Bialellic Mutations in Tetratricopeptide Repeat Domain 7A (TTC7A) Cause Common Variable Immunodeficiency-Like Phenotype with Enteropathy

TTC7A deficiency typically causes severe gastrointestinal manifestations such as multiple intestinal atresia or early-onset inflammatory bowel disease. In some cases, this is associated with severe combined immunodeficiency. Partial loss-of-function mutations appear to be associated with a milder phenotype resulting in common variable immunodeficiency-like condition with enteropathy

Regulation and differentiation in normal and neoplastic urothelium

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Nerve hyperplasia : a unique feature of ketamine cystitis

Background: There is an emerging association between ketamine abuse and the development of urological symptoms including dysuria, frequency and urgency, which have a neurological component. In addition, extreme cases are associated with severe unresolving bladder pain in conjunction with a thickened, contracted bladder and an ulcerated/absent urothelium. Here we report on unusual neuropathological features seen by immunohistology in ketamine cystitis. Results: In all cases, the lamina propria was replete with fine neurofilament protein (NFP+) nerve fibres and in most patients (20/21), there was prominent peripheral nerve fascicle hyperplasia that showed particular resemblance to Morton’s neuroma. The nerve fascicles, which were positive for NFP, S100 and the p75 low-affinity nerve growth factor receptor (NGFR), were generally associated with a well-developed and in places, prominent, epithelial membrane antigen+/NGFR+ perineurium. This peripheral nerve fascicle hyperplasia is likely to account for the extreme pain experienced by ketamine cystitis patients. Urothelial damage was a notable feature of all ketamine cystitis specimens and where urothelium remained, increased NGFR expression was observed, with expansion from a basal-restricted normal pattern of expression into the suprabasal urothelium. Conclusions: The histological findings were distinguishing features of ketamine cystitis and were not present in other painful bladder conditions. Ketamine cystitis afflicts predominantly young patients, with unknown long-term consequences, and requires a strategy to control severe bladder pain in order to remove a dependency on the causative agent. Our study indicates that the development of pain in ketamine cystitis is mediated through a specific neurogenic mechanism that may also implicate the urothelium.7 page(s

Barrier forming potential of epithelial cells from the exstrophic bladder

Bladder exstrophy (BEX) is a rare developmental abnormality resulting in an open, exposed bladder plate. Although normal bladder urothelium is a mitotically quiescent barrier epithelium, histologic studies of BEX epithelia report squamous and proliferative changes that can persist beyond surgical closure. The current study examined whether patient-derived BEX epithelial cells in vitro were capable of generating a barrier-forming epithelium under permissive conditions. Epithelial cells isolated from 11 BEX samples, classified histologically as transitional (n = 6) or squamous (n = 5), were propagated in vitro. In conditions conducive to differentiated tight barrier formation by normal human urothelial cell cultures, 8 of 11 BEX lines developed transepithelial electrical resistances of more than 1000 Ω.cm(2), with 3 squamous lines failing to generate tight barriers. An inverse relationship was found between expression of squamous KRT14 transcript and barrier development. Transcriptional drivers of urothelial differentiation PPARG, GATA3, and FOXA1 showed reduced expression in squamous BEX cultures. These findings implicate developmental interruption of urothelial transcriptional programming in the spectrum of transitional to squamous epithelial phenotypes found in BEX. Assessment of BEX epithelial phenotype may inform management and treatment strategies, for which distinction between reversible versus intractably squamous epithelium could identify patients at risk of medical complications or those who are most appropriate for reconstructive tissue engineering strategies

Loss of Janus Associated Kinase1 alters urothelial cell functionand facilitates the development of bladder cancer

Inherited Primary Immunodeficiency (PID) disorders are associated with increased risk ofmalignancy that may relate to impaired antitumor immune responses or a direct role for PIDgermline mutations in tumorigenesis. We recently identified germline loss of function mutations inJanus Associated Kinase 1 (JAK1) causing primary immunodeficiency characterised by infectionsand associated with early onset, fatal high-grade bladder carcinoma. Somatic mutations in JAK1,required for immune cell signalling in response to interferon gamma (IFNγ), have been associatedwith several non-hematopoietic and hematopoietic cancer cell types but pathogenic mechanismsremain largely unexplored. Here we demonstrate that JAK1 is required for the intrinsic IFNγresponse of urothelial cells impacting immunogenicity and cell survival. Specifically, JAK1-deficient urothelial cells showed reduced surface expression of major histocompatibility complexclass II (MHC II), intercellular adhesion molecule-1 (ICAM-1) and programmed death-ligand-1(PD-L1) after IFNγ stimulation and were resistant to IFNγ-induced apoptosis and lymphocytemediatedkilling. In addition, we identify a previously unknown role for IFNγ signalling inmodulating urothelial differentiation. Together, our findings support a role for urothelial cell JAK1in immune surveillance and development of bladder cancer. Our results have implications forpatients with rare JAK1 PID and, more broadly, inform development of biomarker and targetedtherapies for urothelial carcinoma

Transplantation of Autologous Differentiated Urothelium in an Experimental Model of Composite Cystoplasty

We describe successful application of composite enterocystoplasty in a porcine model comprising an augmenting smooth-muscle segment lined by in vitro–generated autologous urothelium. None of the well-documented complications of conventional enterocystoplasty were encountered in the augmented bladders