Biallelic PI4KA variants cause neurological, intestinal and immunological disease.

Phosphatidylinositol 4-kinase IIIα (PI4KIIIα/PI4KA/OMIM:600286) is a lipid kinase generating phosphatidylinositol 4-phosphate (PI4P), a membrane phospholipid with critical roles in the physiology of multiple cell types. PI4KIIIα's role in PI4P generation requires its assembly into a heterotetrameric complex with EFR3, TTC7 and FAM126. Sequence alterations in two of these molecular partners, TTC7 (encoded by TTC7A or TCC7B) and FAM126, have been associated with a heterogeneous group of either neurological (FAM126A) or intestinal and immunological (TTC7A) conditions. Here we show that biallelic PI4KA sequence alterations in humans are associated with neurological disease, in particular hypomyelinating leukodystrophy. In addition, affected individuals may present with inflammatory bowel disease, multiple intestinal atresia and combined immunodeficiency. Our cellular, biochemical and structural modelling studies indicate that PI4KA-associated phenotypical outcomes probably stem from impairment of PI4KIIIα-TTC7-FAM126's organ-specific functions, due to defective catalytic activity or altered intra-complex functional interactions. Together, these data define PI4KA gene alteration as a cause of a variable phenotypical spectrum and provide fundamental new insight into the combinatorial biology of the PI4KIIIα-FAM126-TTC7-EFR3 molecular complex.

A 33-year-old man with a history of recurrent pneumonia presenting with hypoxemic respiratory failure.

The patient was a 33-year-old man with a history of recurrent pneumonia, autism, bipolar disorder, hypothyroidism, intermittent asthma, and nonischemic cardiomyopathy attributed to cocaine use who was admitted with hypoxemic respiratory distress with bilateral infiltrates seen on a chest radiograph. He was treated for community-acquired pneumonia but progressed to respiratory failure that required intubation and broad-spectrum antibiotic therapy. His medical history was notable for short stature, abnormal facial features, and, since childhood, at least two pneumonias per year that required antibiotics. The initial evaluation for an underlying primary immunodeficiency found that the patient had normal quantitative immunoglobulin levels, with absent CD19+ B cells. This case highlighted the evaluation of the humoral immune system for hospitalized adult patients with recurrent infections as well as the use of genetic testing to diagnose rare immunodeficiency syndromes.

Bacteroides fragilis Toxin Coordinates a Pro-carcinogenic Inflammatory Cascade via Targeting of Colonic Epithelial Cells.

Pro-carcinogenic bacteria have the potential to initiate and/or promote colon cancer, in part via immune mechanisms that are incompletely understood. Using ApcMin mice colonized with the human pathobiont enterotoxigenic Bacteroides fragilis (ETBF) as a model of microbe-induced colon tumorigenesis, we show that the Bacteroides fragilis toxin (BFT) triggers a pro-carcinogenic, multi-step inflammatory cascade requiring IL-17R, NF-κB, and Stat3 signaling in colonic epithelial cells (CECs). Although necessary, Stat3 activation in CECs is not sufficient to trigger ETBF colon tumorigenesis. Notably, IL-17-dependent NF-κB activation in CECs induces a proximal to distal mucosal gradient of C-X-C chemokines, including CXCL1, that mediates the recruitment of CXCR2-expressing polymorphonuclear immature myeloid cells with parallel onset of ETBF-mediated distal colon tumorigenesis. Thus, BFT induces a pro-carcinogenic signaling relay from the CEC to a mucosal Th17 response that results in selective NF-κB activation in distal colon CECs, which collectively triggers myeloid-cell-dependent distal colon tumorigenesis.

Reduction of Murine Colon Tumorigenesis Driven by Enterotoxigenic Bacteroides fragilis Using Cefoxitin Treatment.

BACKGROUND: Chronic inflammation and composition of the colon microbiota have been associated with colorectal cancer in humans. The human commensal enterotoxigenic Bacteroides fragilis (ETBF) is linked to both inflammatory bowel disease and colorectal cancer and, in our murine model, causes interleukin 17A (IL-17A)-dependent colon tumors. In these studies, we hypothesized that persistent colonization by ETBF is required for tumorigenesis. METHODS: We established a method for clearing ETBF in mice, using the antibiotic cefoxitin. Multiple intestinal neoplasia mice were colonized with ETBF for the experiment duration or were cleared of infection after 5 or 14 days. Gross tumors and/or microadenomas were then evaluated. In parallel, IL-17A expression was evaluated in wild-type littermates. RESULTS: Cefoxitin treatment resulted in complete and durable clearance of ETBF colonization. We observed a stepwise increase in median colon tumor numbers as the duration of ETBF colonization increased before cefoxitin treatment. ETBF eradication also significantly decreased mucosal IL-17A expression. CONCLUSIONS: The timing of ETBF clearance profoundly influences colon adenoma formation, defining a period during which the colon is susceptible to IL-17A-dependent tumorigenesis in this murine model. This model system can be used to study the microbiota-dependent and molecular mechanisms contributing to IL-17A-dependent colon tumor initiation.

Redundant Innate and Adaptive Sources of IL17 Production Drive Colon Tumorigenesis.

IL17-producing Th17 cells, generated through a STAT3-dependent mechanism, have been shown to promote carcinogenesis in many systems, including microbe-driven colon cancer. Additional sources of IL17, such as γδ T cells, become available under inflammatory conditions, but their contributions to cancer development are unclear. In this study, we modeled Th17-driven colon tumorigenesis by colonizing Min(Ap) (c+/-) mice with the human gut bacterium, enterotoxigenic Bacteroides fragilis (ETBF), to investigate the link between inflammation and colorectal cancer. We found that ablating Th17 cells by knocking out Stat3 in CD4(+) T cells delayed tumorigenesis, but failed to suppress the eventual formation of colonic tumors. However, IL17 blockade significantly attenuated tumor formation, indicating a critical requirement for IL17 in tumorigenesis, but from a source other than Th17 cells. Notably, genetic ablation of γδ T cells in ETBF-colonized Th17-deficient Min mice prevented the late emergence of colonic tumors. Taken together, these findings support a redundant role for adaptive Th17 cell- and innate γδT17 cell-derived IL17 in bacteria-induced colon carcinogenesis, stressing the importance of therapeutically targeting the cytokine itself rather than its cellular sources. Cancer Res; 76(8); 2115-24. ©2016 AACR.

Headache of neurally mediated syncope.

BACKGROUND: Neurally mediated syncope and migraine have a complex relationship. AIM: The aim of this study was to investigate whether patients developing syncope in the laboratory would experience migraine. METHODS: Thirty-one consecutive patients were evaluated for precipitation of headache during head-up tilt (HUT)-induced syncope (reduction of systolic blood pressure [SBP] >20 mmHg and prodromal symptoms with or without loss of consciousness). Autonomic functions were assessed using heart rate response to deep breathing (HRDB), Valsalva maneuver and HUT. Blood pressure and heart rate (via electrocardiography) were continuously monitored. Headache diagnosis was based on ICHD-3 criteria. RESULTS: Eighteen patients (58%) experienced syncope without headache and 13 (42%) had syncope and headache (SH). No difference was observed in time of syncope onset, reduction in SBP, Valsalva ratio, HRDB or tachycardia during initial 10 minutes of HUT. Of the 13 SH patients, 11 (85%) had a past history of migraine. Two reported headache just before tilt, eight developed headache during tilt and three developed headache only after tilt. Headache resolved within 1-15 minutes in 10 out of 13 patients. No patient experienced migraine. CONCLUSIONS: Syncope did not precipitate migraine. Headache during syncope may be due to cerebral hypoperfusion, and cerebral hyperperfusion may cause post-syncopal headache.