Article Summaries - April 2014
IS THE CONSISTENCY MORE IMPORTANT THAN THE INGREDIENTS FOR STEROID TREATMENT IN EOSINOPHILIC ESOPHAGITIS?
(Parrish DW, Sharma S, Kumar S. Ann Allergy Asthma Immunol 2014; 112: 286-289)
- Eosinophilic esophagitis (EoE): (i) pathogenesis: immune reaction to food or respiratory allergens in the esophagus → infiltration of eosinophils into esophageal mucosa (usually patchy) → chronic eosinophilic inflammation → esophageal dysfunction; (ii) common causal foods in children: milk, egg, soy, wheat, beef, chicken; (iii) common causal foods in adults: legumes, nuts, fruits, wheat, milk, soy, egg; (iv) frequent association with respiratory and skin allergies; (v) often misdiagnosed as GERD.
- Diagnosis of EoE: (i) clinical history: abdominal pain, vomiting, dysphagia, food impaction, heartburn, cough, choking, food aversion, failure to thrive; (ii) esophageal endoscopy: white exudative plaques, mucosal rings (‘trachealization’), strictures, linear furrows, edema; (iii) 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); (iv) allergy testing (SPT, in vitro sIgE detection, patch test) with food and respiratory allergens; (v) food elimination-reintroduction trials; (vi) 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) corticosteroids (most recommended regimen: to swallow viscous budesonide respules mixed into a slurry-type solution with a sucralose-containing artificial sweetener); (iii) biologic therapies targeting the eosinophil (e.g. anti-IL-5 mAb, anti-IL-5R mAb).
- Authors report the case of a 2-yr-old boy (author’s son) with EoE and intolerance to the sucralose-containing artificial sweetener (present in both the viscous budesonide preparation and the milk formula; the family helped a lot to get the correct diagnosis) → successful treatment: utilization of powdered sugar [viscous budesonide + 2 tsp of powdered sugar] and an unflavored aminoacid-based formula.
- Author’s commentaries: (i) the consistency (thick enough to coat the esophagus), rather than the mixing ingredient, is likely the most important aspect of the steroid mixture for EoE treatment; (ii) it is essential to find a mixing food that the child tolerates (e.g. powdered sugar, honey, pancake syrup, pureed meal); (iii) parents’ ideas must be considered by the physicians.
IgG-MEDIATED DOWN-REGULATION OF IgE BOUND TO MAST CELLS: A POTENTIAL NOVEL MECHANISM OF ALLERGEN-SPECIFIC DESENSITIZATION
(Uermösi C, Zabel F, Manolova V, Bauer M, Beerli RR, Senti G, Kündig TM, Saudan P, Bachmann MF. Allergy 2014; 69: 338–347):
- Immune tolerance: nonresponsiveness of the adaptive immune system or active Treg cell response to antigens; mechanisms: Treg generation, anergy/deletion of reactive lymphocytes.
- Immune tolerance is essential to prevent: (i) self-destruction; (ii) inflammatory response to beneficial or harmless exogenous molecules (e.g. food, commensal bacteria, allergens).
- Loss of immune tolerance → allergic or autoimmune disorders (e.g. exposure to allergens in genetically susceptible subjects → specific TH2 responses → IgE-mediated allergies).
- ~30% of the population in industrialized countries suffers from IgE-mediated allergies.
- Allergen immunotherapy (AIT): (i) only therapy that has proved to provide long-term benefit and modulation of allergic disease; (ii) has been widely used to treat asthma, allergic rhinitis and venom allergy; (iii) promising therapy for atopic dermatitis and food allergy; (iv) it is necessary to improve AIT efficacy, safety and convenience.
- How to ↑ efficacy and safety of AIT? (i) adding omalizumab (anti-IgE mAb); (ii) adding adjuvants (e.g. aluminum salts to slower allergen release from the injection site); (iii) using modified allergens (e.g. allergoids [altered allergens using formaldyde or glutaraldehyde to ↓ allergenicity while preserving immunogenicity], recombinant hypoallergenic allergens, tolerogenic peptides, recombinant DNA vaccines, allergens on virus-like particles), (iv) adding immune response modifiers (monophosphoryl lipid A [TLR-4 agonist], CpG-containing DNA [TLR-9 agonist], TLR8 agonists, probiotics, bacterial lysates, virus-like particles); (v) using other administration routes (epicutaneous, intralymphatic, intradermal, intranasal, oral); (vi) personalizing AIT schemes; (vii) inhibiting IgE-mediated cell activation by engaging the inhibitory receptor FcγRIIB (Fcγ-Fcε fusion molecules; allergen-Fcγ fusion molecules).
- Allergen-specific IgG can inhibit IgE-mediated mast cell degranulation by 3 mechanisms: (i) allergen-neutralization (blocking antibodies); (ii) engagement of the inhibitory FcγRIIB → coaggregation of FcγRIIB and FcεRI by IgG and IgE antibodies simultaneously bound to allergen → recruitment of phosphatase SHIP-1 → inhibition of FcεRI-mediated signaling; (iii) engagement of the inhibitory FcγRIIB → ↑ internalization of specific IgE/FcεRI → down-regulation of FcεRI-bound IgE (novel mechanism in mice, reported in the current article).
- Author’s commentary: IgE replacement on mast cells occurs slowly → a rapid IgG-dependent elimination of IgE from the cell surface may allow long-term desensitization of mast cells.
MUCOSAL MAST CELL COUNTS IN PEDIATRIC EOSINOPHILIC GASTROINTESTINAL DISEASE
(Mir SAV, Schady D, Olive AP, Nagy-Szakal D, Kellermayer R. Pediatr Allergy Immunol 2014: 25: 94–95)
- Primary eosinophilic gastrointestinal disorders (EGID): eosinophilic esophagitis (EoE), eosinophilic gastroenteritis, eosinophilic colitis, eosinophilic proctitis.
- Other diseases that can cause mucosal eosinophilia: inflammatory bowel disease, irritable bowel syndrome, celiac disease.
- Mast cell–eosinophil interaction: (i) mast cell-derived IL-13 can recruit eosinophils; (ii) mucosal mast cells can be increased in adults and children with EoE.
- Authors studied biopsies from 12 children with EGID (excluding EoE; average age=10.4 yrs) and 14 healthy controls (average age=12.3 yrs) → (i) there was a significant positive correlation between eosinophil and mast cell counts in control samples; (ii) there was no correlation between eosinophil and mast cell counts in EGID patients (disrupted mast cell–eosinophil interaction?); (iii) study limitation: the utilized staining only detects granulated mast cells (increased degranulated mast cells in EGID patients might have not been detected).
PREVALENCE OF ATOPY, EOSINOPHILIA, AND IgE ELEVATION IN IgG4-RELATED DISEASE
(Della Torre E, Mattoo H, Mahajan VS, Carruthers M, Pillai S, Stone JH. Allergy 2014; 69: 269–272)
- IgG4: (i) 5% of total IgG; (ii) antiinflammatory properties (negligible binding to C1q; exchangeable heavy chains [“Fab arm exchange”] that prevents cross-linking of antigen; higher affinity toward inhibitory FcγRIIb than to activatory FcγRIIa and FcγRIIIa).
- IgG4 autoantibodies are pathogenic in some autoimmune disorders (e.g. pemphigus vulgaris: IgG4 to desmoglein; idiopathic membranous glomerulonephritis: IgG4 to PLA-2 receptor).
- IgG4-related disease (RD): (i) multi-organ fibroinflammatory disease (tumefactive lesions rich in T cells and IgG4-positive plasma cells); (ii) unclear pathogenesis (TH2 cells may have a pathogenic role); (iii) can affect almost every organ; (iv) usually affects middle-aged to elderly men; (v) common clinical manifestations: autoimmune pancreatitis, sialadenitis, orbital disease (typically affecting lacrimal gland), allergic diseases, eosinophilia, ↑ serum IgE; (vi) 30% of patients have normal serum IgG4 concentrations; (vii) histology: diffuse lymphoplasmacytic infiltrate rich in IgG4-positive plasma cells, storiform fibrosis, obliterative phlebitis, ↑ eosinophils; (viii) treatment: corticosteroids, immunosuppressants, rituximab.
- Authors evaluated the prevalence of atopy, peripheral blood eosinophilia (PBE) and ↑ IgE in 70 patients (24–82 yrs old) with biopsy-proven IgG4-RD → (i) 43 patients (61%) had ↑ serum IgG4 levels; (ii) 22 patients (31%) were atopic (similar prevalence of atopy to the US general population); (iii) ~20% of nonatopic subjects had PBE and ↑ IgE (hypothesis: processes inherent to IgG4-RD itself may contribute to PBE and ↑ IgE); (iv) there was a positive correlation between serum IgG4 levels and both serum IgE and eosinophil counts.