Oral disodium cromoglycate and ketotifen for a patient with eosinophilic gastroenteritis, food allergy and protein-losing enteropathy

We present a case report of a 10 years old boy with protein-losing enteropathy and eosinophilic gastroenteritis who had positive histamine release tests, increased allergen-specific IgE antibodies to some food items, and low levels of total serum protein and albumin. Upper gastrointestinal endoscopy revealed a number of polyps and diffuse gastritis. Biopsy specimens of the stomach and duodenum showed widespread eosinophilia and neutrophilia. Although a restricted diet was recommended, a diet which excluded foods with positive results to both histamine release test and allergen-specific IgE antibodies was poorly tolerated, and the patient rejected systemic administration of corticosteroids. Thus, we initiated an oral disodium cromoglycate (DSCG) and ketotifen therapy. After oral DSCG and ketotifen administration, the patient's condition improved gradually. Therefore, oral DSCG and ketotifen therapy might be considered as treatment option in patients with eosinophilic gastroenteritis and protein-losing enteropathy caused by food allergy.     

New-onset hypercholesterolemia as an unusual presenting manifestation of eosinophilic gastroenteritis

We describe an unusual case of new-onset hypercholesterolemia in a 28-year-old man. The presence of low serum albumin and hypercholesterolemia established the suspicion of gastrointestinal disease. Technetium-99m diethylenetriaminepentaacetic acid scintigraphy was performed to identify possible protein-losing enteropathy. The results were consistent with eosinophilic gastroenteritis, a rare disease characterized by eosinophilic infiltration that may involve several digestive tract layers. To our knowledge, this is the first time that hypercholesterolemia has been recognizing as the presenting manifestation of eosinophilic gastroenteritis. The patient has been successfully treated with prednisone and budesonide. Hypercholesterolemia may be an early manifestation of a serious underlying disease, among which eosinophilic gastroenteritis should also be considered.     

Synoviocytes Type A Bind Exogenous Antigens Recognized by Antibodies Present in Rheumatoid Arthritis

The presence of antibodies in rheumatoid arthritis (RA) patients to antigens on the synoviocyte surface has recently been reported (Scand. J. Immunol. 27, 295, 1988). Here we have further characterized these antigens and found that they are exogenous proteins acquired from the bovine serum used in the culture medium. By immunoprecipitation and ELISA studies, we have identified bovine albumin and transferrin as the antigens recognized by the RA antibodies. These specificities were found not only in the sera but also in the synovial fluid from RA patients. A comparative study with a large panel of RA sera did not show a correlation in the antibody specificities for bovine albumin, bovine transferrin, or the 65-kDa heat shock protein from Mycobacterium bovis. Similar experiments using rabbit and monkey sera as well as human synovial fluid and serum as a source of antigen did not reveal any reactivity with a highly positive RA serum. By sequence alignment, a high degree of homology between residues 142-156 from bovine albumin and residues 65-78 from human pro-collagen alpha 1 (I) was found. The capacity of the synoviocytes to bind exogenous antigens and the presence of antibodies to bovine proteins, normally present in the diet, suggest a role for these type A synoviocytes as well as a possible involvement of food antigens in the pathogenesis of RA.     

Studies of human IgE to a sulfonamide determinant

We tested the hypothesis that patients who experience immediate hypersensitivity reactions to sulfonamides (SM) express IgE that can bind to a N4-sulfonamidoyl determinant (N4-SM). Sulfamethoxazole (SMX) was coupled to CNBr-activated cellulose disks to form a matrix predominantly substituted with isourea-linked N4-SMX determinants. After incubation of human sera with these disks or bovine serum albumin substituted disks as a control, the binding of IgE was assessed with 125I-labeled antihuman IgE. The binding ratios (counts per minute SMX disks per counts per minute bovine serum albumin disks) for sera from nonallergic donors and newborn infants averaged 1.11 (+/- 0.21 SD). Sera from 10 patients with histories of apparent immediate hypersensitivity reactions to SM were studied. Ratios greater than or equal to 2.1 (greater than 4 SD above control) were detected in 70% (seven of 10). Significant binding was detected in the sera of three of seven patients with other forms of SM allergy. Preincubation with SMX (80 mmol/L) inhibited binding 7% to 35% in eight of the 10 positive sera tested. Binding of one highly reactive serum was significantly inhibited by SMX, sulfamethizole, and sulfamerazine, but not sulfanilic acid or trimethoprim. The results of this study suggest that N4-SM is a major determinant recognized by IgE to SM and that an in vitro assay capable of detecting IgE to SM has been developed.     

HIV-1 infection complicated by food allergy and allergic gastroenteritis: a case report

A 34-year-old female with HIV-1 infection detected by positive serology in 1983 subsequently developed acute granulomatous interstitial pneumonitis, eosinophilic gastroenteritis, and angioedema associated with the ingestion of vanilla ice cream and tangerines. The enteritis and angioedema symptoms appeared to respond to large doses of oral sodium cromoglycate. Sera collected over several years before clinical symptoms revealed a sharp rise of IgE antibody in 1985 and a subsequent decline to baseline values followed by markedly increased levels of IgE antibodies to a number of inhalant and food allergens. The findings suggest disordered IgE antibody regulation as a consequence of HIV-1 infection and as a cause of allergic manifestations including eosinophilic gastroenteritis and food-induced angioedema.     

Enzyme immunoassay of specific human IgE to purified cows’ milk allergens

An immunometric enzyme immunoassay for specific immunoglobulin E (IgE) against five purified cows’ milk allergens, β‐lactoglobuHn, α‐lactalbumin, bovine serum albumin, lactoferrin and whole casein fraction, has been developed. Allergens were immobilized on microtitration plates. After incubations with sera from allergic patients, specific IgE bound to the plastic were detected using a monoclonal anti‐human IgE antibody labelled with acetylcholinesterase. Quantitative determinations were made by comparison with a dose‐response curve obtained under the same conditions with standard total IgE. A quantification limit of 0.08 IU ml^‐1 can thus be obtained with a coefficient of variation of lower than 5%. This allows specific IgE determinations of clinical significance in sera from allergic patients at a dilution of at least 1/10 (i.e. in a few μl of serum) with good precision and reproducibility. The determinations of specific IgE in sera from 11 patients allergic to cows’ milk showed an excellent correlation of this assay with clinical data.     

Toluene-diisocyanate induced asthma: evaluation of antibodies in the serum of affected workers against a tolyl mono-isocyanate protein conjugate

Radioallergosorbent testing was used to look for the presence of specific IgE antibody against a para-tolyl-mono-isocyanate human serum albumin conjugate in sera from five groups of subjects. The first three groups consisted of individuals exposed to toluene diisocyanate (TDI) who had been shown by bronchial provocation testing with levels of TDI below the threshold limit value of 0.02 parts/10⁶, to have immediate asthmatic reactions, late asthmatic reactions or no respiratory changes at all. The two control groups consisted of atopic and non-atopic individuals who had no respiratory symptoms and no known exposure to TDI. Although RAST showed high ct/min in some of the sera from patients with proven TDI-induced respiratory disease, these levels were not significantly different from controls and appeared to reflect the presence in these sera of high levels of total IgE (> 100 u ml^-1). There is no evidence from this study for the presence of specific IgE antibody against a para-tolyl mono isocyanate human serum albumin conjugate in patients with TDI-induced respiratory disease. This finding may reflect absence of antibodies, or that the techniques for their detection are not always effective even when performed by experienced persons, and there is a potential source of error in the interpretation of results when sera contain large amounts of IgE.     

Serum IgE and IgE antibody levels in patients with bronchial asthma, atopic dermatitis, eosinophilic granulomas of the soft tissue (Kimura's disease) and other diseases

Hyper-IgE immunoglobulinemia was observed in bronchial asthma, atopic dermatitis, eosinophilic granuloma of the soft tissue (Kimura's disease), disseminated visceral eosinophilic granulomas (Zuelzer-Apt syndrome) and disseminated eosinophilic collagen disease, IgE antibodies to environmental allergens (Dermatophagoides farinae mites, Aspergillus fumigatus, mountain cedar pollen, and Candida albicans) were found in bronchial asthma, atopic dermatitis and combinations of the two, but were not significantly detected in the latter three diseases. Hyper-IgE immunoglobulinemia may be divided into two groups on the basis of the presence of specific IgE antibodies directed to environmental allergens. The presence of antimite IgE antibodies in atopic dermatitis sera was confirmed by radioimmunoelectrophoresis. Anti-mite IgE antibodies in atopic dermatitis were heterogeneous in their specificity and the allergenic moieties to which IgE antibodies were directed varied from one case to another.     

Passive cutaneous anaphylaxis (PCA) and specific IgE in cystic fibrosis and their heterozygotes

The serum from 75% of the patients with cystic fibrosis (C.F.) who had a positive prick test in their skin to at least one or more antigens, together with elevated concentrations of total serum IgE, also gave strong immediate PCA reactions in the baboon skin to Aspergillus fumigatus, bovine serum albumin and egg albumin. Of the C.F. patients, 37% also had elevated serum specific IgE to A. fumigatus whereas only 8–10% had either raised specific IgE or PCA reaction to Dermatophagoides pteronyssinus. Abolition of the PCA activity by incubating the C.F. sera or sputum at 56°C suggested that the reaginic antibody was IgE rather than IgG4. PCA reactions to a number of allergens could be detected in both the C.F. sputum and saliva. Several of the C.F. heterozygotes had a strongly positive history of allergy and a significant number of these heterozygotes had an elevated serum total IgE as well as positive PCA to Timothy grass pollen or to D. pteronyssinus similar to the patients with asthma or hay fever. Three C.F. patients who died gave strong prick test reactions to several allergens and their sera also had raised serum IgE and positive PCA to at least three different allergens, suggesting that immediate hypersensitivity is of some significance in patients with C.F.     

Eosinophilic esophagitis is characterized by a non‐IgE‐mediated food hypersensitivity

Eosinophilic esophagitis (EoE) is a chronic disease characterized clinically by symptoms of esophageal dysfunction and histologically by eosinophil‐predominant inflammation. EoE is frequently associated with concomitant atopic diseases and immunoglobulin E (IgE) sensitization to food allergens in children as well as to aeroallergens and cross‐reactive plant allergen components in adults. Patients with EoE respond well to elemental and empirical food elimination diets. Recent research has, however, indicated that the pathogenesis of EoE is distinct from IgE‐mediated food allergy. In this review, we discuss the individual roles of epithelial barrier defects, dysregulated innate and adaptive immune responses, and of microbiota in the pathogenesis of EoE. Although food has been recognized as a trigger factor of EoE, the mechanism by which it initiates or facilitates eosinophilic inflammation appears to be largely independent of IgE and needs to be further investigated. Understanding the pathogenic role of food in EoE is a prerequisite for the development of specific diagnostic tools and targeted therapeutic procedures.     

Rotavirus-specific antibodies in fetal bovine serum and commercial preparations of serum albumin.

Rotavirus-specific antibodies were detected in fetal bovine serum, bovine serum albumin, and human serum albumin by radioimmunoprecipitation with the NCDV strain of bovine rotavirus as the detecting antigen. Fetal bovine sera neutralized bovine rotavirus in a plaque reduction neutralization test to titers of 1:20 or greater. Immunoglobulins purified from fetal bovine serum by protein A-agarose affinity chromatography precipitated rotavirus antigens but did not neutralize bovine rotavirus. Rotavirus antibodies in fetal bovine serum and in purified serum albumin preparations may interfere with diagnostic assays for the detection of rotavirus antigens or antibodies.     

Allergenicity of α-caseins from cow, sheep, and goat

The allergic potential of α-caseins from bovine, ovine, and goat's milk sharing more than 85% identical amino acids was compared. Caseins were purified by anion-exchange chromatography and used for a specific IgE and IgG ELISA with diluted human sera. Sera were from 17 children with immediate-type allergy to cow's milk, from 59 children with atopy but without food allergy, and from 27 healthy children without atopic disease. The sera of cow's milk-allergic children showed a significantly higher IgE and IgG binding to α-caseins from all three species than the sera of the other groups. All groups showed an increased antibody binding to bovine a-casein compared to the sheep and goat proteins, but the differences were significant only in the groups of atopic children and of healthy controls. Furthermore, inhibition of the IgE binding to bovine α-casein with α-casein from cow, goat, and sheep revealed that the a-caseins from these species are highly cross-reactive, on the basis of the small differences in their primary structure. In conclusion, the milk of goat and sheep harbor an allergic potential and is not suitable for the nutrition of milk-allergic patients.     

Allergic cross-reactions between cat and pig serum albumin

After observing a patient allergic to cat dander and pork but devoid of other allergies, we prospectively screened patients known to be allergic to cat for a second sensitization to pork. After collecting the sera of 10 young patients found to contain specific IgE to cat dander and pork, we undertook this study to detect the possible cross-reactive allergen, define its molecular characteristics, and evaluate its clinical relevance. Through immunoblotting techniques, cat and porcine serum albumin were found to be jointly recognized molecules. These findings were further analyzed by specific anti-albumin IgE titrations and cross-inhibition experiments. Cat serum albumin cDNA was obtained from cat liver, and the corresponding amino acid sequence was deduced and compared to the known porcine and human serum albumin sequences. Inhibition experiments showed that the spectrum of IgE reactivity to cat serum albumin completely contained IgE reactivity to porcine serum albumin, suggesting that sensitization to cat was the primary event. In two cohorts of cat-allergic persons, the frequency of sensitization to cat serum albumin was found to lie between 14% and 23%. Sensitization to porcine albumin was found to lie between 3% and 10%. About 1/3 of these persons are likely to experience allergic symptoms in relation to pork consumption. Sensitization to cat serum albumin should be considered a useful marker of possible cross-sensitization not only to porcine serum albumin but also to other mammalian serum albumins.     

Reactivity of antibodies in human serum with antigens of an enteropathogenic bovine coronavirus

Antibodies in human serum against an enteropathogenic bovine coronavirus were detected by double immunodiffusion (DID), neutralization of infectivity, indirect immunofluorescence, and immune electron microscopy. Human sera reacting in the DID test neutralized the infectivity of the bovine coronaviruses to indices of 2.5 to > 5. Nineteen of 40 DID-negative, heat-inactivated sera had neutralizing indices of 1 to 3.0. Human serum with neutralizing and DID antibodies produced juxtanuclear and cytoplasmic fluorescence identical to that of bovine immune serum in cells infected with the bovine coronavirus. Antibodies in human and bovine sera interacted with the peplomeres of the bovine coronavirus, matting and bridging them, when present in excess, and facilitated formation of large viral aggregates when present in equivalent concentrations. Complement added to the virus-antibody complexes did not alter specifically the morphology of single, antibody-laden viral particles or viral particles in aggregates. Evidence of the transmission of coronavirus from experimentally inoculated calves to man, with ensuing gastroenteritis, was found by electron microscopic tracing of the coronavirus and its virus-antibody complexes.     

Immunomodulatory therapy of eosinophil‐associated gastrointestinal diseases

Eosinophil‐associated gastrointestinal disorders (EGIDs), including eosinophilic esophagitis (EE) and eosinophilic gastroenteritis (EG), are a spectrum of increasingly recognized inflammatory diseases characterized by gastrointestinal symptoms and eosinophilic infiltration of the gastrointestinal tract. Significant morbidity is associated with the development of esophageal strictures in some patients. Immune‐mediated reactions to food allergens appear to drive the inflammation in a subset of patients, especially those with solitary EE, but dietary interventions remain difficult in EE and are less effective in EG. Despite the increasing incidence of these disorders and their increased recognition by physicians, there are currently no medications that either United States or European Union regulatory agencies have specifically approved for use in EGIDs. This lack of safe and effective therapies for EGIDs is a major obstacle in the care of these patients and underscores the need for new therapeutic approaches. This review briefly discusses the currently available ‘off label’ drug treatments for EGIDs, most notably topical and systemic corticosteroids. Pathogenesis studies of EGIDs suggest possible therapeutic targets, and conversely, clinical trials of mechanistically‐targeted therapeutics give insight into disease pathogenesis. Thus, EGID pathogenesis is discussed as an introduction to mechanistically‐targeted immunotherapeutics. The two biologic categories that have been used in EGIDs, anti‐IgE (omalizumab) and anti‐IL‐5 (SCH55700/reslizumab and mepolizumab), are discussed. Because there are similarities in the pathogenesis of EGIDs with asthma and atopic dermatitis, biologic therapeutics currently in early trials for asthma management are also briefly discussed as potential therapeutic agents for EGIDs. Given the deficiencies of current therapeutics and the rapidly advancing knowledge of the pathogenesis of these disorders, EGIDs are an ideal model for translating recent advances in understanding immunopathogenesis into mechanistically‐based therapeutics. Further understanding of the early events in pathogenesis is also needed to develop preventive and disease‐modifying treatments.     

Transglutaminase and coeliac disease: endomysial reactivity and small bowel expression

This study was aimed at verifying whether tissue transglutaminase (tTG) is the sole autoantigen eliciting anti-endomysial antibodies in coeliac disease (CoD) and investigating tTG expression in normal and coeliac mucosa. Twelve anti-endomysial-positive coeliac sera and 12 anti-endomysial-negative control sera (10 microl, diluted 1:5-1:400 in PBS pH 7.3) were preincubated with 10, 20 or 50 microg guinea pig liver tTG at 4 degrees C overnight. Monkey oesophagus tissue slides were then tested with tTG-preincubated and non-preincubated sera to search for IgA anti-endomysial reactivity by indirect immunofluorescence. Moreover, six sections of monkey oesophagus were incubated with an anti-tTG mouse MoAb, six sections with an anti-cytokeratin mouse MoAb and six sections with only 3% bovine serum albumin. Finally, endoscopic duodenal biopsy sections obtained from 12 patients affected by untreated CoD, six patients affected by treated CoD and 10 biopsied controls were immunohistochemically stained with a peroxidase-conjugated anti-tTG MoAb. Our results show that (i) preincubation with tTG abolished endomysial immunofluorescence in most, but not in all, coeliac sera; (ii) the incubation of anti-tTG MoAb with sections of monkey oesophagus resulted in an immunofluorescence staining pattern similar but not identical to that of anti-endomysial-positive coeliac sera; (iii) although tTG expression was present at muscularis mucosae and pericryptal fibroblast in both normal and coeliac mucosa, it was slightly more marked and evident in the latter. Although our absorption experiment was performed with guinea pig liver tTG, we confirm that tTG is the predominant antigen of endomysial antibodies, but we speculate that, at least in some patients, it is not the only one.     

Mechanism of allergy to components of commercial bovine thyrotropin

This report describes a systemic immediate-type allergic reaction to commercial thyrotropin in a patient with hypothyroidism and chronic candidiasis. Immunologic studies of the patient's serum revealed precipitating antibodies against bovine albumin and gamma globulin, and the thyrotropin preparation was found to be contaminated with these proteins. Skin testing with purified bovine albumin and commercial thyrotropin produced wheal-and-flare reactions indicating the presence of reaginic antibodies but did not evoke Arthus or delayed-type responses. The patient's serum contained elevated concentrations of thyrotropin consistent with the diagnosis of primary hypothyroidism, but it did not inhibit the biologic activities of human or bovine thyrotropins. Although antibodies against bovine proteins are often found in human serum, they are only rarely associated with disease. In our patient a systemic allergic reaction was apparently the result of the interaction between anti-albumin antibodies and the albumin contaminating the TSH. The studies of the effects of the patient's serum on the biologic activities of bovine or human thyrotropins did not provide evidence for an anti-TSH that could be implicated in the pathogenesis of hypothyroidism.     

The antibody response to methyl isocyanate: experimental and clinical findings

Sera from 99 subjects exposed to the industrial gas leak in Bhopal on December 2, 1984 were studied along with sera from guinea pigs exposed to methyl isocyanate (MIC) to determine the production of antibodies specific to (MIC). Each of the four guinea pigs injected with the reactive isocyanate produced MIC-specific antibodies in titres of 1:5120 to 1:10240, when tested with MIC-guinea pig albumin antigen conjugate. Analogous antigens prepared by reaction of MIC with human serum albumin were used to probe production of antibodies in 264 serially obtained human sera from 99 subjects from Bhopal. MIC-specific antibodies belonging to IgG, IgM and IgE classes were detected in eleven subjects. Though titres were low and transient (declining after several months) these findings indicate that the single large exposure to MIC resulted in an immunologic response. This finding was concomitant with chronic respiratory effects following MIC exposure.     

The intestinal absorption of pig and bovine immune lactoglobulin and human serum albumin by the new-born pig

1. Homologous and heterologous colostral immune globulins and human serum albumin were fed to new-born pigs and an attempt was made to estimate the amounts appearing subsequently in serum.2. All three proteins, fed separately in large amounts to different pigs, appeared in the serum in low concentration about 45 min after feeding, and then rose quickly to a high level. No difference could be detected between the amounts absorbed when equal amounts had been fed but there was a wide variation between pigs. Previous dialysis of pig colostrum against bicarbonate saline did not affect the rate or amount of pig immune globulin absorbed after feeding.3. When pig and bovine colostral IgG were fed together at equal concentrations in bovine colostrum, the absorption of pig IgG was greater than that of bovine IgG. Human serum albumin, added to bovine colostral IgG in bovine colostrum, was absorbed readily and this did not interfere significantly with the absorption of bovine colostral IgG.4. The efficiency with which the pig intestine absorbed bovine colostral IgG depended on the dose and/or concentration fed, increasing as the dose fed was increased to 2 g and remaining constant for higher doses.5. Some of the absorbed immune globulin was shown to exist in a partly degraded form.6. The process of protein transfer across the intestine of the new-born pig may select, to a limited degree, between different proteins, but the digestion of protein shown to take place and the large variation between individual pigs makes interpretation of these results uncertain.