interfaces considered high-risk for virus emergence. Using qualitative and quantitative approaches, PREDICT behavioral research aimed to identify and assess a range of socio-cultural behaviors that could be influential in zoonotic disease emergence, amplification, and transmission. This broad approach to behavioral risk characterization enabled us to identify and characterize human activities that could be linked to the transmission dynamics of new and emerging viruses. This paper provides a discussion of implementation of a social science approach within a zoonotic surveillance framework. We conducted in-depth ethnographic interviews and focus groups to better understand the individual- and community-level knowledge, attitudes, and practices that potentially put participants at risk for zoonotic disease transmission from the animals they live and work with, across 6 interface domains. When we asked highly-exposed individuals (ie. bushmeat hunters, wildlife or guano farmers) about the risk they perceived in their occupational activities, most did not perceive it to be risky, whether because it was normalized by years (or generations) of doing such an activity, or due to lack of information about potential risks. Integrating the social sciences allows investigations of the specific human activities that are hypothesized to drive disease emergence, amplification, and transmission, in order to better substantiate behavioral disease drivers, along with the social dimensions of infection and transmission dynamics. Understanding these dynamics is critical to achieving health security--the protection from threats to health-- which requires investments in both collective and individual health security. Involving behavioral sciences into zoonotic disease surveillance allowed us to push toward fuller community integration and engagement and toward dialogue and implementation of recommendations for disease prevention and improved health security

Pleiotropic Effects of Immune Responses Explain Variation in the Prevalence of Fibroproliferative Diseases

<div><p>Many diseases are differentially distributed among human populations. Differential selection on genetic variants in ancestral environments that coincidentally predispose to disease can be an underlying cause of these unequal prevalence patterns. Selected genes may be pleiotropic, affecting multiple phenotypes and resulting in more than one disease or trait. Patterns of pleiotropy may be helpful in understanding the underlying causes of an array of conditions in a population. For example, several fibroproliferative diseases are more prevalent and severe in populations of sub-Saharan ancestry. We propose that this disparity is due to selection for an enhanced Th2 response that confers resistance to helminthic infections, and concurrently increases susceptibility to fibrosis due to the profibrotic action of Th2 cytokines. Many studies on selection of Th2-related genes for host resistance to helminths have been reported, but the pleiotropic impact of this selection on the distribution of fibrotic disorders has not been explicitly investigated. We discuss the disproportionate occurrence of fibroproliferative diseases in individuals of African ancestry and provide evidence that adaptation of the immune system has shaped the genetic structure of these human populations in ways that alter the distribution of multiple fibroproliferative diseases.</p></div

Pattern of differences between YRI and CEU HapMap populations, as determined by Fst between SNPs.

<p>(A) Th2 variants compared to background (18 genes and 256 SNPs); (B) Th1 variants compared to background (14 genes and 207 SNPs); (C) A comparison of Fst values for Th2 as compared to Th1 SNPs); (D) TGFβ and TGFβ-receptor variants, as compared to background (6 genes and 340 SNPs). Fst was calculated using the method of Weir and Cockerham [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005568#pgen.1005568.ref169" target="_blank">169</a>] and varies from zero (when two populations have identical allele frequencies of a given SNP) to one (when they are fixed for different alleles). Genes used for these analyses are listed in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005568#pgen.1005568.s002" target="_blank">S1 Table</a>.</p

Helminth exposure selects for a protective Th2 immune response that simultaneously increases risk for fibrosis.

<p>The high prevalence of helminths in Africa has selected for genotypes favoring an enhanced Th2 immune response characterized by increased levels of interleukin 4 (IL4), interleukin 13 (IL13), and interleukin 4 receptor (IL4R), and other Th2 factors. This selection also decreases Th1 factors, such as interferon gamma (IFNG) and interferon gamma receptor (IFNGR), and Th2 regulatory factors, such as IL10 and interleukin 13 receptor alpha 2 (IL13RA2). These genotypes increase resistance to helminthic infection and contribute to a subset of fibroproliferative diseases that are more common and/or more severe in individuals of African ancestry. Global distribution of helminth species in upper part of figure adapted from Lustigman et al. [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005568#pgen.1005568.ref168" target="_blank">168</a>].</p

Response to exposure by mouse strain.

<p>Response to exposure by mouse strain.</p

Population-specific allele frequencies (1,000 Genomes, 16 October 2014 release).

<p>^a) increased transcription</p><p>^b) decreased transcription</p><p>^c) increased IgE</p><p>^d) allergic disease/asthma</p><p>^e) resistance to helminthic infection</p><p>^f) fibrosis</p><p>^g) increased Th2 cytokines</p><p>^h) forward strand in 1,000 Genomes and HapMap, but apparently earlier literature reporting similar prevalence differences used complementary strand</p><p>ⁱ) sensitivity to helminthic infection</p><p>Population-specific allele frequencies (1,000 Genomes, 16 October 2014 release).</p

Relative frequencies of certain fibroproliferative diseases in black and white populations.

<p>Location of fibrosis</p><p>^a) airway</p><p>^b) eye</p><p>^c) kidney</p><p>^d) cardiovascular</p><p>^e) skin</p><p>^f) lung</p><p>^g) visceral organs</p><p>^h) uterus</p><p>Relative frequencies of certain fibroproliferative diseases in black and white populations.</p