A zebrafish model for Waardenburg syndrome type IV reveals diverse roles for Sox10 in the otic vesicle.

In humans, mutations in the SOX10 gene are a cause of the auditory-pigmentary disorder Waardenburg syndrome type IV (WS4) and related variants. SOX10 encodes an Sry-related HMG box protein essential for the development of the neural crest; deafness in WS4 and other Waardenburg syndromes is usually attributed to loss of neural-crest-derived melanocytes in the stria vascularis of the cochlea. However, SOX10 is strongly expressed in the developing otic vesicle and so direct roles for SOX10 in the otic epithelium might also be important. Here, we examine the otic phenotype of zebrafish sox10 mutants, a model for WS4. As a cochlea is not present in the fish ear, the severe otic phenotype in these mutants cannot be attributed to effects on this tissue. In zebrafish sox10 mutants, we see abnormalities in all otic placodal derivatives. Gene expression studies indicate deregulated expression of several otic genes, including fgf8, in sox10 mutants. Using a combination of mutant and morphant data, we show that the three sox genes belonging to group E (sox9a, sox9b and sox10) provide a link between otic induction pathways and subsequent otic patterning: they act redundantly to maintain sox10 expression throughout otic tissue and to restrict fgf8 expression to anterior macula regions. Single-cell labelling experiments indicate a small and transient neural crest contribution to the zebrafish ear during normal development, but this is unlikely to account for the strong defects seen in the sox10 mutant. We discuss the implication that the deafness in WS4 patients with SOX10 mutations might reflect a haploinsufficiency for SOX10 in the otic epithelium, resulting in patterning and functional abnormalities in the inner ear.

An immuno-histochemical study of the inflammatory cell infiltrate in the large intestine of Jamaican children with trichuris trichuria infection - abstract

The symptomatology of children with Trichuris Dysentry Syndrome (Ramsey, 1962) has much in common with that of idiopathic inflammatory bowel disease (Crohn's and ulcerative colitis). However, the pathology is confined to the mucosa and includes relatively little disturbance of the crypt architecture or epithelial histology. We undertook an immuno-histochemical study of the faecal mucosa of five heavily infected children with non specific, bloody diarrhoea (in whom such gross inflammatory changes as did exist were confined to the rectum and distal colon). Tissue obtained by colonoscopic biopsy was fixed in formalin and embedded in paraffin wax. Routine histological sections revealed only a non-specific increase in inflammatory cells in the lamina propria and failed to differentiate between trichuriasis and non-specific bloody diarrhoea. Specimens of the fixed tissue were transported to London where a panel of peroxidase-labelled antibodies was applied. Expressing immuno-stained cells as a percentage of total lamina propria cells, we showed marked difference between the Trichuris dysentery and control patients, summarised below using group means: Igm plasma cell, IgE-coated mast cell, Macrophages; TRICHURIS - 12.4, 9.6 33.3 respectively; NON-TRICHURIS - 7.2, 0.5, 8.9 respectively; SIGNIF. LEVEL - 0.05, 0.0001, 0.005 respectively. Further immuno-histochemistry on snap-frozen tissue will allow specification of the type and activation state of the cells involved in the inflammatory response to T. trichiura. It is our hope in due course to relate these changes to the symptomatology, both intestinal and extra-intestinal, of this important disease (AU)

Immediate hypersensitivity in colon of children with chronic Trichuris trichiura dysentery

There are few data on mucosal immune responses to intestinal helminths in human beings, especially those involving the IgE system, which is thought to be important in parasite expulsion. We sought evidence of an immediate hypersensitivity reaction in the colon of children with chronic dysentery due to Trichuris trichiura. 28 children with Trichuris dysentery syndrome (TDS) were compared with 16 control children (with no TDS or worms visible on colonoscopy). All children were aged 1-11 years. Rectal biopsy samples were taken before and after expulsion of the worms by means of mebendazole treatment. Children wtih TDS had significantly greater numbers than controls of mast cells (mean [SD] 10.9 [1.3] vs 3.9 [0.6] percent of all cells; p<0.0003) and of cells with surface IgE (median [range] 11.1 [7.5-11.6] vs 1.0 [0-1.5] percent; p<0.001) in the subepithelial region of the mucosa. On electronmicroscopy, degranulating mast cells were prominent in parasitised children. In culture, rectal biopsy samples from parasitised children showed high rates of spontaneous histamine release, but only low rates of antigen-specific release. After treatment, spontaneous histamine release was significantly reduced and antigen-specific histamine release could be provoked. Thus, an IgE-mediated immune mucosal response to a helminth infection does occur in human beings but is not sufficient to cause appreciable parasite expulsion. (Summary)

Histopathology and immunohistochemistry of the caecum in children with the Trichuris dysentery syndrome

Caecal biopsy specimens from Jamaican children with the Trichuris dysentery syndrome (TDS) and age matched Jamaican controls were investigated by immunohistochemistry and by light microscopy. Biopsy specimens from all children (with TDS and controls) showed a mild to moderate increase in inflamatory cells. Except in the vicinity of the worm, where the epithlium was flattened, there was no other epithelial abnormality. Compared with controls, children with TDS had increased IgM lamina propria plasma cells and decreased intaepithelial T cells. There was also an increase in crypt epithelial cells proliferation. Lamina propia T cells (both activated and non-activated) were no more common in children with the Trichuris syndrome than controls. Epithelial cell HLA-DR and VLA-1 expression (which are increased in other colitides) were the same in both groups. Despite the presence of large worm burdens and chronic dysentery, therefore, only minor changes were seen in the caecal mucosa of children with TDS. (AU)