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Article Summaries - May 2014


ESOPHAGITIS (Merves J, Muir A, Modayur Chandramouleeswaran P, Cianferoni A, Wang M-L, Spergel JM. Ann Allergy Asthma Immunol 2014; 112: 397-403):

  • Eosinophilic esophagitis (EoE): (i) prevalence in general population: ~1/2,000 subjects (may be underestimated); (ii) prevalence in US children: ~1/200; (iii) incidence is rising (~15% of adults undergoing endoscopy for dysphagia); (iv) male to female ratio=3:1; (v) impact: significant morbidity, ? QoL, high cost; (vi) pathogenesis: genetic susceptibility, environmental insults to the esophageal epithelium (e.g. allergens, infections, irritants) ? epithelial barrier dysfunction (e.g. ? expression of the cell adhesion protein DSG-1), ? secretion of TSLP and IL-33 ? ? allergen entry through the epithelium ? immune reaction to food or respiratory allergens ? infiltration of eosinophils into esophageal mucosa ? chronic inflammatory infiltrate (eosinophils, mast cells, a special basophil population, TH2 cells, iNKT cells) ? esophageal fibrosis, remodelling (e.g. transdifferentiation of epithelial cells to a myofibroblast phenotype) and dysfunction; (vii) TSLP and eotaxin-3 gene polymorphisms can ? risk of EoE; (viii) TSLP-mediated basophil response is likely to play an important role in EoE pathogenesis; (ix) IgE does not seem to play an essential role in EoE pathogenesis; (x) common causal foods in children: milk, egg, soy, wheat, beef, chicken; (xi) common causal foods in adults: legumes, nuts, fruits, wheat, milk, soy, egg; (xii) frequent association (40-90%) with other atopic diseases (asthma, allergic rhinitis, food allergy, atopic dermatitis); (xiii) often misdiagnosed as GERD.
  • Diagnosis of EoE: (i) clinical history: abdominal pain, vomiting, dysphagia, heartburn, cough, choking, food aversion; (ii) complications: food impaction, failure to thrive, spontaneous esophageal perforation, mental affectation; (iii) esophageal endoscopy: edema, white exudative plaques, mucosal rings (‘trachealization’), strictures, linear furrows, mucosal tearing; (iv) esophageal biopsy (positive result: =15 eosinophils per high-power field; limitation: 5 biopsies represent only <0.02% of the esophageal surface ? false negative results can occur, especially in mild cases; other findings: superficial layering, microabscesses, extracellular eosinophil granules, basal cell hyperplasia, dilated intercellular spaces, lamina propria fibrosis; before endoscopy, all patients should be treated with high-dose PPI therapy of 20-40 mg bid in adults and 1 mg/kg bid in children for 8-12 wks to exclude GERD and other forms of PPI-responsive esophageal eosinophilia); (v) allergy testing (SPT, in vitro sIgE detection, patch test) with food and respiratory allergens; (vi) food elimination-reintroduction trials; (vii) detection of eosinophil-mediated inflammation (e.g. cationic eosinophil granule proteins) by SPECT imaging.
  • Treatment of EoE: (i) diet options: 6-food elimination diet (milk, egg, wheat, soy, fish/seafood, peanut/tree nuts), diet guided by allergy tests, aminoacid formula, (ii) topical corticosteroids (most recommended regimen: to swallow viscous budesonide respules mixed into a slurry-type solution with a sucralose-containing artificial sweetener; other regimen: to spray MDI fluticasone without a spacer into the mouth and swallow it; swallowed steroids have low bioavailability and low potential for systemic adverse effects but ? risk of local fungal infection); (iii) systemic corticosteroids: effective, severe side effects; (iv) biologic therapies targeting the eosinophil (e.g. anti-IL-5 mAb, anti-IL-5R mAb); (v) esophageal dilation: might provide short-term symptomatic relief, only used if dietary and medical therapy has failed.
  • Human esophageal epithelial cells: (i) express TLRs; (ii) produce proinflammatory cytokines in response to both PAMPs and DAMPs; (iii) can produce the eosinophilic and T-cell chemokine RANTES (CCL5); (iv) may function as nonprofessional APCs.
  • IL-5: (i) important for the production and early growth of eosinophils; (ii) mature eosinophils lose IL-5 receptors and are more dependent on IL-3 and GM-CSF.
  • Activated myofibroblast: (i) exhibits properties of both smooth muscle cells and fibroblasts; (ii) key effector cell in all models of fibrosis (mechanisms: myofibroblast contracts and places tension on the extracellular matrix [ECM] ? activation and differentiation of neighboring cells ? myofibroblast secretes ECM components to stabilize its new contracted position); (iii) TGF-ß stimulates myofibroblast differentiation.


(Noti M, Kim BS, Siracusa MC, Rak GD, Kubo M, Moghaddam AE, Sattentau QA, Comeau MR, Spergel JM, Artis D. J Allergy Clin Immunol 2014; 133: 1390-1399):

  • Food allergy (FA) affects up to 5% of children and 4% of adults in some countries.
  • Atopic dermatitis (AD): (i) known risk factor for FA (hypothesis: sensitization to food allergens through a disrupted and inflamed skin); (ii) human AD skin lesions are associated with ? TSLP expression and basophil infiltration.
  • Skin barrier defect -> pruritus and skin inflammation (including -> TSLP production) -> entry of food allergens through disrupted skin -> activation of TSLP-elicited basophils -> TH2 responses, IgE sensitization -> development of FA.
  • TSLP-basophil axis: novel target to prevent and treat FA.


(Lyons JJ, Sun G, Stone KD, Nelson C, Wisch L, O’Brien M, Jones N, Lindsley A, Komarow HD, Bai Y, Scott LM, Cantave D, Maric I, Abonia JP, Rothenberg ME, Schwartz LB, Milner JD, Wilson TM. J Allergy Clin Immunol 2014; 133: 1471-1474):

  • Allergic diseases are usually multifactorial (several genetic and environmental factors).
  • Monogenic causes of allergic disease and inherited mast cell disorders: (i) Kazal type 5 (SPINK5) mutations in patients with Netherton syndrome; (ii) STAT3 mutations in AD hyper-IgE syndrome; (iii) DOCK8 mutations in AR HIES; (iv) phospholipase C, gamma 2 (PLCG2) mutations in familial cold urticaria; (v) KIT mutations in mastocytosis.
  • Some connective tissue syndromes (Loeys-Dietz, Marfan and Ehlers-Danlos syndromes) have been associated with atopic disease.
  • Authors report subjects from 9 families (dominant inheritance pattern) with persistent high basal serum protryptase levels (mean=21.6±1.4 ng/mL), symptoms of mast cell mediator release (urticaria, flushing, cramping abdominal pain, fecal urgency, diarrhea, asthma, anaphylaxis; spontaneous or triggered by heat, exercise, vibration, stress, foods or minor physical trauma) and additional nonatopic features (eosinophilic GI disease, GERD, irritable bowel syndrome, hypermobility, chronic musculoskeletal pain, autonomic dysfunction, neuropsychiatric symptoms) ? no evidence of mast cell clonal disorders (bone marrow biopsy: significant ? in mast cell numbers, no mast cell aggregates, no aberrant expression of CD2/CD25, no KIT D816V mutations; impaired basophil activation in vitro) ? additional genetic study is ongoing.


(Amoah AS, Boakye DA, van Ree R, Yazdanbakhsh M. Pediatr Allergy Immunol 2014; 25: 208–217):

  • Allergic diseases have dramatically increased (probably due to environmental and lifestyle factors; unlikely due to genetic causes). Risk factor: ? exposure to pathogens during childhood ? insufficient maturation of regulatory immunity.
  • Helminths: (i) metazoan parasites that can ? host’s immunity to prevent their elimination and ? severe pathology in the host; (ii) infect ~1 billion people worldwide; (iii) risk factors for infection: living in tropical regions, poverty, poor sanitation; (iv) immune response to helminths depends on the infected tissue and the type of helminth (e.g. TH2 vs T regulatory responses).
  • Relationship between helminth infections and allergic diseases: (i) helminth infections may protect, promote or have no effect on allergic sensitization/disease (recombinant allergen technology may help to clarify this relationship); (ii) contributing factors: type of helminth, site of infection, host’s characteristics; (iii) antihelmintic therapy may either worsen or relieve allergic sensitization and disease; (iv) helminth infections can induce IgE cross-reactivity (often clinically irrelevant) against allergen proteins (e.g. tropomyosin, paramyosin, glutathione S-transferase) or glycans (e.g. xylose, core-3-linked fucose); (v) a prominent feature of helminth infection consists in high levels of IgE against allergens without SPT reactivity; (vi) helminth products have been used as therapies to promote immune tolerance and treat inflammatory conditions (e.g. Trichuris suis eggs to treat allergies and IBD); (vii) further research is necessary.


(Amoah AS, Boakye DA, van Ree R, Yazdanbakhsh M. Pediatr Allergy Immunol 2014; 25: 208–217):

  • IL-4: (i) essential cytokine for TH2 immune responses; (ii) actions: TH2-cell differentiation, B-cell switching to IgE production, ? MHC-II expression on mast cells (also basophils?); (iii) therapeutic target for allergic diseases.
  • Sources of IL-4: (i) TH2 lymphocytes; (ii) innate lymphoid cells type 2; (iii) basophils
  • IL-4-expressing non-T cells, particularly basophils, might play an essential role in the early development of food allergy.