Skin barrier compromise is a defining characteristic of atopic dermatitis (AD). Research has uncovered several possible explanations for this barrier disruption including lipid and structural defects in the stratum corneum (SC), mutations of the filaggrin gene, and various genetic or acquired abnormalities of proteases and their inhibitors. Scratching irritated skin doesn’t help, either. Part and parcel with this is a persistent, inflammatory Th2-dominant microenvironment. In this month’s issue, De Benedetto et al. (J Allergy Clin Immunol 2011; 127:773-786.e7), for the NIH/NIAID/Atopic Dermatis and Vaccinia Network, report novel evidence that the barrier dysfunction doesn’t stop at the SC.
De Benedetto et al. provide the first evidence that strongly implicates abnormalities of tight junctions (TJs) found in the stratum granulosum in AD patients. They find that claudin-1, a critical component of TJ is significantly reduced in nonlesional epidermis from AD patients. This finding was specific to AD as skin biopsies from psoriasis patients had levels of claudin-1 equal to that of nonatopic, healthy controls. Additionally, nonlesional AD epidermis has increased permeability and decreased trans-epithelial electrical resistance (TEER). Clinically, decreased claudin-1 production was strongly associated with increased total serum IgE and total Eosinophil count in AD patients, as well.
In vitro claudin-1 knockdown caused increased TJ permeability and decreased TEER without affecting other structural components of TJ or the SC, suggesting that claudin-1 is required for a competent epidermal TJ barrier. Further, claudin-1 knockdown caused increased keratinocyte proliferation. De Benedetto et al. speculate that the hyper-proliferation effect of claudin-1 depletion may account for increased epithelial thickness observed even in nonlesional AD skin. Findings that claudin-1 knockdown increased small- and large-pore permeability leads the authors to suggest that AD skin may be more easily breached by allergens, irritants, nanoparticles and microbial products or enable the dendritic processes of antigen presenting cells to sample these products on the skin surface.
In a twist, they find that Th2 cytokines enhance TJ function and increase claudin-1 expression in differentiated keratinocyte monolayers, leading the authors to conclude that impaired claudin-1 expression and TJ dysfunction are not likely the result of Th2 cytokine dominance in AD. In fact they suggest that the TJ defects may be promoting a Th2 immune response that is a response designed to minimize reactions to environmental allergens.
De Benedetto et al. also report on gene association studies in two populations, African Americans (EA) and European Americans (EA). Significant associations were found between CLDN1 gene SNPs and AD or disease severity in both AA and EA.
The authors conclude that barrier compromise in AD involves the secondary skin barrier as well as the stratum corneum and that correlation of serum IgE and total Eosinophil count and claudin-1 expression demonstrates that this deficiency promotes Th2 responses as well.
We asked lead author Anna De Benedetto for more about the implications of this study:
JACI: How do you reconcile the relative importance of claudin defects in comparison with the other defects in barrier function that have now been reported?
Dr. De Benedetto: Our work demonstrating that subjects with atopic dermatitis have a tight junction (TJ) defect complements studies that have reported a number of stratum corneum (SC) defects including altered lipid composition, dysregulated EDC genes, altered protease/antiprotease activity and simply trauma from scratching. We think it is no coincidence that the skin epidermis, which must endure significant environmental exposures, has two formidable barrier structures, namely the SC and TJ. Once the SC is compromised the TJ located just below provide a second line of defense. We believe that immunological responsiveness to environmental insults requires a breach in both structures and that this occurs in subjects with AD. We hope our work will spawn further studies to address the interaction between these two barrier structures and address treatment strategies that would improve either TJ or SC function. If our hypothesis that immunologic responses require a hit to both SC and TJ it may be possible that enhancing the function of one of these barrier structures would be an effective strategy.
Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.
Friday, March 4, 2011
Tuesday, February 1, 2011
The scope and efficacy of intravenous immunoglobulin therapy
Departing AAAAI president, Mark Ballow, MD, chose the mechanism(s) of action of IVIG (intravenous immunoglobulin) therapy as his contribution to this month’s presidential theme issue (J Allergy Clin Immunol 2011;127:315-323). Dr. Ballow reviews the interesting research that has begun to characterize how IGIV modulates the immune and inflammatory pathways that are associated with a variety of diseases.
Dr. Ballow begins by noting that anaphylaxis risks dictated that early IG therapy for humoral and B-cell immune deficiencies be given by intramuscular route, but by the 1980’s an intravenous preparation was available, making the therapy even more effective in establishing normal serum IgG levels in immunodeficiency patients. Serendipitous observation was made that IVIG therapy also increased platelet counts significantly in patients with co-morbid idiopathic thrombocytopenia purpura (ITP) and led to research on IVIG therapy for other autoimmune/inflammatory diseases. Dr. Ballow points out that approximately 70% of IVIG therapy administered currently is used to treat autoimmune and inflammatory disorders.
The review discusses the multiple mechanisms that have been described for IgG therapy in the context of the diseases in which they have been identified. For example, Fc receptor blockade effects by IVIG were first described in patients with ITP. Other authors reported that idiotypic antibodies in the IVIG neutralizes the autoantibodies that lead to acquired hemophilia, though Fc receptor interactions were found more commonly in other disorders. Research on IVIG efficacy for Kawasaki disease, dermatomyositis, and toxic epidermal necrolysis revealed that IgG therapy had the capacity to interfere in many places along and within the inflammatory cascade at the cellular levels and with inflammatory mediators, such as cytokine inhibition, chemokine production, suppression of adhesion molecule activity, inhibition of complement binding, and modulation of apoptotic processes through anti-Fas antibody components.
Dr. Ballow also describes other research on IVIG immune-modulating mechanisms associated with the Fc inhibitory receptor, FcRIIB, and C-type lectin receptors on effector macrophages that may act to reduce circulating autoantibodies. Finally, the author discusses recent findings that IgG increased suppressive function of Tregs and that therapy in Kawasaki disease and Guillain-Barré syndrome is associated with increased numbers of T regulatory cells.
Dr. Ballow wraps up commenting that “the IgG molecule is the single most important naturally occurring specific immune component capable of modulating the immune system.” Further, that many mechanisms for IVIG efficacy have been identified and that it is likely that they all work in concert depending on IVIG dose and disease context.
We asked Dr. Ballow to tell us about why we chose this focus for his presidential theme issue:
Dr. Ballow: This is the 100th year anniversary for "traditional" immunotherapy celebrated in the Jan. issue of JACI. However, allergist/immunologist have to go beyond traditional immunotherapy (IT) to other forms of "immune therapy" including bone marrow transplantation for patients with primary immune deficiency, IVIG as replacement therapy in patients with hypogammaglobulinemia, and immune response modifiers such as monoclonal antibodies, fusion proteins. The latter therapies have carved an important treatment modality in patients with autoimmune diseases (see review by Betty Diamond). In fact, IVIG has turned out to be one of the most important immune response modifiers in the treatment of inflammatory and autoimmune disease. These topics are emphasized in the upcoming annual Academy meeting, and underscores one of my Presidential themes of expanding the scope of practice for the allergist/immunologist. My motto - "better health through immune based therapies."
Dr. Ballow begins by noting that anaphylaxis risks dictated that early IG therapy for humoral and B-cell immune deficiencies be given by intramuscular route, but by the 1980’s an intravenous preparation was available, making the therapy even more effective in establishing normal serum IgG levels in immunodeficiency patients. Serendipitous observation was made that IVIG therapy also increased platelet counts significantly in patients with co-morbid idiopathic thrombocytopenia purpura (ITP) and led to research on IVIG therapy for other autoimmune/inflammatory diseases. Dr. Ballow points out that approximately 70% of IVIG therapy administered currently is used to treat autoimmune and inflammatory disorders.
The review discusses the multiple mechanisms that have been described for IgG therapy in the context of the diseases in which they have been identified. For example, Fc receptor blockade effects by IVIG were first described in patients with ITP. Other authors reported that idiotypic antibodies in the IVIG neutralizes the autoantibodies that lead to acquired hemophilia, though Fc receptor interactions were found more commonly in other disorders. Research on IVIG efficacy for Kawasaki disease, dermatomyositis, and toxic epidermal necrolysis revealed that IgG therapy had the capacity to interfere in many places along and within the inflammatory cascade at the cellular levels and with inflammatory mediators, such as cytokine inhibition, chemokine production, suppression of adhesion molecule activity, inhibition of complement binding, and modulation of apoptotic processes through anti-Fas antibody components.
Dr. Ballow also describes other research on IVIG immune-modulating mechanisms associated with the Fc inhibitory receptor, FcRIIB, and C-type lectin receptors on effector macrophages that may act to reduce circulating autoantibodies. Finally, the author discusses recent findings that IgG increased suppressive function of Tregs and that therapy in Kawasaki disease and Guillain-Barré syndrome is associated with increased numbers of T regulatory cells.
Dr. Ballow wraps up commenting that “the IgG molecule is the single most important naturally occurring specific immune component capable of modulating the immune system.” Further, that many mechanisms for IVIG efficacy have been identified and that it is likely that they all work in concert depending on IVIG dose and disease context.
We asked Dr. Ballow to tell us about why we chose this focus for his presidential theme issue:
Dr. Ballow: This is the 100th year anniversary for "traditional" immunotherapy celebrated in the Jan. issue of JACI. However, allergist/immunologist have to go beyond traditional immunotherapy (IT) to other forms of "immune therapy" including bone marrow transplantation for patients with primary immune deficiency, IVIG as replacement therapy in patients with hypogammaglobulinemia, and immune response modifiers such as monoclonal antibodies, fusion proteins. The latter therapies have carved an important treatment modality in patients with autoimmune diseases (see review by Betty Diamond). In fact, IVIG has turned out to be one of the most important immune response modifiers in the treatment of inflammatory and autoimmune disease. These topics are emphasized in the upcoming annual Academy meeting, and underscores one of my Presidential themes of expanding the scope of practice for the allergist/immunologist. My motto - "better health through immune based therapies."
Monday, January 31, 2011
The lung microbiome and asthma pathogenesis
In this issue, Huang et al. (J Allergy Clin Immunol 2011;127: 372-381.e3), reporting on behalf of the NHLBI’s Asthma Clinical Research Network [ACRN], report first-ever research findings associating the composition of airway flora with clinical features of asthma. They postulate that the airway supports a complex community of bacteria that may contribute to clinical features of asthma among asthmatics taking inhaled corticosteroids (ICS). The researchers use a microarra-based method that detects distinct 16S rRNA gene sequences permitting detection and identification of bacterial taxa without previous knowledge of their presence in the relevant sample. Huang et al. report that using this tool, taxa in the phylum Proteobacteria were the most abundant in the cohort of patients studied.
The study occurred in parallel with a clinical trial examining the effects of long-term clarithromycin therapy in subjects with sub-optimal asthma control. Bronchial brushings were obtained from 65 asthma subjects and 10 healthy subjects. The authors find that airway colonization is variable in both healthy and asthmatic subjects, but that asthmatic subjects had significantly greater bacterial diversity than controls. Further, subjects in the clarithromycin treatment group with the highest bacterial diversity pre-treatment, had the greatest improvement in airway hyperresponsiveness following treatment.
Huang et al. comment that finding an airway microbiota in asthma patients on ICS therapy may not be surprising, but in fact, is also consistent with the notion that disturbances in epithelial/mucosal-associated microbiomes are known to be associated with disease as is the case with intestinal inflammatory diseases. They suggest that colonization by specific bacteria may contribute to persistence of inflammation, disease presentation, and/or disease heterogeneity; in particular, they cite the example of bacteria in the family Comamonadaceae, which are known to have steroid degrading capacity, as potentially contributory to steroid-resistant asthma pathology. Further, Huang et al. propose that the effectiveness of macrolide therapy on reducing airway reactivity may be a combined effect of their anti-inflammatory and antibacterial properties.
The authors state that discerning whether increased bacterial burden and diversity is a function of having asthma or being on ICS therapy is an important research question in light of the widespread use of ICS in many airway diseases. Concluding, Huang et al. comment that their findings open new research paths on disease mechanisms in asthma.
We asked senior author Dr. Susan Lynch, PhD, from the University of California - San Francisco, to tell us a little more about the study:
JACI: Your findings have far-reaching implications for airway disease and systems biology research. In your opinion, what are the proximate priorities?
Dr. Lynch: Establishment of cross-disciplinary, integrated research efforts to define microbiota structure, function and host interplay in well defined cohorts of patients. Openness to the possibility that this field of research may dramatically change our long-held perceptions of chronic inflammatory disease genesis and progression.
Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.
The study occurred in parallel with a clinical trial examining the effects of long-term clarithromycin therapy in subjects with sub-optimal asthma control. Bronchial brushings were obtained from 65 asthma subjects and 10 healthy subjects. The authors find that airway colonization is variable in both healthy and asthmatic subjects, but that asthmatic subjects had significantly greater bacterial diversity than controls. Further, subjects in the clarithromycin treatment group with the highest bacterial diversity pre-treatment, had the greatest improvement in airway hyperresponsiveness following treatment.
Huang et al. comment that finding an airway microbiota in asthma patients on ICS therapy may not be surprising, but in fact, is also consistent with the notion that disturbances in epithelial/mucosal-associated microbiomes are known to be associated with disease as is the case with intestinal inflammatory diseases. They suggest that colonization by specific bacteria may contribute to persistence of inflammation, disease presentation, and/or disease heterogeneity; in particular, they cite the example of bacteria in the family Comamonadaceae, which are known to have steroid degrading capacity, as potentially contributory to steroid-resistant asthma pathology. Further, Huang et al. propose that the effectiveness of macrolide therapy on reducing airway reactivity may be a combined effect of their anti-inflammatory and antibacterial properties.
The authors state that discerning whether increased bacterial burden and diversity is a function of having asthma or being on ICS therapy is an important research question in light of the widespread use of ICS in many airway diseases. Concluding, Huang et al. comment that their findings open new research paths on disease mechanisms in asthma.
We asked senior author Dr. Susan Lynch, PhD, from the University of California - San Francisco, to tell us a little more about the study:
JACI: Your findings have far-reaching implications for airway disease and systems biology research. In your opinion, what are the proximate priorities?
Dr. Lynch: Establishment of cross-disciplinary, integrated research efforts to define microbiota structure, function and host interplay in well defined cohorts of patients. Openness to the possibility that this field of research may dramatically change our long-held perceptions of chronic inflammatory disease genesis and progression.
Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.
Friday, January 7, 2011
Gene-environment protective effects are context-dependent in development of asthma
Recent genomic studies have begun to demonstrate that adaptive genotypes are only adaptive when expressed in their relevant context. In this month’s issue, Ege et al. and the European consortium, GABRIEL, present surprising findings from a gene-environment (G*E) interaction analysis for childhood asthma and the farming environment (J Allergy Clin Immunol 2011;127:138-144.e4).
Ege et al. report that previously identified common SNPs associated with asthma in urban populations did not interact with farming environment parameters. Previously identified interactions with farming related exposures were not confirmed despite adequate statistical power.
Among rarer SNPs, however, significant interactions were detected with farming related exposures such as
consumption of raw milk, and exposure to cow and/or straw. By this approach the authors identified new genes that differed from those reported as asthma-associated. SNPs in the GRM1 (metabotropic glutamate receptor 1) gene specifically and significantly interacted with farm exposures. The GRM1 is involved in immunological and neuronal synaptic function. The authors note that these results must be interpreted carefully as the SNPs are rare.
Ege et al. conclude that there may exist different phenotypes of asthma that are susceptible to either genetic or environmental effects, but rarely to both at the same time. They propose that genotypes which are protective for one exposed population do not carry an effect in an unexposed population.
Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments below. All questions and comments will be forwarded to the authors for a response.
Ege et al. report that previously identified common SNPs associated with asthma in urban populations did not interact with farming environment parameters. Previously identified interactions with farming related exposures were not confirmed despite adequate statistical power.
Among rarer SNPs, however, significant interactions were detected with farming related exposures such as
consumption of raw milk, and exposure to cow and/or straw. By this approach the authors identified new genes that differed from those reported as asthma-associated. SNPs in the GRM1 (metabotropic glutamate receptor 1) gene specifically and significantly interacted with farm exposures. The GRM1 is involved in immunological and neuronal synaptic function. The authors note that these results must be interpreted carefully as the SNPs are rare.
Ege et al. conclude that there may exist different phenotypes of asthma that are susceptible to either genetic or environmental effects, but rarely to both at the same time. They propose that genotypes which are protective for one exposed population do not carry an effect in an unexposed population.
Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments below. All questions and comments will be forwarded to the authors for a response.
Thursday, January 6, 2011
Advances in immunotherapy for allergies have increased safety and effectiveness
Casale and Stokes take a look at new technologies and experimental therapies developed to improve on the standard approach of subcutaneous injection of increasing concentrations of allergens (SCIT) in this month’s issue (J Allergy Clin Immunol 2011;127:8-15). They discuss omalizumab add-on therapy to conventional SCIT and report on studies in which omalizumab was administered concurrently and prior to initiation of SCIT. Omalizumab plus SCIT showed significant reduction in allergic rhinitis symptoms, and less use of rescue medication compared to SCIT alone. When omalizumab was given as pre-treatment to SCIT, both allergic rhinitis and allergic asthma subjects had fewer severe reactions and more subjects were able to achieve target maintenance dose than subjects receiving placebo plus SCIT.
The authors continue with recent efforts to mobilize mitigating Th1 responses through Toll-like receptor (TLR) agonists and CpG immunostimulatory responses. Combined allergen and TLR therapy is reported to provide significant improvements in rhinitis symptoms and medication use in both adults and children. They also discuss effectiveness associated with bonding immunostimulatory CpG sequences with ragweed allergen to influence T cell responses toward Th1 dominance and reduced eosinophilia; however, clinical impact was minimal. Engineering the allergen and CpG sequences, as well as CpG sequences alone, into virus-like particles provided significantly greater improvements in symptoms and immunologic markers.
Casale and Stokes cover the use of T-cell derived peptides in the treatment of allergies including cat allergy and bee venom allergy. They describe increased benefit and safety of SCIT therapy with newer preparations of Fel d 1 peptides, and early impressive results with Api m 1 and phospholipase A2.
Different routes of administration are also reviewed by the authors such as intranasal and intrabronchial, focusing on escalating oral and sublingual (SLIT) therapies. They report encouraging results from oral desensitization/tolerance studies for subjects with food allergies, which included decreased inflammation markers, decreased specific IgE, increased specific IgG, and achievement of tolerance in a majority of subjects. Results from SLIT therapy trials have been positive as well. SLIT clinical trials for grass and ragweed allergies have shown efficacy in subjects with seasonal allergic rhinitis, and there are positive results noted for other allergens in seasonal allergic rhinitis and allergic asthma.
In conclusion, the authors comment that adjunct omalizumab therapy clearly improves safety and TLR agonists are more effective for shifting to Th1 response. They are optimistic about the future of immunotherapy, although they feel that with the rapid evolution in new technology and increased knowledge of the immune system, how immunotherapy will be used in the future will be substantially different than what is occurring today.
The authors continue with recent efforts to mobilize mitigating Th1 responses through Toll-like receptor (TLR) agonists and CpG immunostimulatory responses. Combined allergen and TLR therapy is reported to provide significant improvements in rhinitis symptoms and medication use in both adults and children. They also discuss effectiveness associated with bonding immunostimulatory CpG sequences with ragweed allergen to influence T cell responses toward Th1 dominance and reduced eosinophilia; however, clinical impact was minimal. Engineering the allergen and CpG sequences, as well as CpG sequences alone, into virus-like particles provided significantly greater improvements in symptoms and immunologic markers.
Casale and Stokes cover the use of T-cell derived peptides in the treatment of allergies including cat allergy and bee venom allergy. They describe increased benefit and safety of SCIT therapy with newer preparations of Fel d 1 peptides, and early impressive results with Api m 1 and phospholipase A2.
Different routes of administration are also reviewed by the authors such as intranasal and intrabronchial, focusing on escalating oral and sublingual (SLIT) therapies. They report encouraging results from oral desensitization/tolerance studies for subjects with food allergies, which included decreased inflammation markers, decreased specific IgE, increased specific IgG, and achievement of tolerance in a majority of subjects. Results from SLIT therapy trials have been positive as well. SLIT clinical trials for grass and ragweed allergies have shown efficacy in subjects with seasonal allergic rhinitis, and there are positive results noted for other allergens in seasonal allergic rhinitis and allergic asthma.
In conclusion, the authors comment that adjunct omalizumab therapy clearly improves safety and TLR agonists are more effective for shifting to Th1 response. They are optimistic about the future of immunotherapy, although they feel that with the rapid evolution in new technology and increased knowledge of the immune system, how immunotherapy will be used in the future will be substantially different than what is occurring today.
Monday, December 6, 2010
SARP reports differences in asthma genotypes & phenotypes are race-associated
In this month’s issue, the Severe Asthma Research Program [SARP] presents their findings from a cross-sectional study of the SARP database, which holds clinical, immunological, and physiological data for over 1300 subjects with asthma (Gamble C, Talbott E, Youk A, Holguin F, Pitt B, Silveira L, et al. Racial differences in biologic predictors of severe asthma: Data from the Severe Asthma Research Program. J Allergy Clin Immunol 126;1149-1156.e1). Gamble et al. partition the severe asthma subjects into two categories, “blacks” and “whites” 40 years of age and older, to evaluate variability in asthma presentation. The authors employ a univariable model and a multivariate model to detect in- and between-group differences.
In univariable analyses, higher BMI, reported GERD, and current employment are associated with severe asthma in blacks. Additionally, the presence of 2 or more family members with asthma is positively associated with severe asthma; however, the presence of atopy and 5 or more positive prick skin tests are negatively associated. Whites are more likely to report additional co-morbidities, such as hypertension and diabetes, as well as GERD, and a positive family history of asthma was not significant in whites. Interestingly, owning a pet decreased the risk of severe asthma in whites. Unlike blacks, current employment is not significant in whites with severe asthma. In both blacks and whites, second-hand smoke exposure and serum IgE are not risk factors.
Multivariate models reveal that, unlike the univariable modeling, IgE was strongly associated with severe asthma and a family history of asthma doubled the risk of severe asthma in blacks. Current employment drops out as a risk factor for blacks in this model. Blacks with GERD, high serum IgE, baseline % predicted FEV1, and 2 or more family members with asthma strongly associate with severe asthma. While whites share GERD and baseline % predicted FEV1 as risk factors with blacks, not having a pet, and no family history of asthma predict risk for severe asthma in whites.
Gamble et al. conclude that biologic/genetic factors and family history are equally or more important than socioeconomic factors as in accounting for risk of severe asthma in blacks. We asked the authors about the implications for their study. According to first author, Christy Gamble, DrPHc, MPH, and senior author, Sally Wenzel, MD, “the different predictors for blacks and whites suggest the mechanisms for severe asthma could be different and thus, approaches to treatment of severe asthma in blacks may very well differ from those in whites.”
Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.
In univariable analyses, higher BMI, reported GERD, and current employment are associated with severe asthma in blacks. Additionally, the presence of 2 or more family members with asthma is positively associated with severe asthma; however, the presence of atopy and 5 or more positive prick skin tests are negatively associated. Whites are more likely to report additional co-morbidities, such as hypertension and diabetes, as well as GERD, and a positive family history of asthma was not significant in whites. Interestingly, owning a pet decreased the risk of severe asthma in whites. Unlike blacks, current employment is not significant in whites with severe asthma. In both blacks and whites, second-hand smoke exposure and serum IgE are not risk factors.
Multivariate models reveal that, unlike the univariable modeling, IgE was strongly associated with severe asthma and a family history of asthma doubled the risk of severe asthma in blacks. Current employment drops out as a risk factor for blacks in this model. Blacks with GERD, high serum IgE, baseline % predicted FEV1, and 2 or more family members with asthma strongly associate with severe asthma. While whites share GERD and baseline % predicted FEV1 as risk factors with blacks, not having a pet, and no family history of asthma predict risk for severe asthma in whites.
Gamble et al. conclude that biologic/genetic factors and family history are equally or more important than socioeconomic factors as in accounting for risk of severe asthma in blacks. We asked the authors about the implications for their study. According to first author, Christy Gamble, DrPHc, MPH, and senior author, Sally Wenzel, MD, “the different predictors for blacks and whites suggest the mechanisms for severe asthma could be different and thus, approaches to treatment of severe asthma in blacks may very well differ from those in whites.”
Do you have any questions for the authors, or comments about this study? We want to hear from you. Please feel free to post your own questions or comments. All questions and comments will be forwarded to the authors for a response.
Maternal antioxidant SNPs modify link between acetaminophen exposure in utero and childhood asthma
Shaheen and colleagues report their findings from studies on acetaminophen and childhood asthma from the Avon Longitudinal Study of Parents and Children (ALSPAC) cohort in this month’s issue (Shaheen SO, Newson RB, Rose-Zerilli MJ, Holloway JW, Henderson AJ. Prenatal and infant acetaminophen exposure, antioxidant gene polymorphisms, and childhood asthma. J Allergy Clin Immunol 2010;126:1141-1148.e7). The authors follow up on their previous studies demonstrating association of childhood asthma with acetaminophen use in pregnancy by investigating possible causality between the two.
Shaheen et al. reason that prenatal acetaminophen exposure may increase the risk of childhood asthma by increasing oxidative stress and glutathione depletion and that polymorphisms in antioxidant genes may influence acetaminophen toxicity in the womb. They genotyped transcription factor nuclear erythroid 2 p45-related factor 2 (Nrf2), a primary regulator of antioxidant genes, and the glutathione-S-transferases GSTM1, -P1, and T1, which protect the lung from oxidative stress. Previous research has shown that Nrf2-negative mice readily develop liver toxicity in response to acetaminophen exposure.
The authors find that early [≤20 weeks gestation] and late [≥20 weeks gestation] acetaminophen exposure in utero is associated with increased risk for wheezing and asthma in childhood. Late gestation acetaminophen exposure has a more profound effect on wheezing and, in addition, is associated with increased serum IgE.
They also find that effects of prenatal acetaminophen exposure on asthma risk are modified by Nrf2 and GST variants in the mother, but not in the child, strengthening evidence that the link between acetaminophen use in pregnancy and childhood asthma may be causal.
Shaheen et al. reason that prenatal acetaminophen exposure may increase the risk of childhood asthma by increasing oxidative stress and glutathione depletion and that polymorphisms in antioxidant genes may influence acetaminophen toxicity in the womb. They genotyped transcription factor nuclear erythroid 2 p45-related factor 2 (Nrf2), a primary regulator of antioxidant genes, and the glutathione-S-transferases GSTM1, -P1, and T1, which protect the lung from oxidative stress. Previous research has shown that Nrf2-negative mice readily develop liver toxicity in response to acetaminophen exposure.
The authors find that early [≤20 weeks gestation] and late [≥20 weeks gestation] acetaminophen exposure in utero is associated with increased risk for wheezing and asthma in childhood. Late gestation acetaminophen exposure has a more profound effect on wheezing and, in addition, is associated with increased serum IgE.
They also find that effects of prenatal acetaminophen exposure on asthma risk are modified by Nrf2 and GST variants in the mother, but not in the child, strengthening evidence that the link between acetaminophen use in pregnancy and childhood asthma may be causal.
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