Malnutrition enteropathy in Zambian and Zimbabwean children with severe acute malnutrition: A multi-arm randomized phase II trial.

Malnutrition underlies almost half of all child deaths globally. Severe Acute Malnutrition (SAM) carries unacceptable mortality, particularly if accompanied by infection or medical complications, including enteropathy. We evaluated four interventions for malnutrition enteropathy in a multi-centre phase II multi-arm trial in Zambia and Zimbabwe and completed in 2021. The purpose of this trial was to identify therapies which could be taken forward into phase III trials. Children of either sex were eligible for inclusion if aged 6-59 months and hospitalised with SAM (using WHO definitions: WLZ <-3, and/or MUAC <11.5 cm, and/or bilateral pedal oedema), with written, informed consent from the primary caregiver. We randomised 125 children hospitalised with complicated SAM to 14 days treatment with (i) bovine colostrum (n = 25), (ii) N-acetyl glucosamine (n = 24), (iii) subcutaneous teduglutide (n = 26), (iv) budesonide (n = 25) or (v) standard care only (n = 25). The primary endpoint was a composite of faecal biomarkers (myeloperoxidase, neopterin, α1-antitrypsin). Laboratory assessments, but not treatments, were blinded. Per-protocol analysis used ANCOVA, adjusted for baseline biomarker value, sex, oedema, HIV status, diarrhoea, weight-for-length Z-score, and study site, with pre-specified significance of P < 0.10. Of 143 children screened, 125 were randomised. Teduglutide reduced the primary endpoint of biomarkers of mucosal damage (effect size -0.89 (90% CI: -1.69,-0.10) P = 0.07), while colostrum (-0.58 (-1.4, 0.23) P = 0.24), N-acetyl glucosamine (-0.20 (-1.01, 0.60) P = 0.67), and budesonide (-0.50 (-1.33, 0.33) P = 0.32) had no significant effect. All interventions proved safe. This work suggests that treatment of enteropathy may be beneficial in children with complicated malnutrition. The trial was registered at ClinicalTrials.gov with the identifier NCT03716115.

Detection and management of milk allergy: Delphi consensus study.

BACKGROUND: There is significant overdiagnosis of milk allergy in young children in some countries, leading to unnecessary use of specialized formula. This guidance, developed by experts without commercial ties to the formula industry, aims to reduce milk allergy overdiagnosis and support carers of children with suspected milk allergy. METHODS: Delphi study involving two rounds of anonymous consensus building and an open meeting between January and July 2021. Seventeen experts in general practice, nutrition, midwifery, health visiting, lactation support and relevant areas of paediatrics participated, located in Europe, North America, Middle East, Africa, Australia and Asia. Five authors of previous milk allergy guidelines and seven parents provided feedback. FINDINGS: Participants agreed on 38 essential recommendations through consensus. Recommendations highlighted the importance of reproducibility and specificity for diagnosing milk allergy in children with acute or delayed symptoms temporally related to milk protein ingestion; and distinguished between children directly consuming milk protein and exclusively breastfed infants. Consensus was reached that maternal dietary restriction is not usually necessary to manage milk allergy, and that for exclusively breastfed infants with chronic symptoms, milk allergy diagnosis should only be considered in specific, rare circumstances. Consensus was reached that milk allergy diagnosis does not need to be considered for stool changes, aversive feeding or occasional spots of blood in stool, if there is no temporal relationship with milk protein ingestion. When compared with previous guidelines, these consensus recommendations resulted in more restrictive criteria for detecting milk allergy and a more limited role for maternal dietary exclusions and specialized formula. INTERPRETATION: These new milk allergy recommendations from non-conflicted, multidisciplinary experts advise narrower criteria, more prominent support for breastfeeding and less use of specialized formula, compared with current guidelines.

Common determinants of severe Covid-19 infection are explicable by SARS-CoV-2 secreted glycoprotein interaction with the CD33-related Siglecs, Siglec-3 and Siglec-5/14.

SARS-CoV-2 interaction with the ACE-2 receptor cannot alone explain the demography and remarkable variation in clinical progression of Covid-19 infection. Unlike SARS-CoV, the cause of SARS, several SARS-CoV-2 spike glycans contain sialic acid residues. In contrast to the SARS secreted glycoprotein (SGP), SARS-CoV-2 SGP are thus potential ligands for Sialic acid-binding Siglecs on host immune cells, known to regulate immune function. Such SARS-CoV-2 glycoproteins would contribute to immune deviation. CD33-related Siglecs are important immune regulators. Siglec-5 and -14 are paired receptors with opposed actions on the NLRP3 inflammasome, which is critical in early viral clearance. SGP binding in persons of Siglec-14 null genotype (30-70% in Black, Asian and Minority Ethnic (BAME) persons, 10% in North Europeans) would induce unopposed inhibitory signalling, causing viral persistence through inflammasome inhibition. Siglec-3 (CD33) and Siglec-5 are expressed on CD33 myeloid derived suppressor cells (CD33 MDSC). Immunosuppressive CD33 MDSC populations are increased in all groups at risk of severe Covid-19 infection. CD33 expression is increased in persons with the CD33 rs3865444 CC allele, associated with Alzheimer's disease, who would thus show enhanced susceptibility. Viral SGP ligation of CD33, potentially in conjunction with Siglec-5, would promote expansion of CD33 MDSC cells, as occurs in cancers but at much greater scale. CD33 is expressed on CNS microglia, potentially activated by SGP penetration through the porous cribriform plate to cause anosmia. Genotyping of severe or fatal Covid-19 cases can confirm or refute this pathophysiological mechanism. Early data have confirmed extremely high-level increase of CD33 MDSC numbers in severe Covid-19 infection, consistent with the proposed mechanism.

Matrix expansion and syncytial aggregation of syndecan-1+ cells underpin villous atrophy in coeliac disease.

BACKGROUND: We studied the expression of sulphated glycosaminoglycans (GAGs) in coeliac disease (CD) mucosa, as they are critical determinants of tissue volume, which increases in active disease. We also examined mucosal expression of IL-6, which stimulates excess GAG synthesis in disorders such as Grave's ophthalmopathy. METHODS: We stained archival jejunal biopsies from 5 children with CD at diagnosis, on gluten-free diet and challenge for sulphated GAGs. We then examined duodenal biopsies from 9 children with CD compared to 9 histological normal controls, staining for sulphated GAGs, heparan sulphate proteoglycans (HSPG), short-chain HSPG (Δ-HSPG) and the proteoglycan syndecan-1 (CD138), which is expressed on epithelium and plasma cells. We confirmed findings with a second monoclonal in another 12 coeliac children. We determined mucosal IL-6 expression by immunohistochemistry and PCR in 9 further cases and controls, and used quantitative real time PCR for other Th17 pathway cytokines in an additional 10 cases and controls. RESULTS: In CD, HSPG expression was lost in the epithelial compartment but contrastingly maintained within an expanded lamina propria. Within the upper lamina propria, clusters of syndecan-1(+) plasma cells formed extensive syncytial sheets, comprising adherent plasma cells, lysed cells with punctate cytoplasmic staining and shed syndecan ectodomains. A dense infiltrate of IL-6(+) mononuclear cells was detected in active coeliac disease, also localised to the upper lamina propria, with significantly increased mRNA expression of IL-6 and IL-17A but not IL-23 p19. CONCLUSIONS: Matrix expansion, through syndecan-1(+) cell recruitment and lamina propria GAG increase, underpins villous atrophy in coeliac disease. The syndecan-1(+) cell syncytia and excess GAG production recapitulate elements of the invertebrate encapsulation reaction, itself dependent on insect transglutaminase and glutaminated early response proteins. As in other matrix expansion disorders, IL-6 is upregulated and represents a logical target for immunotherapy in patients with coeliac disease refractory to gluten-free diet.

Mesalazine in the initial management of severely acutely malnourished children with environmental enteric dysfunction: a pilot randomized controlled trial.

BACKGROUND: Environmental enteric dysfunction (EED) is an acquired syndrome of impaired gastrointestinal mucosal barrier function that is thought to play a key role in the pathogenesis of stunting in early life. It has been conceptualized as an adaptive response to excess environmental pathogen exposure. However, it is clinically similar to other inflammatory enteropathies, which result from both host and environmental triggers, and for which immunomodulation is a cornerstone of therapy. METHODS: In this pilot double-blind randomized placebo-controlled trial, 44 children with severe acute malnutrition and evidence of EED were assigned to treatment with mesalazine or placebo for 28 days during nutritional rehabilitation. Primary outcomes were safety and acceptability of the intervention. RESULTS: Treatment with mesalazine was safe: there was no excess of adverse events, evidence of deterioration in intestinal barrier integrity or impact on nutritional recovery. There were modest reductions in several inflammatory markers with mesalazine compared to placebo. Depression of the growth hormone--insulin-like growth factor-1 axis was evident at enrollment and associated with inflammatory activation. Increases in the former and decreases in the latter correlated with linear growth. CONCLUSIONS: Intestinal inflammation in EED is non-essential for mucosal homeostasis and is at least partly maladaptive. Further trials of gut-specific immunomodulatory therapies targeting host inflammatory activation in order to optimize the growth benefits of nutritional rehabilitation and to address stunting are warranted. Funded by The Wellcome Trust. TRIAL REGISTRATION: Registered at Clinicaltrials.gov NCT01841099.

Intraepithelial lymphocyte eotaxin-2 expression and perineural mast cell degranulation differentiate allergic/eosinophilic colitis from classic IBD.

OBJECTIVES: Allergic colitis shows overlap with classic inflammatory bowel disease (IBD). Clinically, allergic colitis is associated with dysmotility and abdominal pain, and mucosal eosinophilia is characteristic. We thus aimed to characterise mucosal changes in children with allergic colitis compared with normal tissue and classic IBD, focusing on potential interaction between eosinophils and mast cells with enteric neurones. METHODS: A total of 15 children with allergic colitis, 10 with Crohn disease (CD), 10 with ulcerative colitis (UC), and 10 histologically normal controls were studied. Mucosal biopsies were stained for CD3 T cells, Ki-67, eotaxin-1, and eotaxin-2. Eotaxin-2, IgE, and tryptase were localised compared with mucosal nerves, using neuronal markers neurofilament protein, neuron-specific enolase, and nerve growth factor receptor. RESULTS: Overall inflammation was greater in patients with CD and UC than in patients with allergic colitis. CD3 T-cell density was increased in patients with allergic colitis, similar to that in patients with CD but lower than in patients with UC, whereas eosinophil density was higher than in all other groups. Eotaxin-1 and -2 were localised to basolateral crypt epithelium in all specimens, with eotaxin-1+ lamina propria cells found in all of the colitis groups. Eotaxin-2+ intraepithelial lymphocyte (IEL) density was significantly higher in allergic colitis specimens than in all other groups. Mast cell degranulation was strikingly increased in patients with allergic colitis (12/15) compared with that in patients with UC (1/10) and CD (0/1). Tryptase and IgE colocalised on enteric neurons in patients with allergic colitis but rarely in patients with IBD. CONCLUSIONS: Eotaxin-2+ IELs may contribute to the periepithelial eosinophil accumulation characteristic of allergic colitis. The colocalisation of IgE and tryptase with mucosal enteric nerves is likely to promote the dysmotility and visceral hyperalgesia classically seen in allergic gastrointestinal inflammation.

Enteric neural disruption in necrotizing enterocolitis occurs in association with myenteric glial cell CCL20 expression.

OBJECTIVE: The aetiology of necrotising enterocolitis (NEC) is unknown, but luminal factors and epithelial leakiness appear critical triggers of an inflammatory cascade. A separate finding has been suggested in mouse models, in which disruption of glial cells in the myenteric plexus induced a severe NEC-like lesion. We have thus looked for evidence of neuroglial abnormality in NEC. METHODS: We studied full-thickness resected specimens from 20 preterm infants with acute NEC and from 13 control infants undergoing resection for other indications. Immunohistochemical analysis was performed for immunological (CD3, syndecan-1, human leucocyte antigen-DR), neural (glial fibrillary acidic protein [GFAP], nerve growth factor receptor, neurofilament protein, neuron-specific enolase), and functional markers (Ki67), and for potential inflammatory regulators (interleukin-12, transforming growth factor-ß, CCL20, CCR6). RESULTS: Expression of the chemokine CCL20 and its receptor CCR6 was significantly upregulated in myenteric plexus in NEC, with CCL20 strongly expressed by glial cells. In 9 of 20 cases with NEC, myenteric plexus architecture and GFAP+ glial cells were normal, with preserved submucosal and mucosal innervation; however, 11 cases showed disrupted myenteric plexus architecture, reduced GFAP expression, and loss of submucosal and mucosal innervation. Persistent abnormalities were identified in the 2 infants who had ongoing inflammation at ileostomy closure. CONCLUSIONS: Our findings identified heterogeneity among patients with NEC. Approximately half showed evidence of marked neural abnormality extending from the deeper layers of the intestine, associated with glial activation and myenteric plexus disruption. The factors that may activate enteric glia in this manner, potentially including bacterial products or viruses, remain to be determined.

Potential for improving therapy and defining new research targets in eosinophilic oesophagitis based on understanding of immunopathogenesis.

OBJECTIVES: This review considers the potential for therapeutic advances in the management of eosinophilic oesophagitis (EoE) based on recently increased understanding of the pathophysiology of the disorder. METHODS: This is a review of publications characterising mucosal changes and leucocyte recruitment patterns in human and experimental EoE. RESULTS: EoE, although diagnosed by epithelial infiltration of eosinophils, is actually a transmural inflammation in which eosinophil recruitment occurs via the deeper layers. Penetration of eosinophils into the epithelium is variable, explaining the need for multiple biopsies to diagnose what may be a clearly visible disorder. Fibrosis and neuromuscular dysfunction both occur within the subepithelial tissues. Recent murine studies have identified that T-cell recruitment underpins antigen-specific oesophageal eosinophil recruitment. Involvement of innate immunity is also suggested by the role of invariant natural killer T cells in experimental EoE. CONCLUSIONS: Looking beyond present therapeutic options with a view to future studies, we identify T cells as candidates for "upstream therapy" if antigen specificity or homing markers are determined. Evidence of aeroallergen sensitisation suggests the possibility of lymphocyte priming within nasal-associated lymphoid tissue or Waldeyer ring, with the potential for topical therapy. We consider acquired neuromuscular dysfunction as a therapeutic target in acute symptomatic deterioration or bolus obstruction. We assess possible similarities with therapeutic stratagems for chronic asthma, recognising at the same time the anatomic specificity of the oesophagus and the difficulty in delivering effective topical medication to subepithelial tissues in this location compared with the airway.

Enterotoxin-producing staphylococci cause intestinal inflammation by a combination of direct epithelial cytopathy and superantigen-mediated T-cell activation.

BACKGROUND: Enterotoxin-producing Staphylococcus aureus may cause severe inflammatory intestinal disease, particularly in infants or immunodeficient or elderly patients. They are also recognized to be associated with sudden infant death syndrome. Little is known, however, about mucosal responses to staphylococci. METHODS: The mucosal lesion in three infants with staphylococcal enterocolitis was assessed by immunohistochemistry and electron microscopy. The organisms underwent extensive molecular analysis. Their toxins were assessed for capacity to induce T-cell activation and host mucosal responses examined by in vitro organ culture. Epithelial responses were studied by coculture with HEp-2 and Caco-2 cells. RESULTS: Intestinal biopsies from the patients showed marked epithelial damage with mucosal inflammation. The three staphylococci, representing two distinct clones, were methicillin-sensitive, producing SEG/I enterotoxins and Rho-inactivating EDIN toxins. Their enterotoxins potently activated T cells, but only whole organisms could induce in vitro enteropathy, characterized by remarkable epithelial desquamation uninhibited by tacrolimus. EDIN-producing staphylococci, but not their supernatants, induced striking cytopathy in HEp-2 epithelial cells but not in Caco-2 cells. Although HEp-2 and Caco-2 cells produced similar IL-8, CCL20, and cathelicidin LL37 responses upon bacterial exposure, only Caco-2 cells expressed mRNA for the ß-defensins HBD2 and HBD3, while HEp-2 cells were unable to do so. CONCLUSIONS: Staphylococci induce enterocolitis by a combination of direct enterocyte cytopathy mediated by EDIN toxins, disrupting the epithelial barrier, and enterotoxin superantigen-induced mucosal T-cell activation. Gut epithelial production of ß-defensins may contribute to host defense against invasive staphylococcal disease.

Bacterial-epithelial contact is a key determinant of host innate immune responses to enteropathogenic and enteroaggregative Escherichia coli.

BACKGROUND: Enteropathogenic (EPEC) and Enteroaggregative (EAEC) E. coli have similar, but distinct clinical symptoms and modes of pathogenesis. Nevertheless when they infect the gastrointestinal tract, it is thought that their flagellin causes IL-8 release leading to neutrophil recruitment and gastroenteritis. However, this may not be the whole story as the effect of bacterial adherence to IEC innate response(s) remains unclear. Therefore, we have characterized which bacterial motifs contribute to the innate epithelial response to EPEC and EAEC, using a range of EPEC and EAEC isogenic mutant strains. METHODOLOGY: Caco-2 and HEp-2 cell lines were exposed to prototypical EPEC strain E2348/69 or EAEC strain O42, in addition to a range of isogenic mutant strains. E69 [LPS, non-motile, non-adherent, type three secretion system (TTSS) negative, signalling negative] or O42 [non-motile, non-adherent]. IL-8 and CCL20 protein secretion was measured. Bacterial surface structures were assessed by negative staining Transmission Electron Microscopy. The Fluorescent-actin staining test was carried out to determine bacterial adherence. RESULTS: Previous studies have reported a balance between the host pro-inflammatory response and microbial suppression of this response. In our system an overall balance towards the host pro-inflammatory response is seen with the E69 WT and to a greater extent O42 WT, which is in fit with clinical symptoms. On removal of the external EPEC structures flagella, LPS, BFP, EspA and EspC; and EAEC flagella and AAF, the host inflammatory response is reduced. However, removal of E69 lymphostatin increases the host inflammatory response suggesting involvement in the bacterial mediated anti-inflammatory response. CONCLUSION: Epithelial responses were due to combinations of bacterial agonists, with host-bacterial contact a key determinant of these innate responses. Host epithelial recognition was offset by the microbe's ability to down-regulate the inflammatory response. Understanding the complexity of this host-microbial balance will contribute to improved vaccine design for infectious gastroenteritis.

Reduced production of sulfated glycosaminoglycans occurs in Zambian children with kwashiorkor but not marasmus.

BACKGROUND: Kwashiorkor, a form of severe malnutrition with high mortality, is characterized by edema and systemic abnormalities. Although extremely common, its pathophysiology remains poorly understood, and its characteristic physical signs are unexplained. OBJECTIVE: Because kwashiorkor can develop in protein-losing enteropathy, which is caused by a loss of enterocyte heparan sulfate proteoglycan (HSPG), and previous observations suggest abnormal sulfated glycosaminoglycan (GAG) metabolism, we examined whether intestinal GAG and HSPG are abnormal in children with kwashiorkor. DESIGN: Duodenal biopsy samples collected from Zambian children with marasmus (n = 18), marasmic kwashiorkor (n = 8), and kwashiorkor (n = 15) were examined for expression of HSPG, GAGs, and immunologic markers and compared against reference samples from healthy UK control children. GAG and HSPG expression density and inflammatory cell populations were quantitated by computerized analysis. RESULTS: The kwashiorkor group was less wasted and had a lower HIV incidence than did the other groups. All duodenal biopsy samples showed inflammation compared with the histologically uninflamed control samples. Biopsy samples from marasmic children had greater inflammation and greater CD3+ and HLA-DR (human leukocyte antigen DR)-positive cell densities than did samples from children with kwashiorkor. Expression of both HSPG and GAGs was similar between marasmic and well-nourished UK children but was markedly lower in children with kwashiorkor in both the epithelium and lamina propria. Although underglycosylated and undersulfated, epithelial syndecan-1 protein was normally expressed in kwashiorkor, which confirmed that abnormalities arise after core protein synthesis. CONCLUSIONS: Intestinal HSPG loss occurs in kwashiorkor, which may precipitate protein-losing enteropathy to cause edema. If occurring systemically, impaired HSPG expression could cause several previously unexplained features of kwashiorkor. We speculate that a genetic predisposition to reduced HSPG biosynthesis may offer a contrasting selective advantage, by both diminishing protein catabolism during transient undernutrition and protecting against specific infectious diseases.

Desquamative enteropathy and pyloric atresia without skin disease caused by a novel intracellular beta4 integrin mutation.

BACKGROUND: Mutations in alpha6 or beta4 integrins (ITGA6, ITGB4) are known to cause junctional epidermolysis bullosa with pyloric atresia (JEB-PA), often lethal in infancy through skin desquamation. There is 1 report of pyloric atresia associated with a desquamatory enteropathy but without skin disease, of unknown molecular basis. PATIENTS AND METHODS: We report 2 Kuwaiti siblings with pyloric atresia and life-threatening intestinal desquamation without significant skin abnormality. The older sibling died of intractable diarrhoea, and the younger sibling suffered episodes of massive protein-losing enteropathy, triggered by viral infections, in addition to obstructive uropathy. Mutation analysis was performed for ITGA6 and ITGB4 and expression of ITGA6 and ITGB4 protein was examined in skin and intestinal biopsies. Her serum also was incubated with normal intestine. RESULTS: We identified a novel mutation in ITGB4, with homozygous deletion of a single residue (isoleucine 1314) within the intracellular plectin-binding domain. Expression of ITGA6 and ITGB4 within skin, duodenal, and colonic epithelium was normal or minimally reduced, in contrast to previous reports. Biopsies taken during relapse showed accumulation of immunoglobulin G and C1q within intestinal basement membrane, whereas immunoglobulin G from her serum bound to basement membrane of normal small intestine. Immunomodulatory therapy induced significant improvement following relapses. CONCLUSIONS: ITGB4 mutation may induce a desquamative enteropathy in infancy without significant skin disease. A history of pyloric atresia is important in infants with severe chronic diarrhoeal disease and should prompt investigation for JEB-PA associated mutations. Acquired immune responses may exacerbate primary genetic disorders of epithelial adhesion and immunomodulatory therapy may be beneficial.

Do not laparotomize food-protein-induced enterocolitis syndrome.

Food protein-induced enterocolitis syndrome is a severe cell-mediated, non-immunoglobulin E-mediated gastrointestinal food allergy, typically to milk and soy. It may masquerade as more common pediatric presentations, where the temporal relationship between symptomatology and exposure to food offers a vital clue to the underlying pathology. A case of food protein-induced enterocolitis syndrome presenting with features similar to intussusception, leading to unnecessary surgery, is presented.

Massive gastrointestinal haemorrhage in isolated intestinal Henoch-Schonlein purpura with response to intravenous immunoglobulin infusion.

There is increasing recognition that Henoch-Schonlein purpura may present in an atypical form in which gastrointestinal symptoms may predominate, and classic cutaneous changes may be delayed or absent. This may lead to significant diagnostic delay. We report the case of a 9-year-old girl who presented acutely with life-threatening gastrointestinal haemorrhage from multiple intestinal sites, with no skin rash and only mild evidence of renal involvement. Henoch-Schonlein purpura was confirmed by finding IgA deposition on vessels within gastric and duodenal mucosa, while immunohistochemistry also identified dense focal T cell infiltration in gastric mucosa and within duodenal epithelium. After initial stabilisation, the patient became shocked due to further gastrointestinal haemorrhage. Isotope bleeding scan identified multiple bleeding sites. Her endoscopically confirmed gastritis was sufficiently severe to preclude corticosteroids, and she was thus treated with intravenous immunoglobulin. This therapy induced prompt and sustained resolution of symptoms, and she has remained well since. Our patient's response concords with previous reports in corticosteroid-resistant cases to suggest that severe intestinal Henoch-Schonlein purpura may respond preferentially to intravenous immunoglobulin (IVIG) therapy. In severe cases where there is significant gastritis, IVIG provides an effective alternative to corticosteroids that may be employed as first-line therapy.

Long polar fimbriae and tissue tropism in Escherichia coli O157:H7.

In vitro organ culture has demonstrated the human intestinal tropism of enterohaemorrhagic Escherichia coli O157:H7 for follicle associated epithelium overlying Peyer's patches of the terminal ileum. Long polar (LP) fimbriae are considered to mediate the attachment of Salmonella enterica serovar Typhimurium to Peyer's patch epithelium and, as homologous genes have been identified in O157:H7, we hypothesised that LP fimbriae in O157:H7 may perform the same function. However, mutation of LP fimbriae in O157:H7 strain 85/170 resulted in the novel phenotype of proximal and distal small intestinal colonisation with attaching/effacing lesion formation, while retaining adhesion to follicle associated epithelium. Application of whole genome DNA array technology did not identify changes in known fimbrial genes that could explain the change in tropism, but highlighted several genes that require further investigation. LP fimbrial genes are the first genes to be identified outside the locus of enterocyte effacement pathogenicity island that influence O157:H7 human intestinal tissue tropism.

Clinical manifestations of food allergy: the old and the new.

Food allergies are increasing in incidence, and the variety of triggering antigens is widening. There is also an increased recognition of the breadth of immunologically mediated responses to dietary antigens; the area of non-IgE-mediated food allergy is belatedly acquiring scientific respectability, aided by improved clinical recognition and basic scientific studies. The role of mucosal mast cells and eosinophils in intestinal allergic responses is now better recognized, and conditions such as eosinophilic oesophagitis are more prevalent than previously thought. However, the diagnostic difficulties of non-IgE-mediated allergies remain challenging.

Focal-enhanced gastritis in regressive autism with features distinct from Crohn's and Helicobacter pylori gastritis.

BACKGROUND: Immunohistochemistry allowed recent recognition of a distinct focal gastritis in Crohn's disease. Following reports of lymphocytic colitis and small bowel enteropathy in children with regressive autism, we aimed to see whether similar changes were seen in the stomach. We thus studied gastric antral biopsies in 25 affected children, in comparison to 10 with Crohn's disease, 10 with Helicobacter pylori infection, and 10 histologically normal controls. All autistic, Crohn's, and normal patients were H. pylori negative. METHODS: Snap-frozen antral biopsies were stained for CD3, CD4, CD8, gammadelta T cells, HLA-DR, IgG, heparan sulphate proteoglycan, IgM, IgA, and C1q. Cell proliferation was assessed with Ki67. RESULTS: Distinct patterns of gastritis were seen in the disease states: diffuse, predominantly CD4+ infiltration in H. pylori, and focal-enhanced gastritis in Crohn's disease and autism, the latter distinguished by striking dominance of CD8+ cells, together with increased intraepithelial lymphocytes in surface, foveolar and glandular epithelium. Proliferation of foveolar epithelium was similarly increased in autism, Crohn's disease and H. pylori compared to controls. A striking finding, seen only in 20/25 autistic children, was colocalized deposition of IgG and C1q on the subepithelial basement membrane and the surface epithelium. CONCLUSIONS: These findings demonstrate a focal CD8-dominated gastritis in autistic children, with novel features. The lesion is distinct from the recently recognized focal gastritis of Crohn's disease, which is not CD8-dominated. As in the small intestine, there is epithelial deposition of IgG.