Spontaneous pneumothorax in primary cavitating lung carcinoma

Primary cavitating lung carcinomas have not previously been described with spontaneous pneumothorax as the presenting manifestation. Two patients whose pneumothoraces resulted in the initial diagnosis of a primary cavitary lung carcinoma are described. Pathologic evidence of vascular invasion suggests tumor necrosis with secondary rupture into the pleural space as a likely mechanism for pneumothorax.     

Innate immune signaling in defense against intestinal microbes

The gastrointestinal system is a common entry point for pathogenic microbes to access the inner environment of the body. Anti-microbial factors produced by the intestinal mucosa limit the translocation of both commensal and pathogenic microbes across the intestinal epithelial cell barrier. The regulation of these host defense mechanisms largely depends on the activation of innate immune receptors by microbial molecules. Under steady-state conditions, the microbiota provides constitutive signals to the innate immune system, which helps to maintain a healthy inflammatory tone within the intestinal mucosa and, thus, enhances resistance to infection with enteric pathogens. During an acute infection, the intestinal epithelial cell barrier is breached, and the detection of microbial molecules in the intestinal lamina propria rapidly stimulates innate immune signaling pathways that coordinate early defense mechanisms. Herein, we review how microbial molecules shed by both commensal and pathogenic microbes direct host defenses at the intestinal mucosa. We highlight the signaling pathways, effector molecules, and cell populations that are activated by microbial molecule recognition and, thereby, are involved in the maintenance of homeostatic levels of host defense and in the early response to acute enteric infection. Finally, we discuss how manipulation of these host defense pathways by stimulating innate immune receptors is a potential therapeutic strategy to prevent or alleviate intestinal disease.     

A founder mutation in BBS2 is responsible for Bardet‐Biedl syndrome in the Hutterite population: utility of SNP arrays in genetically heterogeneous disorders

Innes AM, Boycott KM, Puffenberger EG, Redl D, MacDonald IM, Chudley AE, Beaulieu C, Perrier R, Gillan T, Wade A, Parboosingh JS. A founder mutation in BBS2 is responsible for Bardet‐Biedl syndrome in the Hutterite population: utility of SNP arrays in genetically heterogeneous disorders. Bardet‐Biedl syndrome (BBS) is a multisystem genetically heterogeneous disorder, the clinical features of which are largely the consequence of ciliary dysfunction. BBS is typically inherited in an autosomal recessive fashion, and mutations in at least 14 genes have been identified. Here, we report the identification of a founder mutation in the BBS2 gene as the cause for the increased incidence of this developmental disorder in the Hutterite population. To ascertain the Hutterite BBS locus, we performed a genome‐wide single nucleotide polymorphism (SNP) analysis on a single patient and his three unaffected siblings from a Hutterite family. The analysis identified two large SNP blocks that were homozygous in the patient but not in his unaffected siblings, one of these regions contained the BBS2 gene. Sequence analysis and subsequent RNA studies identified and confirmed a novel splice site mutation, c.472‐2A>G, in BBS2. This mutation was also found in homozygous form in three subsequently studied Hutterite BBS patients from two different leuts, confirming that this is a founder mutation in the Hutterite population. Further studies are required to determine the frequency of this mutation and its role, if any, in the expression of other ciliopathies in this population.     

Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2

Monocytes recruited to tissues mediate defense against microbes or contribute to inflammatory diseases. Regulation of the number of circulating monocytes thus has implications for disease pathogenesis. However, the mechanisms controlling monocyte emigration from the bone marrow niche where they are generated remain undefined. We demonstrate here that the chemokine receptor CCR2 was required for emigration of Ly6C(hi) monocytes from bone marrow. Ccr2(-/-) mice had fewer circulating Ly6C(hi) monocytes and, after infection with Listeria monocytogenes, accumulated activated monocytes in bone marrow. In blood, Ccr2(-/-) monocytes could traffic to sites of infection, demonstrating that CCR2 is not required for migration from the circulation into tissues. Thus, CCR2-mediated signals in bone marrow determine the frequency of Ly6C(hi) monocytes in the circulation.     

Quantitative studies of CD8+ T-cell responses during microbial infection

MHC class I tetramer staining, intracellular cytokine staining and ELISPOT assays have made it possible to quantify CD8(+) T-cell responses precisely during and following viral and bacterial infection. Although these quantitative methods are by now familiar and trusted components of the immunologist's toolbox, their application to models of microbial infection continues to provide surprising insights into mammalian adaptive immunity. In the past year there have been many exciting new findings on CD8(+) T-cell priming, expansion and memory formation in response to microbial infection.     

Gut microbiota dysbiosis and diarrhea in kidney transplant recipients

Posttransplant diarrhea is associated with kidney allograft failure and death, but its etiology remains unknown in the majority of cases. Because altered gut microbial ecology is a potential basis for diarrhea, we investigated whether posttransplant diarrhea is associated with gut dysbiosis. We enrolled 71 kidney allograft recipients for serial fecal specimen collections in the first 3 months of transplantation and profiled the gut microbiota using 16S ribosomal RNA (rRNA) gene V4‐V5 deep sequencing. The Shannon diversity index was significantly lower in 28 diarrheal fecal specimens from 25 recipients with posttransplant diarrhea than in 112 fecal specimens from 46 recipients without posttransplant diarrhea. We found a lower relative abundance of 13 commensal genera (Benjamini‐Hochberg adjusted P ≤ .15) in the diarrheal fecal specimens including the same 4 genera identified in our prior study. The 28 diarrheal fecal specimens were also evaluated by a multiplexed polymerase chain reaction (PCR) assay for 22 bacterial, viral, and protozoan gastrointestinal pathogens, and 26 specimens were negative for infectious etiologies. Using PICRUSt (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States) to predict metagenomic functions, we found that diarrheal fecal specimens had a lower abundance of metabolic genes. Our findings suggest that posttransplant diarrhea is not associated with common infectious diarrheal pathogens but with a gut dysbiosis.     

Coordinate regulation of tissue macrophage and dendritic cell population dynamics by CSF-1

Tissue macrophages (Mφs) and dendritic cells (DCs) play essential roles in tissue homeostasis and immunity. How these cells are maintained at their characteristic densities in different tissues has remained unclear. Aided by a novel flow cytometric technique for assessing relative rates of blood-borne precursor recruitment, we examined Mφ and DC population dynamics in the pregnant mouse uterus, where rapid tissue growth facilitated a dissection of underlying regulatory mechanisms. We demonstrate how Mφ dynamics, and thus Mφ tissue densities, are locally controlled by CSF-1, a pleiotropic growth factor whose in situ level of activity varied widely between uterine tissue layers. CSF-1 acted in part by inducing Mφ proliferation and in part by stimulating the extravasation of Ly6C(hi) monocytes (Mos) that served as Mφ precursors. Mo recruitment was dependent on the production of CCR2 chemokine receptor ligands by uterine Mφs in response to CSF-1. Unexpectedly, a parallel CSF-1-regulated, but CCR2-independent pathway influenced uterine DC tissue densities by controlling local pre-DC extravasation rates. Together, these data provide cellular and molecular insight into the regulation of Mφ tissue densities under noninflammatory conditions and reveal a central role for CSF-1 in the coordination of Mφ and DC homeostasis.