Hayley R. James

Relationship between red meat allergy and sensitization to gelatin and galactose-α-1,3-galactose

BACKGROUND We have observed patients clinically allergic to red meat and meat-derived gelatin. OBJECTIVE We describe a prospective evaluation of the clinical significance of gelatin sensitization, the predictive value of a positive test result, and an examination of the relationship between allergic reactions to red meat and sensitization to gelatin and galactose-α-1,3-galactose (α-Gal). METHODS Adult patients evaluated in the 1997-2011 period for suspected allergy/anaphylaxis to medication, insect venom, or food were skin tested with gelatin colloid. In vitro (ImmunoCAP) testing was undertaken where possible. RESULTS Positive gelatin test results were observed in 40 of 1335 subjects: 30 of 40 patients with red meat allergy (12 also clinically allergic to gelatin), 2 of 2 patients with gelatin colloid-induced anaphylaxis, 4 of 172 patients with idiopathic anaphylaxis (all responded to intravenous gelatin challenge of 0.02-0.4 g), and 4 of 368 patients with drug allergy. Test results were negative in all patients with venom allergy (n = 241), nonmeat food allergy (n = 222), and miscellaneous disorders (n = 290). ImmunoCAP results were positive to α-Gal in 20 of 24 patients with meat allergy and in 20 of 22 patients with positive gelatin skin test results. The results of gelatin skin testing and anti-α-Gal IgE measurements were strongly correlated (r = 0.46, P < .01). α-Gal was detected in bovine gelatin colloids at concentrations of approximately 0.44 to 0.52 μg/g gelatin by means of inhibition RIA. CONCLUSION Most patients allergic to red meat were sensitized to gelatin, and a subset was clinically allergic to both. The detection of α-Gal in gelatin and correlation between the results of α-Gal and gelatin testing raise the possibility that α-Gal IgE might be the target of reactivity to gelatin. The pathogenic relationship between tick bites and sensitization to red meat, α-Gal, and gelatin (with or without clinical reactivity) remains uncertain.

Serum IgE measurement and detection of food allergy in pediatric patients with eosinophilic esophagitis

BACKGROUND Although associated allergies are common and the mechanism may include long-term exposure to allergens, measurement of serum specific IgE levels has not been studied in pediatric eosinophilic esophagitis (EE). OBJECTIVE To compare the results of serum IgE testing, patch testing, and epicutaneous skin testing to measure allergic sensitization in pediatric patients with EE. METHODS In a cross-sectional study of 53 pediatric patients with EE, relevant history was obtained by questionnaire, and patch testing to foods was performed. Food and inhalant sensitivities were also assessed using skin prick testing and serum specific IgE measurement. Streptavidin CAP was used to measure specific IgE to cross-reactive carbohydrate determinants and Helicobacter pylori. RESULTS The overall prevalence of food and inhalant sensitization was 80%, with higher total IgE levels in sensitized vs nonsensitized patients (median, 150 vs 13 IU/mL; P < .001). For foods, serum IgE measurement detected more positive results than did skin prick testing. Specific IgE to milk was most common (43%). Inhalants were implicated as frequently as were foods. In keeping with this, 32% of patients had a cluster of multiple sensitivities that included pollens, soy, grains, peanut, and tree nuts and had higher total IgE levels (P = .001). Patch test results were interpreted as positive in 39% of patients (rye, wheat, and soy were the most common). CONCLUSIONS Most, but not all, patients with EE are highly atopic individuals with frequent allergic sensitivities. Thus, serum IgE measurement of low-titer IgE antibody may be useful in identifying relevant food sensitivities and in distinguishing subgroups of patients with EE, making a more directed approach to food avoidance possible.

Delayed clinical and ex vivo response to mammalian meat in patients with IgE to galactose-alpha-1,3-galactose

BACKGROUND In 2009, we reported a novel form of delayed anaphylaxis to red meat related to serum IgE antibodies to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal). Although patients were remarkably consistent in their description of a 3- to 6-hour delay between eating mammalian meat and the appearance of symptoms, this delay has not been demonstrated under observed studies. OBJECTIVES We sought to formally document the time course of clinical symptoms after the ingestion of mammalian meat in subjects with IgE to alpha-gal and to monitor ex vivo for the appearance of markers of an allergic reaction. METHODS Open food challenges were performed with mammalian meat in 12 subjects with a history of severe urticarial reactions 3 to 6 hours after eating beef, pork, or lamb, as well as in 13 control subjects. Blood samples were taken hourly during each challenge. RESULTS Ten of 12 subjects with IgE to alpha-gal had clinical evidence of a reaction during the food challenge (vs none of the control subjects, P < .001). The reactions occurred 3 to 7 hours after the initial ingestion of mammalian meat and ranged from urticaria to anaphylaxis. Tryptase levels were positive in 3 challenges. Basophil activation, as measured by increased expression of CD63, correlated with the appearance of clinical symptoms. CONCLUSION The results presented provide clear evidence of an IgE-mediated food allergy that occurs several hours after ingestion of the inciting allergen. Moreover, here we report that in vivo basophil activation during a food challenge occurs in the same time frame as clinical symptoms and likely reflects the appearance of the antigen in the bloodstream.

Anti-galactose-α-1,3-galactose IgE from allergic patients does not bind α-galactosylated glycans on intact therapeutic antibody Fc domains

Anti-galactose-α-1,3-galactose IgE from allergic patients does not bind α-galactosylated glycans on intact therapeutic antibody Fc domains

Galactose-α-1,3-Galactose–Specific IgE Is Associated with Anaphylaxis but Not Asthma

RATIONALE IgE antibodies to the mammalian oligosaccharide galactose-α-1,3-galactose (α-gal) are common in the southeastern United States. These antibodies, which are induced by ectoparasitic ticks, can give rise to positive skin tests or serum assays with cat extract. OBJECTIVES To evaluate the relationship between IgE antibodies to α-gal and asthma, and compare this with the relationship between asthma and IgE antibodies to Fel d 1 and other protein allergens. METHODS Patients being investigated for recurrent anaphylaxis, angioedema, or acute urticaria underwent spirometry, exhaled nitric oxide, questionnaires, and serum IgE antibody assays. The results were compared with control subjects and cohorts from the emergency department in Virginia (n = 130), northern Sweden (n = 963), and rural Kenya (n = 131). MEASUREMENTS AND MAIN RESULTS Patients in Virginia with high-titer IgE antibodies to α-gal had normal lung function, low levels of exhaled nitric oxide, and low prevalence of asthma symptoms. Among patients in the emergency department and children in Kenya, there was no association between IgE antibodies to α-gal and asthma (odds ratios, 1.04 and 0.75, respectively). In Sweden, IgE antibodies to cat were closely correlated with IgE antibodies to Fel d 1 (r = 0.83) and to asthma (P < 0.001). CONCLUSIONS These results provide a model of an ectoparasite-induced specific IgE response that can increase total serum IgE without creating a risk for asthma, and further evidence that the main allergens that are causally related to asthma are those that are inhaled.

Initial description of pork-cat syndrome in the United States

To the Editor: Despite meat being an important source of protein in Western diets, development of meat allergy is uncommon. For mammalian meat, the extensive homology of proteins across mammalian species decreases the likelihood of creating a specific IgE (sIgE) response. In fact, when clinically relevant reactivity to meats has been demonstrated, the results point to cross-reactivity (eg, serum albumin [SA] and actin) and not to a sensitization with meat-specific epitopes. In keeping with this cross-reactivity, reports of IgE antibodies that bind various mammalian albumins do exist, notably pork-cat syndrome. In this uncommon syndrome patients have an IgE antibody response specific for cat SA that cross-reacts with porcine albumin and can lead to severe or even fatal allergic reactions on occasions when pork is consumed. Interestingly, the reported cases of pork-cat syndrome are largely European. We have recently evaluated numerous patients with suspected ‘‘meat allergy’’; in so doing, we have found and report here for the first time 8 cases of pork-cat syndrome in the United States. Representative clinical history and evaluations of 2 patients are described, including detailed IgE specificity and a clinical response to elimination diet, both of which strongly suggested the diagnosis. However, confirmatory food challenges were not performed in any of the 8 patients. Published data regarding pork-cat syndrome have suggested that sensitization to cat SA represents the primary event in the development of the cross-reactive IgE. In that investigation of sera from young patients in Luxembourg, it was shown that anti-cat SA IgE reactivity completely contained the anti-pork reactivity, whereas the reverse was not true. The patients in that report were all selected on the basis of being highly allergic to cat, whereas the 8 subjects reported here each presented for evaluation of suspected meat allergy. Patient E364 (Table I) reported symptoms of abdominal cramping, nausea, itching, and hives beginning 20 minutes after a meal of pork tenderloin, potatoes, and green beans. His abdominal symptoms worsened. He reported lightheadedness and was taken to the local emergency department, where he was treated for anaphylaxis. Given the proximity of his symptoms to the meal, a role for IgE antibody to galactose-a-1,3-galactose (a-gal) seemed unlikely. Positive immunoassay results to cat, dog, and pork without concomitant sensitization to beef or lamb prompted further investigation with SAs and gelatin (Table I). Positive results were obtained for cat and dog SA (Re220 and Re221, respectively), whereas results for bovine SA (Re204) were negative (Table I). Taken together, the results suggested that the anaphylactic reaction was triggered by pork because of cross-reacting IgE, which is consistent with pork-cat syndrome. The patient was advised to avoid eating pork and has been followed for 2 years without additional reactions. A second illustrative case is that of patient T559, a 14-year-old girl. She presented with recurrent bouts of abdominal pain 30 to 45 minutes after a meal. The pain occurred 3 to 5 times a month over the course of 14months and would resolvewithout treatment in 45 to 60 minutes. There was no associated nausea, vomiting, or diarrhea and no noticed changes in bowel movements. No association was made with a particular food or drink. On some occasions, the abdominal pain was accompanied by urticaria. Our work-up revealed the presence of sIgE to cat and dog albumin and pork, as shown in Table I (case 4), plus a negative result for sIgE antibody to alpha-gal. She was advised to remove pork from her diet but allowed to continue to eat beef. After 9 months of followup, no additional episodes of abdominal pain or urticaria were reported. As Table I shows, this uncommon syndrome is similar to other food allergies in that a range of presentations are seen and the clinical symptoms are not consistently predicted by the titer of IgE to the allergen cat SA. Assessment of binding specificity was performed, as previously described, on sera from 3 patients where sufficient quantity existed (Table II). The IgE response to cat SA and pork was significantly reduced by preincubation with cat albumin, whereas pork albumin and human albumin did not show significant inhibition of the cat SA response (Table II; note that porcine SA and human SA share 82% and 76% protein homologywith cat SA, respectively). The IgE response of the patients reported here shows similar specificity to published data and is also consistent with cat SA as the primary sensitizing antigen. There are 4 notable aspects to pork-cat syndrome that merit discussion. First, the sensitivity to pork does not arise early in life: most reported patients are older than age 8 years, with the majority being adults or teens. It appears that the sensitization to cat SA develops over time, and therefore onset of a ‘‘new’’ food allergy in an older child or adult might prompt consideration of pork-cat syndrome. Second, patients do not report reactions with each instance of eating pork. Both in the 3 patients described byHilger et al and in the 8 patients reported here, fresh meat or dried and smoked pork (ie, barbecue) were more consistent provocateurs of allergic reactions. However, well-cooked meat was associated with fewer reactions. Third, reactions to pork begin soon after eating the meat. In many ways, the timing of these reactions is most helpful in differentiating pork-cat syndrome from delayed anaphylaxis caused by IgE to a-gal. Both food allergies are IgE mediated, involve mammalian meat, and can show similar responses with certain skin tests and immunoassays; however, symptoms from pork-cat syndrome can occur rapidly and might initially present with oral pruritus during the meal. In general, reactions to pork begin within 30 to 45 minutes of consumption, often with gastrointestinal symptoms, such as abdominal cramping. Fourth, the natural history of pork-cat syndrome is not well established, but it appears that the levels of sIgE to cat SA might slowly decrease over time. Perhaps continued exposure to cat is important for maintaining the sensitization, and this might explain why certain patients can eventually consume pork again safely. In fact, existing data indicate that of appropriately sensitized patients, approximately 30% experience allergic symptoms in relation to pork consumption. Interestingly, whereas patients with IgE antibody toa-gal show positive immunoassay results to beef and pork, the crossreactivity to bovine albumin in patients with pork-cat syndrome is variable. Thus certain patients with pork-cat syndrome report

Differences in both prevalence and titre of specific immunoglobulin E among children with asthma in affluent and poor communities within a large town in Ghana

Background Reports from several African countries have noted an increasing prevalence of asthma in areas of extensive urbanization.

Estrogen modulation of endosome-associated toll-like receptor 8: an IFNα-independent mechanism of sex-bias in systemic lupus erythematosus.

Females of child-bearing age are more resistant to infectious disease and have an increased risk of systemic lupus erythematosus (SLE). We hypothesized that estrogen-induced gene expression could establish an immunoactivated state which would render enhanced defense against infection, but may be deleterious in autoimmune development. Using peripheral blood mononuclear cells (PBMCs), we demonstrate enhanced responses with immunogen stimulation in the presence of 17β-estradiol (E2) and gene array analyses reveal toll-like receptor 8 (TLR8) as an E2-responsive candidate gene. TLR8 expression levels are up-regulated in SLE and PBMCs stimulated with TLR8 agonist display a female sex-biased, E2-sensitive response. Moreover, we identify a putative ERα-binding region near the TLR8 locus and blocking ERα expression significantly decreases E2-mediated TLR8 induction. Our findings characterize TLR8 as a novel estrogen target gene that can lower the inflammatory threshold and implicate an IFNα-independent inflammatory mechanism that could contribute to higher SLE incidence in women.