Mycobacterium tuberculosis phagosome

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75241/1/j.1365-2958.1999.01279.x.pd

Gene expression variation in the adult human retina

Despite evidence that differences in gene expression levels contribute significantly to phenotypic variation across individuals, there has been only limited effort to study gene expression variation in human tissue. To characterize expression variation in the normal human retina, the authors utilized a custom retinal microarray to analyze 33 normal retinas from 19 donors, aged 29 to 90 years. Statistical models were designed to separate and quantify biological and technical sources of variation, including age, gender, eye laterality, gene function, and age-by-gender interaction. Although the majority of the 9406 genes analyzed showed relatively stable expression across different donors (for an average gene the expression level value of 95 out of a 100 individual fell within a 1.23-fold range), 2.6% of genes showed significant donor-to-donor variation, with a false discovery rate of 10%. The mean expression ratio standard deviation was 0.15 ± 0.8, log 2, with a range of 0.09 to 0.99. Genes selectively expressed in photoreceptors showed higher expression variation than other gene classes. Gender, age, and other donor-specific factors contributed significantly to the expression variation of multiple genes, and groups of genes with age- or gender-associated expression pattern were identified. These findings show that a significant fraction of gene expression variation in the normal human retina is attributable to identifiable biologic factors. The greater expression variability of many genes central to retinal function (including photoreceptor-specific gene) may be partially explained by the dynamics of the vision process, and raises the possibility that photoreceptor gene expression levels may contribute to phenotypic diversity across normal adult retinas. Additionally, as such diversity may result in different levels of disease susceptibility, exploring its sources may provide insights into the pathogenesis of retinal disease.—Hans E. Grossniklau

Innate Sensing through Mesenchymal TLR4/MyD88 Signals Promotes Spontaneous Intestinal Tumorigenesis

Koliaraki et al. show that MyD88 in mesenchymal cells is responsible for its tumor-promoting role in the Apc min/+ model. They further show that this is a TLR4-mediated mechanism that leads to the production of pro-tumorigenic molecules, also identified in human CAFs. © 2018 The Author(s) MyD88, an adaptor molecule downstream of innate pathways, plays a significant tumor-promoting role in sporadic intestinal carcinogenesis of the Apc min/+ model, which carries a mutation in the Apc gene. Here, we show that deletion of MyD88 in intestinal mesenchymal cells (IMCs) significantly reduces tumorigenesis in this model. This phenotype is associated with decreased epithelial cell proliferation, altered inflammatory and tumorigenic immune cell infiltration, and modified gene expression similar to complete MyD88 knockout mice. Genetic deletion of TLR4, but not interleukin-1 receptor (IL-1R), in IMCs led to altered molecular profiles and reduction of intestinal tumors similar to the MyD88 deficiency. Ex vivo analysis in IMCs indicated that these effects could be mediated through downstream signals involving growth factors and inflammatory and extracellular matrix (ECM)-regulating genes, also found in human cancer-associated fibroblasts (CAFs). Our results provide direct evidence that during tumorigenesis, IMCs and CAFs are activated by innate TLR4/MyD88-mediated signals and promote carcinogenesis in the intestine. © 2018 The Author(s

Necrotizing enterocolitis induces T lymphocyte-mediated injury in the developing mammalian brain.

Necrotizing enterocolitis (NEC) causes acute intestinal necrosis in premature infants and is associated with severe neurological impairment. In NEC, Toll-like receptor 4 is activated in the intestinal epithelium, and NEC-associated brain injury is characterized by microglial activation and white matter loss through mechanisms that remain unclear. We now show that the brains of mice and humans with NEC contained CD4 <sup>+</sup> T lymphocytes that were required for the development of brain injury. Inhibition of T lymphocyte influx into the brains of neonatal mice with NEC reduced inflammation and prevented myelin loss. Adoptive intracerebroventricular delivery of gut T lymphocytes from mice with NEC into Rag1 <sup>-/-</sup> recipient mice lacking CD4 <sup>+</sup> T cells resulted in brain injury. Brain organoids derived from mice with or without NEC and from human neuronal progenitor cells revealed that IFN-γ release by CD4 <sup>+</sup> T lymphocytes induced microglial activation and myelin loss in the organoids. IFN-γ knockdown in CD4 <sup>+</sup> T cells derived from mice with NEC abrogated the induction of NEC-associated brain injury after adoptive transfer to naïve Rag1 <sup>-/-</sup> recipient mice. T cell receptor sequencing revealed that NEC mouse brain-derived T lymphocytes shared homology with gut T lymphocytes from NEC mice. Intraperitoneal injection of NEC gut-derived CD4 <sup>+</sup> T lymphocytes into naïve Rag1 <sup>-/-</sup> recipient mice induced brain injury, suggesting that gut-derived T lymphocytes could mediate neuroinflammation in NEC. These findings indicate that NEC-associated brain injury may be induced by gut-derived IFN-γ-releasing CD4 <sup>+</sup> T cells, suggesting that early management of intestinal inflammation in children with NEC could improve neurological outcomes