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2.  Familial Cold Autoinflammatory Syndrome 
Familial cold autoinflammatory syndrome is an autosomal dominant inherited inflammatory disease characterized by episodes of rash, fever, and joint pain following generalized exposure to cold. Attacks usually occur 1–2 hours after exposure and last less than 24 hours. It has been reported primarily in families from North America and Europe, but sporadic cases have also been reported. The diagnosis is based on clinical presentation and can be confirmed by the identification of a NALP3 mutation. No clinical trials have been performed with FCAS patients, but anakinra, an IL-1 receptor antagonist, has been effective at preventing symptoms prior to a cold challenge and as a maintenance medication in several patients. The NALP3 gene, also known as CIAS1, is expressed in peripheral blood leukocytes and chondrocytes and codes a protein also known as Cryopyrin. NALP3 mutations have also been identified in Muckle Wells syndrome and Chronic infantile neurologic cutanaeous articular syndrome. There are several laboratories in Europe and North America where sequencing of NALP3 is performed.
PMCID: PMC4321996  PMID: 11590390
familial cold urticaria; CIAS1; cryopyrin; Pypaf1; NALP3; autosomal dominant transmission; inflammatory disorder
3.  Monocytes from familial cold autoinflammatory syndrome patients are activated by mild hypothermia 
Familial cold autoinflammatory syndrome (FCAS) is characterized by rash, fever, and arthralgia in response to cold exposure. CIAS1, the gene that codes for cryopyrin, is mutated in FCAS. Treatment with anakinra (IL-1 receptor antagonist) prevents symptoms, indicating a crucial role for IL-1 in this disease.
To study cytokine responses to cold exposure in monocytes from subjects with FCAS.
Adherence-enriched monocytes were incubated at 32°C or 37°C. Transcription and release of IL-1β, IL-6, and TNF-α were monitored by quantitative PCR and ELISA.
The FCAS monocytes but not control cells responded to 4 h incubation at 32°C with significant secretion of IL-1β. At 16 h, IL-1β, IL-6, and TNF-α were all significantly elevated in FCAS monocytes at 32°C. Increased cytokine transcription was observed in all monocytes at 4 hours, but at 16 hours it was only seen in FCAS monocytes incubated at 32°C. Incubation at 32°C for as little as 1 hour sufficed to induce measurable IL-1β release. Caspase-1 inhibitors prevented the cold-induced IL-1β release, whereas a purinergic antagonist did not. Anakinra had no effect on the early IL-1β release but significantly reduced the late-phase transcription and release of all cytokines.
FCAS monocytes respond to mild hypothermia with IL-1β release, which in turn induces autocrine transcription and secretion of IL-6 and TNF-α as well as stimulation of further IL-1β production.
Clinical implications
These results confirm the central role of IL-1β in FCAS and support the use of IL-1 targeted therapy in these patients.
PMCID: PMC4322003  PMID: 17320940
Cold; autoinflammatory syndrome; cryopyrin; CIAS1; interleukin-1β; monocytes; caspase-1; anakinra; inflammation
4.  Glucocorticoid Receptor Hetero-Complex Gene STIP1 Is Associated with Improved Lung Function in Asthmatics Treated with Inhaled Corticosteroids 
Corticosteroids exert their anti-inflammatory action by binding and activating the intracellular the glucocorticoid receptor (GR) hetero-complex.
Evaluate the genes HSPCB, HSPCA, STIP1, HSPA8, DNAJB1, PTGES3, FKBP5, and FKBP4 on corticosteroid response.
Caucasian asthmatics (382) randomized to once daily flunisolide or conventional inhaled corticosteroid therapy were genotyped. Outcome measures were baseline FEV1, % predicted FEV1, and % change in FEV1 after corticosteroid treatment. Multivariable analyses adjusted for age, gender, and height, were performed fitting the most appropriate genetic model based on quantitative mean derived from ANOVA models to determine if there was an independent effect of polymorphisms on change in FEV1 independent of baseline level.
Positive recessive model correlations for STIP1 SNPs were observed for baseline FEV1 [rs4980524, p=0.009; rs6591838, p=0.0045; rs2236647, p=0.002; and rs2236648; p=0.013], baseline % predicted FEV1 [rs4980524, p=0.002; rs6591838, p=0.017; rs2236647, p=0.003; and rs2236648; p=0.008] ; % change in FEV1 at 4 weeks [rs4980524, p=0.044; rs6591838, p=0.016; rs2236647; p=0.01] and 8 weeks therapy [rs4980524, p=0.044; rs6591838, p=0.016; rs2236647; p=0.01]. Haplotypic associations were observed for baseline FEV1 and % change in FEV1 at 4 weeks therapy [p=0.05 and p=0.01, respectively]. Significant trends towards association were observed for baseline % predicted FEV1 and % change in FEV1 at 8 weeks therapy. Positive correlations between haplotypes and % change in FEV1 were also observed.
STIP1 genetic variations may play a role in regulating corticosteroid response in asthmatics with reduced lung function. Replication in a second asthma population is required to confirm these observations.
Clinical Implications
Identifying genes that regulate corticosteroid responses could allow a priori determination of individual responses to corticosteroid therapy, leading to more effective dosing and/or selection of drug therapies for treating asthma.
PMCID: PMC4317788  PMID: 19254810
corticosteroid; pharmacogenetics; glucocorticoid receptor; SNP; heat shock protein; heat shock organizing protein; immunophilin
5.  [No title available] 
PMCID: PMC3938989  PMID: 23992748
6.  [No title available] 
PMCID: PMC3959655  PMID: 24636470
7.  [No title available] 
PMCID: PMC3959659  PMID: 24636473
8.  [No title available] 
PMCID: PMC3960290  PMID: 24636475
9.  [No title available] 
PMCID: PMC3960309  PMID: 24238647
10.  [No title available] 
PMCID: PMC3960312  PMID: 24139498
11.  [No title available] 
PMCID: PMC3960313  PMID: 24331379
12.  [No title available] 
PMCID: PMC3960315  PMID: 24075232
13.  [No title available] 
PMCID: PMC3960323  PMID: 24131825
14.  [No title available] 
PMCID: PMC3960328  PMID: 24373353
15.  [No title available] 
PMCID: PMC3960329  PMID: 24084071
16.  [No title available] 
PMCID: PMC3960331  PMID: 24361082
17.  [No title available] 
PMCID: PMC3960335  PMID: 24290285
18.  [No title available] 
PMCID: PMC3960337  PMID: 24331381
19.  [No title available] 
PMCID: PMC3960360  PMID: 24139607
20.  [No title available] 
PMCID: PMC3960405  PMID: 24139497
21.  [No title available] 
PMCID: PMC4086475  PMID: 24636478
22.  Peanut oral immunotherapy results in increased antigen-induced Treg function and hypomethylation of FOXP3 
The mechanisms contributing to clinical immune tolerance remain incompletely understood. This study provides evidence for specific immune mechanisms that are associated with a model of operationally defined clinical tolerance.
Our overall objective was to study laboratory changes associated with clinical immune tolerance in antigen-induced T cells, basophils, and antibodies in subjects undergoing oral immunotherapy (OIT) for peanut allergy.
In a phase 1, single site study, we studied participants (n=23) undergoing peanut OIT and compared them to age-matched allergic controls (n=20) undergoing standard of care (abstaining from peanut) for 24 months. Participants were operationally defined as clinically immune tolerant (IT) if they had no detectable allergic reactions to a peanut oral food challenge after 3 months of therapy withdrawal (IT, n=7) while those that had an allergic reaction were categorized as non-tolerant (NT, n=13).
Antibody and basophil activation measurements did not statistically differentiate between NT vs. IT. However, T-cell function and demethylation of FOXP3 CpG sites in antigen-induced Treg were significantly different between IT vs. NT participants. When IT participants were withdrawn from peanut therapy for an additional 3 months (total of 6 months); only 3 participants remained "immune tolerant" and 4 participants regained sensitivity along with increased methylation of FOXP3 CpG sites in antigen-induced Treg.
In summary, modifications at the DNA level of antigen-induced T-cell subsets may be predictive of a state of operationally-defined clinical "immune tolerance" during peanut OIT.
PMCID: PMC4121175  PMID: 24636474
Food allergy; allergy; oral immunotherapy; peanut; T regulatory cells; desensitization; tolerance; epigenetics; Foxp3
23.  D prostanoid receptor 2 (chemoattractant receptor–homologous molecule expressed on TH2 cells) protein expression in asthmatic patients and its effects on bronchial epithelial cells 
The D prostanoid receptor 2 (DP2; also known as chemoattractant receptor–homologous molecule expressed on TH2 cells) is implicated in the pathogenesis of asthma, but its expression within bronchial biopsy specimens is unknown.
We sought to investigate the bronchial submucosal DP2 expression in asthmatic patients and healthy control subjects and to explore its functional role in epithelial cells.
DP2 protein expression was assessed in bronchial biopsy specimens from asthmatic patients (n = 22) and healthy control subjects (n = 10) by using immunohistochemistry and in primary epithelial cells by using flow cytometry, immunofluorescence, and quantitative RT-PCR. The effects of the selective DP2 agonist 13, 14-dihydro-15-keto prostaglandin D2 on epithelial cell migration and differentiation were determined.
Numbers of submucosal DP2+ cells were increased in asthmatic patients compared with those in healthy control subjects (mean [SEM]: 78 [5] vs 22 [3]/mm2 submucosa, P < .001). The bronchial epithelium expressed DP2, but its expression was decreased in asthmatic patients compared with that seen in healthy control subjects (mean [SEM]: 21 [3] vs 72 [11]/10 mm2 epithelial area, P = .001), with similar differences observed in vitro by primary epithelial cells. Squamous metaplasia of the bronchial epithelium was increased in asthmatic patients and related to decreased DP2 expression (rs = 0.69, P < .001). 13, 14-Dihydro-15-keto prostaglandin D2 promoted epithelial cell migration and at air-liquid interface cultures increased the number of MUC5AC+ and involucrin-positive cells, which were blocked with the DP2-selective antagonist AZD6430.
DP2 is expressed by the bronchial epithelium, and its activation drives epithelial differentiation, suggesting that in addition to its well-characterized role in inflammatory cell migration, DP2 might contribute to airway remodeling in asthmatic patients.
PMCID: PMC4314591  PMID: 25312757
Expression; asthma; immunohistochemistry; prostaglandin D2; biopsy; ALI, Air-liquid interface; COPD, Chronic obstructive pulmonary disease; CRTH2, Chemoattractant receptor–homologous molecule expressed on TH2 cells; DK-PGD2, 13, 14-Dihydro-15-keto prostaglandin D2; DP1, D prostanoid receptor 1; DP2, D prostanoid receptor 2; PGD2, Prostaglandin D2
24.  Expired nitric oxide and airway reactivity in infants at risk for asthma 
Family histories of atopy, as well as histories of atopic dermatitis and food allergy, are important risk factors for an infant to have asthma. Although atopic sensitization appears to contribute to the development of asthma, it is unclear when the airways become involved with the atopic process and whether airway function relates to the atopic characteristics of the infant.
We sought to evaluate whether atopic infants without prior episodes of wheezing have increased expired nitric oxide (eNO) levels and heightened airway reactivity.
Infants with eczema were recruited, and atopic status was defined by specific IgE levels to foods or aeroallergens and total IgE levels. eNO, forced expiratory flow at 75% exhaled volume (FEF75), and airway reactivity to inhaled methacholine were measured in sedated infants. Airway reactivity was quantified by using the provocative concentration to decrease FEF75 by 30%.
Median age for the 114 infants evaluated was 10.7 months (range, 2.6–19.1 months). Infants sensitized to egg or milk compared with infants sensitized to neither egg nor milk had lower flows (FEF75: 336 vs 285 mL/s, P < .003) and lower lnPC30 (mg/mL) provocative concentrations to decrease FEF75 by 30% (−0.6 vs −1.2, P < .02) but no difference in eNO levels. Infants with total serum IgE levels of greater than 20 IU/mL had higher eNO levels compared with infants with IgE levels of 20 IU/mL or less (14.6 vs 11.2 ppb, P < .023) but no difference in forced flows or airway reactivity.
Our findings suggest that atopic characteristics of the infant might be important determinants of the airway physiology of forced expiratory flows, airway reactivity, and eNO.
PMCID: PMC4308034  PMID: 18760452
Atopy; eczema; airway reactivity
25.  Omalizumab Increases the Intrinsic Sensitivity of Human Basophils to IgE-Mediated Stimulation 
Treatment of allergic patients with omalizumab results in a paradoxical increase in their basophil histamine release response, ex vivo, to crosslinking anti-IgE antibody. It is not known whether this change in response is associated with an increase in intrinsic cellular sensitivity, which would be a paradoxical response.
To determine if the increase in response to anti-IgE Ab is a reflection of an increased cellular sensitivity, expressed as molecules of antigen-specific IgE per basophil required to produce a 50% of maximal response.
Patients were treated with omalizumab or placebo agent for 12 weeks (NCT01003301 at and the metric of basophil sensitivity was assessed at 4 time points, baseline, 6–8 weeks, 12 weeks (after which treatment stopped) and 24 weeks (12 weeks after the end of treatment).
As observed previously, treatment with omalizumab resulted in a marked increase in the maximal histamine release induced by crosslinking anti-IgE Ab. This change was accompanied by a marked shift in intrinsic basophil sensitivity, ranging from 2.5 to 125 fold, with an average of 6 fold at the midpoint of the treatment to 12 fold after 12 weeks. The magnitude of the increase in cellular sensitivity was inversely related to the starting sensitivity or the starting maximum histamine release. The increased cellular sensitivity also occurred when using LTC4 secretion as a metric of the basophil response. 12 weeks after the end of treatment, cellular sensitivity was found to shift towards the baseline level although the return to baseline was not yet complete at this time point.
Treatment with omalizumab results in a markedly increased sensitivity of basophils to IgE-mediated stimulation, in terms of the number of IgE molecules required to produce a given response. These results provide a better quantitative sense of the phenotypic change that occurs in basophils during omalizumab treatment which has implications both mechanistic and clinical.
PMCID: PMC4302343  PMID: 23791510
Human; Basophil; Allergy; Fc Receptors

Results 1-25 (911)