In the May issue of JACI, Guttman-Yassky et al. (J Allergy Clin Immunol 2011;127:1110-1118), in part 1 of a 2-part review, covered the clinical and pathological similarities and differences between psoriasis and atopic dermatitis (AD) with AD as the point of reference. They finish up in this month’s issue (J Allergy Clin Immunol 2011;127:1420-1432) with a broad discussion comparing the immune phenotypes and therapies for AD and psoriasis.
In part 1, Guttman-Yassky et al. pointed out that psoriasis and AD both present with defects in skin barrier function, skin lesions infiltrated by increased numbers of T cells and dendritic cells and upregulation of epidermal proliferation genes. They note that the chronic phase of AD is more similar to psoriasis than the acute phase. There are distinct differences though. AD patients are susceptible to bacterial and viral skin infections, which is not true for psoriasis patients. Also, AD skin is characterized by decreases in keratinocyte differentiation, cornification, moisture and lipid content. Though lipid depletion is also observed for psoriasis, it is characterized by increased differentiation and cornification. Cytokine milieu in AD is dominated by TH2 cells, while psoriasis is associated with TH1 and TH17 cytokines. Additionally, AD is associated with structural protein anomalies (e.g., filaggrin dysfunction) that are not observed in psoriasis.
The authors discuss in part 2 how the disorders were thought to be mediated by polarized T helper cell responses with TH2 dominance seen in AD; however, this simple dichotomy did not account for all observations, such as hyperkeratinization, seen in chronic AD. They point out that the discovery that TH17 and T22 cells affected epidermal activation eventually led to a new working model wherein psoriasis is mediated by TH1 and TH17 immunity, and AD is mediated by TH2 and T22 cell effects. Production of anti-microbial peptides (AMP) is known to be compromised in AD compared to psoriasis. This was originally attributed to the TH2 environment, but the authors comment that IL-17 deficiency as well as excessive TH2 cytokines can explain the decreased AMP production found in AD. Guttman-Yassky et al note that the impaired AMP production would explain increased susceptibility to skin infections in AD. In contrast, psoriasis is characterized by increased AMP production. The authors also discuss basic differences between AD and psoriasis with regard to differences in dendritic cell populations, AD-associated eosinophilia, barrier defects and inflammation, and mast cell production of interferon gamma (IFN-γ) in psoriasis.
Guttman-Yassky et al. finish up part II with a discussion of the prognosis and intervention for psoriasis and AD. Unlike AD, they note that active psoriasis can be completely resolved and treatment time is short. The authors comment that, in spite of their differences, both AD and psoriasis share epidermal hyperplasia, aberrant immunity, and skin barrier anomalies. This would suggest that immune-based strategies to correct barrier defects that have been developed for psoriasis might be effective for AD. Guttman-Yassky et al. detail current AD treatments and make a case for psoriasis therapies as intervention for AD.
Tell us what you think. Please feel free to post your own comments and/or predictions below.
Thursday, June 2, 2011
Chronic mucocutaneous candidiasis associated with impaired TH17 cell differentiation
In this month’s issue, Hanna and Etzoni (J Allergy Clin Immunol 2011;127:1433-1437) shed light on the primary players in the pathogenesis of chronic mucosal candidiasis (CMC). They review current knowledge of CMC as it is most commonly observed; namely, as secondary to other clinical conditions, particularly those that cause immunocompromise, such as HIV, diabetes mellitus, and T-cell deficiency disorders. Hanna and Etzoni then discuss CMC as a primary symptom in immunodeficiency disease, such as in hyper-IgE syndrome (HIES) and autoimmune polyendocrinopathy with candidiasis and ectodermal dysplasia (APECED), or, more rarely, with no other related clinical presentation.
The authors review the primary innate immune defense against Candida albicans, noting that activation of the Dectin-1 and -2 receptors mediate host response through spleen tyrosine kinase (Syk) and caspase recruitment domain member 9 (CARD9) to initiate T cell differentiation to produce multiple cytokines, particularly those associated with TH17 differentiation, IL-17 and IL-22. T regulatory cells are also mobilized and critical for containing the TH17 inflammatory response to C. albicans.
Hanna and Etzoni move on to discuss CMC as the primary clinical feature of HIES and point to research that has shown that a heterozygous mutation in the transcription factor, STAT3, is the cause of this syndrome. Impaired STAT3 signaling negatively impacts RORγt function, which is required for TH17 cell development. The authors point out that this is supported by clinical findings of very low circulating markers for TH17 cell lineage in patients with HIES.
They also review severe CMC as a major feature of the autoimmune disease, APECED. Unlike the transcription dysregulation in HIES, CMC in APECED results from high titers of neutralizing autoantibodies against IL-17 and IL-22. Finally, Hanna and Etzoni describe less common presentations of non-syndromic CMC, some of which are idiopathic, while others have autosomal inheritance associations. In the latter, the authors discuss a genetic analysis of familial CMC in 5 generations of an Iranian family, which revealed a loss-of-function mutation in CARD9.
The authors conclude noting that in most non-syndromic CMC cases the genetic defects are still unknown, though abnormal TH17 function or production was observed.
Tell us what you think. Please feel free to post your own comments and/or predictions below.
The authors review the primary innate immune defense against Candida albicans, noting that activation of the Dectin-1 and -2 receptors mediate host response through spleen tyrosine kinase (Syk) and caspase recruitment domain member 9 (CARD9) to initiate T cell differentiation to produce multiple cytokines, particularly those associated with TH17 differentiation, IL-17 and IL-22. T regulatory cells are also mobilized and critical for containing the TH17 inflammatory response to C. albicans.
Hanna and Etzoni move on to discuss CMC as the primary clinical feature of HIES and point to research that has shown that a heterozygous mutation in the transcription factor, STAT3, is the cause of this syndrome. Impaired STAT3 signaling negatively impacts RORγt function, which is required for TH17 cell development. The authors point out that this is supported by clinical findings of very low circulating markers for TH17 cell lineage in patients with HIES.
They also review severe CMC as a major feature of the autoimmune disease, APECED. Unlike the transcription dysregulation in HIES, CMC in APECED results from high titers of neutralizing autoantibodies against IL-17 and IL-22. Finally, Hanna and Etzoni describe less common presentations of non-syndromic CMC, some of which are idiopathic, while others have autosomal inheritance associations. In the latter, the authors discuss a genetic analysis of familial CMC in 5 generations of an Iranian family, which revealed a loss-of-function mutation in CARD9.
The authors conclude noting that in most non-syndromic CMC cases the genetic defects are still unknown, though abnormal TH17 function or production was observed.
Tell us what you think. Please feel free to post your own comments and/or predictions below.
Friday, May 6, 2011
Dietary fat intake linked directly to airway inflammation
What you eat determines how you breathe whether or not you have asthma. Wood et al. (J Allergy Clin Immunol 2011;127:1133-1140) present first-ever findings on the local inflammatory effects of high fat food, in this month’s issue.
The authors examine the effect of single high-fat or low-fat meals on non-obese subjects with asthma. Then, healthy, non-obese subjects and obese subjects with asthma were administered a single high-fat meal. All groups that consumed a high fat meal showed increased neutrophilic airway inflammation as measured by sputum induction and IL-6 levels, decreased % predicted FEV1 post-bronchodilator, and increased TLR4 expression and TNF-α levels. Wood et al. report that increased total plasma fatty acid levels were correlated significantly to increases in TNF-α and neutrophil percentage in sputum. Additionally, increased fatty acid levels were inversely correlated to change in % FEV1, %FVC, and FEV1/FVC.
They also examined the effect of meals containing trans-fatty acids as compared to meals with no trans-fatty acids. Subjects consuming trans-fatty acids demonstrated increased sputum neutrophilia compared to those that consumed no trans-fatty acids, which is consistent with other research reporting the pro-inflammatory properties of trans-fat.
Wood et al. state in conclusion that consumption of a high fat meal causes local airway inflammation and asthma worsening through activation of the innate immune response. They recommend that future research on this subject should focus on the effects of chronic consumption of high fat food in patients with asthma.
Have a comment? Tell us what you think. Please feel free to post your own comments and/or predictions below.
The authors examine the effect of single high-fat or low-fat meals on non-obese subjects with asthma. Then, healthy, non-obese subjects and obese subjects with asthma were administered a single high-fat meal. All groups that consumed a high fat meal showed increased neutrophilic airway inflammation as measured by sputum induction and IL-6 levels, decreased % predicted FEV1 post-bronchodilator, and increased TLR4 expression and TNF-α levels. Wood et al. report that increased total plasma fatty acid levels were correlated significantly to increases in TNF-α and neutrophil percentage in sputum. Additionally, increased fatty acid levels were inversely correlated to change in % FEV1, %FVC, and FEV1/FVC.
They also examined the effect of meals containing trans-fatty acids as compared to meals with no trans-fatty acids. Subjects consuming trans-fatty acids demonstrated increased sputum neutrophilia compared to those that consumed no trans-fatty acids, which is consistent with other research reporting the pro-inflammatory properties of trans-fat.
Wood et al. state in conclusion that consumption of a high fat meal causes local airway inflammation and asthma worsening through activation of the innate immune response. They recommend that future research on this subject should focus on the effects of chronic consumption of high fat food in patients with asthma.
Have a comment? Tell us what you think. Please feel free to post your own comments and/or predictions below.
A look at commensal gut bacteria, probiotics and atopy and obesity
In a clinical review in this month’s issue, Ly et al. (J Allergy Clin Immunol 2011;127:1087-1094) pull together what is known currently about gut microbiota influence on immunity, the association of abnormal microflora with eczema, asthma and obesity, the usefulness of probiotics for normalizing commensal gut bacteria, and newer information about vitamin D interactions with intestinal flora.
The authors begin commenting on how infants achieve gut colonization peri- and post-natally and note that vaginal delivery results in different gut flora in the infant than cesarean delivery. In particular, infants delivered by cesarean establish gut flora dominated by Klebsiella and Clostridum species, and enterobacteria other than E. coli, with later and less colonization by Bacteroides sp. and Bifidobacterium sp. Ly et al. point out that hospitalized neonates have gut flora similar to infants delivered by cesarean, suggesting that standard of care antibiotic use could be related to the decreased colonization by healthy bacteria.
They continue with a review of current knowledge of differential gut microbial populations between atopic and non-atopic infants, noting that atopic infants have lower fractions of lactobacilli, bifidobacteria, and Bacteroides sp. than their non-atopic counterparts. Ly et al. comment that current studies on neonatal gut commensalism and atopy are inconclusive, then discuss the design variability and limitations that result in contradictory findings.
The authors move to the evidence supporting a relationship between disturbance of the gut microflora and diet-related obesity, linking it to inflammation and impaired energy metabolism. They further note that gut flora composition shifts toward healthier bacteria dominance in obese subjects on dietary restriction for weight loss.
Ly et al. wrap up with a discussion of the equivocal findings from studies employing probiotics as prevention or mitigation of atopic diseases and a short note on the requirement of vitamin D for healthy gut microbial effects on inflammation. They conclude stating that evidence suggests early diversity of microbiota is pivotal to healthy gut-immune dynamics and that future research must comprise data on maternal flora-neonate flora interactions, vitamin D’s role and dietary confounders.
Have a comment? Tell us what you think. Please feel free to post your own comments and/or predictions below.
The authors begin commenting on how infants achieve gut colonization peri- and post-natally and note that vaginal delivery results in different gut flora in the infant than cesarean delivery. In particular, infants delivered by cesarean establish gut flora dominated by Klebsiella and Clostridum species, and enterobacteria other than E. coli, with later and less colonization by Bacteroides sp. and Bifidobacterium sp. Ly et al. point out that hospitalized neonates have gut flora similar to infants delivered by cesarean, suggesting that standard of care antibiotic use could be related to the decreased colonization by healthy bacteria.
They continue with a review of current knowledge of differential gut microbial populations between atopic and non-atopic infants, noting that atopic infants have lower fractions of lactobacilli, bifidobacteria, and Bacteroides sp. than their non-atopic counterparts. Ly et al. comment that current studies on neonatal gut commensalism and atopy are inconclusive, then discuss the design variability and limitations that result in contradictory findings.
The authors move to the evidence supporting a relationship between disturbance of the gut microflora and diet-related obesity, linking it to inflammation and impaired energy metabolism. They further note that gut flora composition shifts toward healthier bacteria dominance in obese subjects on dietary restriction for weight loss.
Ly et al. wrap up with a discussion of the equivocal findings from studies employing probiotics as prevention or mitigation of atopic diseases and a short note on the requirement of vitamin D for healthy gut microbial effects on inflammation. They conclude stating that evidence suggests early diversity of microbiota is pivotal to healthy gut-immune dynamics and that future research must comprise data on maternal flora-neonate flora interactions, vitamin D’s role and dietary confounders.
Have a comment? Tell us what you think. Please feel free to post your own comments and/or predictions below.
Tuesday, April 5, 2011
Severity of human rhinovirus infection in infants linked to maternal atopy
Human rhinoviruses (HRV) are known to be associated with asthma exacerbations in both children and adults. Additionally, bronchiolitis, which is usually associated with respiratory syncytial virus (RSV), is being associated with HRV as well. Typically, HRV is a viral infection associated with older children and has not been closely examined in infants with low risk for atopy.
Miller and colleagues in this month’s issue (J Allergy Clin Immunol 2011;127:883-891) examine the HRV burden in upper respiratory infections (URI) and bronchiolitis among children that had participated in the Tennessee Children’s Respiratory Initiative. They collected atopy risk information, clinical severity from hospital admission records, and performed type testing on the three HRV strains, A, B, and C.
Miller et al find that both URI and bronchiolitis in healthy infants are commonly caused by HRV. Maternal atopy and asthma were associated significantly with risk of more severe bronchiolitis, with maternal atopy conferring more than double the severity risk. Of the three strains of HRV, the newly described group, HRVC was very common and occurred more often in black infants thnt HRVA and HRVB. Infants infected with HRVB had higher severity scores and were more likely to require oxygen supplementation and have longer hospital stays.
The authors conclude that an infant’s susceptibility to severe HRV illness is significantly correlated to asthma and atopy susceptibility in the mother.
Tell us what you think. Please feel free to post your own comments below.
Miller and colleagues in this month’s issue (J Allergy Clin Immunol 2011;127:883-891) examine the HRV burden in upper respiratory infections (URI) and bronchiolitis among children that had participated in the Tennessee Children’s Respiratory Initiative. They collected atopy risk information, clinical severity from hospital admission records, and performed type testing on the three HRV strains, A, B, and C.
Miller et al find that both URI and bronchiolitis in healthy infants are commonly caused by HRV. Maternal atopy and asthma were associated significantly with risk of more severe bronchiolitis, with maternal atopy conferring more than double the severity risk. Of the three strains of HRV, the newly described group, HRVC was very common and occurred more often in black infants thnt HRVA and HRVB. Infants infected with HRVB had higher severity scores and were more likely to require oxygen supplementation and have longer hospital stays.
The authors conclude that an infant’s susceptibility to severe HRV illness is significantly correlated to asthma and atopy susceptibility in the mother.
Tell us what you think. Please feel free to post your own comments below.
Developing countries feeling the effects of increased traffic-related pollution
Studies of proximity to major roadways and asthma symptoms in urban environments are demonstrating that there is a significant relationship between the two. There are some reports that traffic pollution also affects FEV1. For the most part, these studies have measured pollution effects from multiple traffic networks, such as mass transit, in developed countries. Few studies in developing countries, with a focus on the impact of individual roadways, have been attempted.
Peru has the highest reported prevalence of childhood asthma symptoms in Latin America, and its capital, Lima, is representative of rapid urban development and expansion. In this month’s issue, Baumann et al. (J Allergy Clin Immunol 2011; 127:875-882) examine the effect of a single, high traffic road in a shanty town outside of Lima, Peru. They evaluate current asthma symptoms, pollution inside and outside the home, and allergen sensitivity as a marker of atopy.
The authors find asthma symptoms and atopy are inversely correlated to proximity to the high traffic road that runs through the shanty town. Airflow limitation was also negatively correlated to roadway proximity, but only in girls. The authors report no increase in airway inflammation or indoor pollution in homes closer to the road. Interestingly, they did find that greater than half the children that participated were atopic, with 23% testing positive to 3 or more allergens. The authors note that theirs is the first epidemiologic report correlating proximity to a roadway and atopy risk.
Tell us what you think. Please feel free to post your own comments below.
Peru has the highest reported prevalence of childhood asthma symptoms in Latin America, and its capital, Lima, is representative of rapid urban development and expansion. In this month’s issue, Baumann et al. (J Allergy Clin Immunol 2011; 127:875-882) examine the effect of a single, high traffic road in a shanty town outside of Lima, Peru. They evaluate current asthma symptoms, pollution inside and outside the home, and allergen sensitivity as a marker of atopy.
The authors find asthma symptoms and atopy are inversely correlated to proximity to the high traffic road that runs through the shanty town. Airflow limitation was also negatively correlated to roadway proximity, but only in girls. The authors report no increase in airway inflammation or indoor pollution in homes closer to the road. Interestingly, they did find that greater than half the children that participated were atopic, with 23% testing positive to 3 or more allergens. The authors note that theirs is the first epidemiologic report correlating proximity to a roadway and atopy risk.
Tell us what you think. Please feel free to post your own comments below.
Friday, March 4, 2011
Tight junctions compromised in atopic dermatitis
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.
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.
Subscribe to:
Posts (Atom)