Immunological responses of mice following administration of natural rubber latex proteins by different routes of exposure.

Although the prevalence of IgE-mediated latex allergy has increased over the past decade, the circumstances which culminate in sensitization remain uncertain. The objective of these studies was to evaluate the role which sensitization route plays in the development of latex allergy using murine models representative of potential exposure routes by which health care workers (topical and respiratory) and spina bifida patients (subcutaneous) may be sensitized. BALB/c mice administered latex proteins by the subcutaneous, topical, intranasal, or intratracheal routes exhibited dose-responsive elevations in total IgE. In vitro splenocyte stimulation initially demonstrated specificity of the murine immune response to latex proteins. Subsequently, immunoblot analysis was used to compare latex-specific IgE production amongst sensitization routes. Immunoblots of IgE from subcutaneously sensitized mice demonstrated recognition of latex proteins with molecular weights near 14 kDa and 27 kDa. These protein sizes are consistent with the molecular weights of major latex allergens (Hev b 1 and Hev b 3), to which high percentages of spina bifida patients develop antibodies. Mice sensitized by intratracheal or topical administration exhibited combined IgE recognition of latex proteins near 14 kDa, 35 kDa, and 92 kDa. These molecular weights are similar to other latex allergens (Hev b 6, Hev b 2, and Hev b 4) commonly recognized by IgE of health care workers. Mice sensitized to latex proteins by topical, intranasal, or intratracheal exposures exhibited bronchoconstriction as evaluated by whole body plethysmography following respiratory challenge with latex proteins. Subcutaneously sensitized mice were unresponsive. These differences in latex-specific IgE immunoblot profiles and altered pulmonary function amongst the four different sensitization routes suggest that exposure routes leading to sensitization may play a role in determining the primary allergen(s), and the clinical manifestation of the allergic responses.     

Latex allergy in the workplace.

While less than 1% of the general population is sensitized to latex, the U.S. Occupational Safety and Health Administration estimates that 8-12% of health-care workers are sensitized. The major source of workplace exposure is powdered natural rubber latex (NRL) gloves. NRL is harvested from HEVEA: brasiliensis trees and ammoniated to prevent coagulation resulting in the hydrolysis of the latex proteins. Prior to use in manufacturing, the latex is formulated by the addition of multiple chemicals. Thus, human exposure is to a mixture of residual chemicals and hydrolyzed latex peptides. Clinical manifestations include irritant contact dermatitis, allergic contact dermatitis (type IV), and type I immediate hypersensitivity response. Type I (IgE-mediated) NRL allergy includes contact urticaria, systemic urticaria, angioedema, rhinitis, conjunctivitis, bronchospasm, and anaphylaxis. Taking an accurate history, including questions on atopic status, food allergy, and possible reactions to latex devices makes diagnosis of type-I latex allergy possible. To confirm a diagnosis, either in vivo skin prick testing (SPT) or in vitro assays for latex-specific IgE are performed. While the SPT is regarded as a primary confirmatory test for IgE-mediated disease, the absence of a U.S. Food and Drug Administration-licensed HEVEA: brasiliensis latex extract has restricted its use in diagnosis. Serological tests have, therefore, become critically important as alternative diagnostic tests. Three manufacturers currently have FDA clearance for in vitro tests, to detect NRL-specific IgE. The commercially available assays may disagree on the antibody status of an individual serum, which may be due to the assay's detecting anti-NRL IgEs to different allergenic NRL proteins. Sensitized individuals produce specific IgE antibody to at least 10 potent HEVEA: allergens, Hev b 1-Hev b 10, each of which differs in its structure, size, and net charge. The relative content and ratios of Hevs in the final allergen preparation most probably could effect diagnostic accuracy. The Hev proteins have been cloned and expressed as recombinant proteins. Sequencing demonstrates both unique epitopes and sequences commonly found in other plant proteins. Sequence homology helps to explain the cross reactivity to a variety of foods experienced by latex allergic individuals. The development of recombinant allergens provides reagents that should improve the diagnostic accuracy of tests for latex allergy. Although clinical and exposure data have been gathered on the factors affecting response in latex-allergic individuals, less is known regarding the development of sensitization. Coupled with in vitro dermal penetration studies, murine models have been established to investigate the route of exposure in the development of latex sensitization. Time-course and dose-response studies have shown subcutaneous, intratracheal, or topical administrations of non-ammoniated latex proteins to induce IgE production. Both in vitro penetration and in vivo studies highlight the importance of skin condition in the development of latex allergy, with enhanced penetration and earlier onset of IgE production seen with experimentally abraded skin. The diagnosis of latex allergy is complicated by these variables, which in turn hinder the development of intervention strategies. Further epidemiological assessment is needed to more explicitly define the scope, trends, and demographics of latex allergy. Diagnostic accuracy can be improved through greater knowledge of proteins involved in the development of latex allergy, and better documentation of the presently available diagnostic tests. In vivo and in vitro models can elucidate mechanisms of sensitization and provide an understanding of the role of the exposure route in latex allergy-associated diseases. Together, these efforts can lead to intervention strategies for reducing latex allergy in the workplace.     

A discussion of natural rubber latex allergy with special reference to children: clinical considerations

Latex allergy is an increasingly common condition, because the use of latex products is widespread. Three types of reactions can occur in persons using natural latex rubber products: 1) Irritant contact dermatitis, 2) Allergic contact dermatitis, 3) and Type I hypersensitivity. Children's subpopulations at particular risk include: atopics, individuals with spina bifida, or individuals who required frequent surgical instrumentations. An association between allergy to latex and allergy to various fruits and vegetables has been reported. Recently, an homology between latex allergens and mold allergens has been reported leading to postulate a possible existence of a "latex-mold syndrome". Diagnosis of allergy is based initially on history, skin prick test and search for specific serum IgE. Provocation tests may confirm the suspicion, although these are seldom performed on children because they are not easy to bear with. The most effective strategy to decrease the incidence of NRL (natural rubber latex) sensitization is avoidance; however, this is virtually impossible, given the large number of latex products we encounter since childhood. Studies of secondary prophylaxis among children demonstrate that notwithstanding recommendations, children could manifest yet adverse reactions to latex products and have detectable levels of anti latex IgE.     

Impact of interleukin-13 and -18 promoter polymorphisms in health care workers with natural rubber latex allergy

It is a matter of debate whether single nucleotide polymorphisms (SNP) in the promoter region of interleukin (IL)-13, an IgE regulator, and IL-18, an inducer of immune responses, modulating the respective protein expression, are accompanied by an increased risk of atopy, allergic asthma, and total IgE levels. The suspected associations were noted in health care workers (HCW) with and without latex allergy. IL-13 (-1055C>T) and three IL-18 (-656T>G,?-607C>A,?-137G>C) SNP were studied in 523 HCW with natural rubber latex (NRL) exposure and diagnosis in the late 1990s. Three hundred and thirty-four HCW displayed NRL sensitization and allergic symptoms, 93 with latex-allergic asthma, and 189 HCW with neither symptoms nor NRL sensitization. SNP analyses were performed by real-time polymerase chain reaction (PCR) using newly developed LightCycler assays. Analysis of IL-13?-1055C>T by analysis of variance (ANOVA) revealed significantly elevated total IgE levels in HCW carrying the CT or TT variant compared with the CC variant. None of the studied SNP showed an association with NRL-specific IgE. The IL-18 variants -656GG and -607CC displayed 99.5% linkage disequilibrium. Frequencies of alleles -656GG and -607CC were elevated in HCW with NRL asthma (48.4%) compared with HCW without symptoms (37.6%). In contrast, IL-18?-137G>C variants displayed an overall homogenous distribution. The association between the IL-13 -1055T allele and elevated total IgE levels confirms the role of a genetic background for total IgE regulation. The studied IL-18 SNP demonstrated no significant association with the clinical outcome, total IgE, or specific IgE in HCW with natural rubber latex allergy.     

Cross-reactivity between natural rubber latex and food allergens

Immediate-type hypersensitivity to latex is a growing problem, especially among health care workers (HCWs) and patients requiring long-term catheterization and multiple operations. The responsible allergens are latex proteins, which are found in raw latex, as well as in various latex-containing products. More than 200 polypeptides can be discerned in latex sap and of these, 60 proteins showed reactivity with IgE antibodies from patients with latex allergy. Several of these proteins have been characterized at the molecular level and their role in latex allergy has been elucidated. Latex allergy is often associated with hypersensitivity to certain fruits and vegetables like avocado, kiwi, banana, sweet pepper, and tomato. Several case reports demonstrate a potential for serious allergic reactions to foods in latex allergic patients. Nevertheless, comprehensive studies on the clinical significance and relevance of this co-sensitization are missing. Although some of the latex allergens are ubiquitous plant proteins or share structural features with plant proteins, the molecular bases of these cross-reactivities have not yet been clarified.     

A latex-induced allergic airway inflammation model in mice

Latex allergy is important due to serious health impacts and widespread use of its products. Latex allergic reactions can be induced in skin and mucosal surfaces including the respiratory tract. The development of murine models of allergic airway inflammation has provided a framework to dissect out the cellular and molecular mechanisms of allergic respiratory inflammation. In this study we have developed a new mouse model of latex allergic airway inflammation using aerosol inhalation. The allergic inflammatory responses were characterized in this model. Mice were injected intraperitoneally with 0, 10, 50, or 200 microg of latex extract and their serum anti-latex IgE titers were determined. In the second stage, a standard protocol of inhalation was designed and three doses of latex extract solutions including 1%, 0.1%, and 0.01% were used to induce allergic airway inflammation. Bronchoalveolar lavage cytokines (IL-5 and IL-13) and serum anti-latex IgE and IgG(1) titers were determined by ELISA. Eosinophil levels in lung, peripheral blood, bronchoalveolar lavage and bone marrow were also evaluated. Histological analysis of lung tissue was also performed after latex inhalation. The aerosol inhalation of 1% latex allergens solution and presensitization with 50 mug of latex in this study resulted in the development of allergic airway inflammation characterized by elevated allergen specific IgE and IgG(1), peripheral blood, bronchoalveolar lavage and bone marrow eosinophilia. Histological analysis of the lung revealed an inflammatory response characterized by eosinophil accumulation. Elevated levels of Th2 cytokines IL-5 and IL-13 also were shown in bronchoalveolar lavage samples. These studies demonstrate that sensitization and subsequent aerosol inhalational challenge of latex allergen extract promotes allergic airway inflammation characterized by elevated IL-5 and IL-13 and eosinophils.     

Predictors of Bothrops jararaca venom allergy in snake handlers and snake venom handlers.

Since allergic sensitization to snake venom has been reported, anaphylactic reactions to snake venom might be an underestimated factor contributing to fatal snakebites, independently from the toxicity of the venom itself. However, little information is available on the determinants of such reaction. Hence, we studied a group of workers exposed to Bothrops jararaca venom (BJV), in order to clarify the factors related with snake venom allergy. The aim of this work was to investigate the prevalence and predictors of venom allergy among workers exposed to BJV and to confirm the involvement of IgE-mediated mechanisms in this condition. Workers exposed to BJV were assessed for venom allergy using questionnaires and immunological tests. The presence of BJV sensitization was determined through quantification of specific IgE. Allergens were studied using the Western blots and inhibition assays. Of the 67 workers evaluated, 7 (10.4%) presented specific IgE antibodies to BJV. Of those, 6 presented typical symptoms of an IgE-mediated allergic reaction when exposed to BJV. Venom sensitization was associated with length of employment (P=0.042), high levels of total IgE (P=0.034), atopy (P=0.051), and specific tasks, primarily the handling of dried venom (P=0.014). Our observations suggest that exposure to BJV can result in allergic sensitization in snake handlers through IgE-mediated mechanisms. The prevalence rate of this condition appears to be high among these workers, and the handling of dried venom, total IgE level above 100 kU/L, length of employment, and probably history of atopy were predictors of its occurrence.     

Latex allergy

Allergy to natural rubber latex is an important clinical condition that occurred after the institution of universal precautions to protect healthcare workers. A rapid increase and production of both examination and surgical gloves resulted in an epidemic of allergy to latex protein. Healthcare workers in both the medical and dental environments, as well as specific groups of individuals including those with spina bifida, myelodysplasia, and food allergies (banana, kiwi, avocado, and others), were at increased risk of sensitization. Clinical symptoms in the latex allergic individual ranged from type I hypersensitivity reaction including rhinoconjunctivitis, asthma, and systemic reaction to type IV hypersensitivity reaction, which occur from the chemicals added during the manufacturing process. Diagnosis of latex allergy is based on a clinical history that correlates the development of symptoms in relationship to exposure. In the United States there are no skin tests approved by the Food and Drug Administration. Therefore a combination of clinical judgment and serologic testing such as ImmunoCAP and Immulite is helpful. The primary treatment of latex allergy is avoidance of exposure to the latex protein.     

The clinical meaning of positive latex sIgE in patients with food/pollen adverse reactions

Natural rubber latex allergy (NRL-A) is an international problem of public health. About 50-60% of NRL-A patients may present adverse reactions after ingestion of cross-reacting vegetable foods. This condition, called "Latex-fruit Syndrome", is a matter of research. The aim of our study is to distinguish between clinical/subclinical latex-fruit syndrome and cross-sensitization to latex and food/pollen allergens on the basis of latex recombinant allergens. We studied 51 patients with food hypersensitivity and serological evidence of NRL sensitization. The subjects underwent an accurate allergological evaluation (skin prick test with latex, food and pollen extracts, specific IgE to latex and recombinant allergens, challenge provocation tests). The patients were divided in two groups: group A) 34 patients with clinical and serological latex and fruit/vegetable allergies; group B) 17 patients allergic to fruits/vegetables and/or pollens, with serological, but not clinical NRL-A. All the latex challenge tests resulted positive in group A patients and only two patients of group B presented positive cutaneous challenge tests. Moreover, specific IgE-antibodies were detected to rHev b 5, to rHev b 6.01, to rHev b 6.02 and to rHev b 8 (and other profilins) of group A patients, while in group B we observed a monosensitization to Hev b8, probably linked to a cross-sensitization to pollens and foods. At the present state of knowledge, we need a multi-parametric approach based on a combination of clinical history, diagnostic tests (CRD) and latex challenge tests to make diagnosis of latex-fruit syndrome.     

Allergen specific nasal challenge to latex in children with latex allergy: clinical and immunological evaluation

There are no data concerning the significance of allergen specific nasal challenge to latex (ASNCL) in the pediatric population and the effect of mometasone furoate nasal spray (MFNS), topic corticosteroid exerting a potent anti-inflammatory activity in children with latex allergic rhinitis. The aims of this study are: to investigate the clinical and immune pathological effects of ASNCL in children with latex allergy; to study the effects of MFNS pre-medication on the clinical and immune pathological effects of ASNCL in children with latex allergy. Thirteen children: 6 male and 7 female, mean (SD) age 9.6 (2.9) years, with latex allergy and seven children: 3 male and 4 female, mean (SD) age 9.9 (3.8) years, without latex allergy underwent ASNCL. Nasal symptoms were recorded, nasal lavage fluid was collected to measure tryptase, eosinophil cationic protein (ECP), interleukin-5, interferon-gamma levels, and spirometric test was performed for each patient without or with premedication with MFNS. ASNCL induced a clinical allergic response and increased tryptase levels only in children with latex allergy. No serious adverse events occurred after ASNCL. MFNS premedication reduced both tryptase and ECP levels only in children with latex allergy. ASNCL is a simple, reliable and useful tool to make or confirm the diagnosis of nasal symptoms due to latex; it allows us to study both clinical symptoms and local immunological changes. MFNS premedication before an ASNCL may prevent some immunological responses induced by ASNCL without clinical allergic modifications.     

Chemicals in food and allergy: fact and fiction

The prevalence of the atopic diseases asthma, rhinitis and atopic eczema has increased in the past two to three decades. It is not unusual to read the statement that food additives and other chemicals in food increase the risk of allergy. From a theoretical standpoint chemicals in the diet may influence allergic sensitization and elicitation in different ways: (i) they may directly cause allergy because they are allergens or haptens; (ii) they may act as adjuvants facilitating allergy to other (dietary) components; (iii) they may modulate the immune system by direct immunotoxicity and in theory be able to change the balance from tolerance to IgE production; and (iv) they may trigger non-allergic intolerance reactions. With the present knowledge of chemicals in foods, the human exposure to these chemicals, and the described trends in this exposure, there is no supportive evidence confirming that chemicals in foods are contributing to the reported increase in the prevalence of atopic diseases.     

Skin barrier dysfunction and systemic sensitization to allergens through the skin

Most allergic, atopic and hypersensitive reactions are associated with Th2-biased immune responses and allergen-specific IgE antibodies. Pathological allergic disorders are on an alarming increase in the industrialized world. Understanding the mechanism of primary sensitization to allergens is important in elucidating the pathogenesis of these diseases and for possibly preventing their development. In this article, we review recent information supporting that epidermal allergen exposure may contribute to systemic allergic diseases and that atopy may be secondary to skin barrier dysfunction in some dermatoses. The skin is an active immunological organ, which functions as a primary defence and biosensor to the external environment. The critical permeability barrier function is mediated by the outmost layer of the epidermis, the stratum corneum. Perturbation of the stratum corneum initiates a chain of event, which activates homeostatic responses in the underlying epidermis. Repeated barrier-disruption, whether environmentally or genetically determined, may however stimulate signaling cascades that lead to inflammation and epidermal hyperplasia. Skin barrier dysfunction may also allow entry of allergens, which can lead to primary systemic sensitization. The altered epidermal microenvironment in barrier-disrupted skin appears to be particularly well suited for the induction of potent Th2-type responses with production of allergen-specific IgE. Epidermal exposure to food antigens can prevent the normal induction of oral tolerance and also lead to airway eosinophilia following inhalation. Exposure to allergens on barrier-disrupted skin may as such serve as a natural sensitization pathway for food allergy and respiratory allergic disease.     

Ultra-short-course seasonal allergy vaccine (Pollinex Quattro)

This novel ultra-short-course seasonal allergy vaccine, containing glutaraldehyde-modified allergens and the adjuvants 3-deacylated monophosphoryl lipid A (MPL) and L-tyrosine, requires a preseasonal course of only four injections to be effective in the treatment of seasonal allergic rhinitis. In patients with seasonal allergic rhinitis and/or allergic asthma, a four-injection vaccination course with either the grass pollen or tree pollen allergy vaccine significantly reduced skin prick sensitivity reactions, significantly elevated allergen-specific IgG levels and significantly reduced the seasonally induced boost of IgE. Preseasonal vaccination of adult patients with either grass pollen or tree pollen allergy vaccine significantly reduced the median combined symptom/medication score compared with placebo. Similarly, preseasonal vaccination of children and adolescents with allergies to grass pollen or tree pollen significantly reduced the global symptom and medication use scores compared with the previous pollen season. Postmarketing surveillance indicated that after a course of vaccination, 82% of patients experienced reduced symptoms and 62% reduced their rescue medication use compared with the previous season. The allergy vaccine was generally well tolerated. Local reactions, mainly injection-site redness and swelling, were more common than systemic reactions. There were no serious adverse events.     

Assessing the risk of type 1 allergy to enzymes present in laundry and cleaning products: Evidence from the clinical data

Microbial enzymes have been used in laundry detergent products for several decades. These enzymes have also long been known to have the potential to give rise to occupational type 1 allergic responses. A few cases of allergy among consumers using dusty enzyme detergents were reported in the early 1970s. Encapsulation of the enzymes along with other formula changes were made to ensure that consumer exposure levels were sufficiently low that the likelihood of either the induction of IgE antibody (sensitization) or the elicitation of clinical symptoms be highly improbable. Understanding the consumer exposure to enzymes which are used in laundry and cleaning products is a key step to the risk management process. Validation of the risk assessment conclusions and the risk management process only comes with practical experience and evidence from the marketplace. In the present work, clinical data from a range of sources collected over the past 40 years have been analysed. These include data from peer reviewed literature and enzyme specific IgE antibody test results in detergent manufacturers’ employees and from clinical study subjects. In total, enzyme specific IgE antibody data were available on 15,765 individuals. There were 37 individuals with IgE antibody. The majority of these cases were from the 1970s where 23 of 4687 subjects (0.49%) were IgE positive and 15 of the 23 were reported to have symptoms of allergy. The remaining 14 cases were identified post-1977 for a prevalence of 0.126% (14/11,078). No symptoms were reported and no relationship to exposure to laundry and cleaning products was found. There was a significant difference between the pre- and post-1977 cohorts in that the higher rates of sensitization with symptoms were associated with higher exposure to enzyme. The clinical testing revealed that the prevalence of enzyme specific IgE in the population is very rare (0.126% since 1977). This demonstrates that exposure to these strong respiratory allergens via use of laundry and cleaning products does not lead to the development of sensitization and disease. These data confirm that the risk to consumers has been properly assessed and managed and support the concept that thresholds of exposure exist for respiratory allergy. Expansion of enzyme use into new consumer product categories should follow completion of robust risk assessments in order to continue ensuring the safe use of enzymes among consumers.     

Epidemiology of alternaria alternata allergy: a prospective study in 6840 Italian asthmatic children

BACKGROUND: The prevalence of Alternaria Alternata (AA), a mold causing in children severe asthma is scarcely known, also due to the underdiagnosis of AA allergy, frequently due to multiple sensitizations to molds. OBJECTIVE: To analyze this issue we prospectively studied all children attending our Division between January 4, 1990 and December 31, 1997. METHODS: A total of 6840 children with asthma or allergic rhinitis were evaluated. Diagnosis was established by family and personal history, physical examination, skin prick tests (SPTs) and RAST (Radio Allergo-Sorbent Test) for inhalants including AA. We further evaluated: (1) sensitization only to AA allergens without positivity for additional inhalants; (2) prevalence of AA positivity among children with asthma or allergic rhinitis; (3) concordance between SPTs and RAST for allergy to molds, (4) proportion of children treated with specific immunotherapy (SIT). RESULTS: Among the 6840 children 213 were positive to AA (3.3%), only 89/6840 children (1.3%) had AA monosensitization (p = 0.0001), a concordance between SPTs and RAST was present in 21/89 (23.6%) children (p = 0.0009), and only 9 children out of 89 were SIT treated. Concerning the clinical manifestations, 83 had asthma or allergic rhinitis, and 6 had asthma associated with atopic dermatitis. Family history was positive in 82.9% of children. The mean onset of AA sensitivity was at age 4 for males, and at age 5 for females. CONCLUSIONS: In childhood, AA allergy is a genetic affection. The SPT concordance with history and clinical examination appears to be operative. Due to life-threatening reactions in children with AA allergy, we suggest that those with suspected inhalant allergy be tested with AA allergens, and treated with SIT if positive.     

鱼腥草注射液新制剂致敏性评价实验研究

目的:采用Beagle犬致敏实验研究来评价鱼腥草注射液新制剂(new Houttuynia Cordata injec-tion,NYI)的致敏性。方法:在类过敏和过敏试验中,通过静脉注射不同剂量的NYI,观察给药后Beagle犬的行为学变化,检测血浆中组胺、IgE的含量变化。结果:NYI在致敏给药后未出现明显的行为异常,类过敏试验中血浆组胺和IgE升高不明显,在过敏试验中血浆组胺和IgE未见升高。结论:NYI对Beagle犬未发现有明显的过敏性反应,为临床安全用药提供了实验依据。     

Cow-milk allergy

Hereditary predisposition is the major denominator of allergy, and hypersensitivity reactions contribute to the expression of the genetic predisposition. The route of sensitization varies with age so that dietary antigens predominate in infancy. The immaturity of the immune system and the gastrointestinal barrier may explain the peak prevalence of food allergies at an early age. The treatment of choice for cow-milk allergy is complete avoidance of cow-milk antigens. The approach to control allergic inflammation by antigen elimination, however, has not been satisfactory. New approaches are urgently needed for the management of patients with cow-milk allergy. These may include: (i) immunotherapy to counteract the immunological dysfunction, and (ii) stabilisation of the gut mucosal barrier to strengthen endogenous defence mechanisms.