Assessing Asthma Control by Impulse Oscillometry and Fractional Expiratory Nitric Oxide in Children With Normal Spirometry.

BACKGROUND: Because spirometric parameters fail to address current status of asthma in some patients, additional tests are required for better evaluation of asthma. OBJECTIVE: We aimed to test the ability of impulse oscillometry (IOS) and fractional expiratory nitric oxide (FeNO) in identifying inadequately controlled asthma (ICA) that was not uncovered by spirometry. METHODS: Recruited asthmatic children between ages of 8 and 16 years underwent spirometry, IOS, and FeNO measurements on the same day. Only subjects who had spirometric indices within normal range were included. Asthma Control Questionnaire-6 scores of 0.75 or lower and greater than 0.75 indicated well-controlled asthma (WCA) and ICA. Percent predicted values of IOS parameters and IOS reference values for upper and lower limits of normal (>95th and <5th percentiles, respectively) were calculated on the basis of previously published equations. RESULTS: There were no significant differences in all spirometric indices between the WCA (n = 59) and the ICA (n = 101) groups. The % predicted values of IOS parameters except resistance at 20 Hz (R20) were significantly different between the 2 groups. Receiver operating characteristic analysis showed that the highest and lowest areas under the curve were 0.81 and 0.67 for the difference between the resistances at 5 Hz and 20 Hz (R5-R20) and R20 in discrimination of ICA versus WCA. The areas under the curve for IOS parameters were improved by combination with FeNO. The better discriminative ability of IOS was also supported by the higher values of the concordance index for the resistance at 5 Hz (R5), R5-R20, the reactance at 5 Hz (X5), and the resonant frequency of reactance than those for spirometric parameters. Compared with those with normal values, subjects with abnormal IOS parameters or high FeNO had significantly higher odds of having ICA. CONCLUSIONS: The IOS parameters and FeNO were shown to be useful in identifying children with ICA when spirometry was normal.

A novel likely pathogenic PLCG2 variant in a patient with a recurrent skin blistering disease and B-cell lymphopenia.

Pathogenic variants of PLCG2 encoding phospholipase C gamma 2 (PLCγ2) were first reported in 2012 and their clinical manifestations vary widely. PLCG2-associated antibody deficiency and immune dysregulation (PLAID) and autoinflammation and PLCγ2-associated antibody deficiency and immune dysregulation (APLAID) are representative examples of PLCG2 pathogenic variants. In this report, we describe a 17-year-old male with recurrent blistering skin lesions, B-cell lymphopenia, and asthma. Distinct from the patients in previous reports, this patient had the heterozygous de novo c.2119T > C missense variant (NM_002661.4) resulting in a serine to proline amino acid substitution (p.Ser707Pro). The variant located to the PLCγ2 C-terminal Src homology 2 (cSH2) domain, which is a critical site for the restriction of intrinsic enzyme activity. This variant could be classified as "likely pathogenic" according to American College of Medical Genetics and Genomics guidelines. Laboratory results showed a reduction in circulating B cells without a decrease of serum IgG and IgA. Our findings expand the variety of clinical phenotypes for PLCG2 missense variants.

Systematic review of literature and analysis of big data from the National Health Insurance System on primary immunodeficiencies in Korea.

There are very scant data on the epidemiology of primary immunodeficiency diseases (PIDs) in Korea. Here we attempted to estimate the PID epidemiology and disease burden in Korea. A systematic review was performed of studies retrieved from the PubMed, KoreaMed, and Google Scholar databases. Studies on PIDs published in Korean or English between January 2001 and November 2018 were analyzed. The number of PID patients and the healthcare costs were estimated from Health Insurance Review and Assessment Service (HIRA) Korea data for 2017. A total of 398 PID patients were identified from 101 reports. Immunodeficiencies affecting cellular and humoral immunity were reported in 11 patients, combined immunodeficiency with associated or syndromic features in 40, predominantly antibody deficiencies in 144, diseases of immune dysregulation in 58, congenital defects of phagocytes in 104, defects in the intrinsic and innate immunity in 1, auto-inflammatory disorders in 4, complement deficiencies in 36, and phenocopies of PID in none. From the HIRA reimbursement data, a total of 1,162 outpatients and 306 inpatients were treated for 8,166 and 6,149 days, respectively. In addition, reimbursement was requested for 8,200 outpatient and 1,090 inpatient cases and $1,924,000 and $4,715,000 were reimbursed in 2017, respectively. This study systematically reviewed published studies on PID and analyzed the national open data system of the HIRA to estimate the disease burden of PID, for the first time in Korea.

Combining spirometry and fractional exhaled nitric oxide improves diagnostic accuracy for childhood asthma.

OBJECTIVES: There are insufficient evidences supporting the use of spirometric indices along with tests for airway inflammation to improve diagnostic accuracy for asthma. We aimed to study the utility of combination of spirometric indices and fractional exhaled nitric oxide (FeNO) measured at the initial visit in diagnosing asthma. METHODS: Consecutive children aged 8-16 years who were referred for evaluation of possible asthma were included. At referral, all participants completed FeNO measurements and spirometry. The diagnosis of asthma was established with conventional criteria. Diagnostic performance of the spirometric indices and FeNO was determined using receiver-operator characteristic (ROC) curve analyses. RESULTS: Of 275 participants, 191 children were diagnosed with asthma and showed lower spirometric indices and higher FeNO than non-asthmatics. In the ROC curve analyses, forced expiratory flow between 25% and 75% of vital capacity (FEF25-75 ) percent predicted demonstrated diagnostic performance with the area under the ROC curve (AUC) value of 0.81 (95% CI: 0.76-0.87) which was significantly higher than those for forced expiratory volume in the first second (FEV1 ) percent predicted and FEV1 /forced vital capacity. The combined use of FEF25-75 percent predicted and FeNO improved the AUC to 0.90 (95% CI: 0.86-0.93). In addition, compared to FEF25-75 percent predicted or FeNO alone, this combination improved sensitivity with comparable specificity. CONCLUSIONS: FEF25-75 percent predicted had a better diagnostic value in detection of childhood asthma than other standard spirometric indices and its combination with FeNO improves the diagnostic accuracy for childhood asthma.

Clinical similarities between influenza A and B in children: a single-center study, 2017/18 season, Korea.

BACKGROUND: The global burden of seasonal influenza on medical care has been one of the greatest in the pediatric population. The attention drawn to influenza B was relatively low compared to influenza A, probably because the influenza B virus was thought to be less virulent and have a lower pandemic potential. This study aimed to compare the clinical features of influenza A and B in children. METHODS: This retrospective study included children diagnosed and treated for influenza as inpatients or outpatients during the 2017/18 influenza season at a tertiary referral hospital. Data regarding clinical characteristics, diagnoses, laboratory results, and vaccination histories were collected and reviewed. RESULTS: Over the study period, 128 patients with influenza A and 109 patients with influenza B were identified. The mean age of patients with influenza B was significantly higher than that of patients with influenza A (5.6 ± 4.4 vs 4.1 ± 4.4 years, p = 0.010). Fever was the most common manifestation of influenza followed by respiratory symptoms. No single symptom was specifically associated with either type of influenza. The total duration of fever (4.3 ± 2.3 vs 3.7 ± 2.6 days), 'time from fever onset to initiation of antivirals', and 'time from initiation of antivirals to defervescence' were similar between the two influenza types, even though all three time periods tended to be longer for influenza B. The platelet counts and proportions of neutrophils were higher for influenza A than for influenza B infections, although the values were within normal limits for both influenza types. CONCLUSIONS: We found overall clinical similarities between influenza A and B with no less clinical significance or severity of influenza B compared to those of influenza A. Equal levels of awareness and attention should be paid to both influenza types.

Accuracy of maximal expiratory flow-volume curve curvilinearity and fractional exhaled nitric oxide for detection of children with atopic asthma.

PURPOSE: Airway pathology in children with atopic asthma can be reflected by the concave shape of the maximal expiratory flow-volume (MEFV) curve and high fractional exhaled nitric oxide (FeNO) values. We evaluated the capacity of the curvilinearity of the MEFV curve, FeNO, and their combination to distinguish subjects with atopic asthma from healthy individuals. METHODS: FeNO and angle ß, which characterizes the general configuration of the MEFV curve, were determined in 119 steroid-naïve individuals with atopic asthma aged 8 to 16 years, and in 92 age-matched healthy controls. Receiver operating characteristic (ROC) curve analyses were performed to determine the cutoff points of FeNO and angle ß that provided the best combination of sensitivity and specificity for asthma detection. RESULTS: Asthmatic patients had a significantly smaller angle ß and higher FeNO compared with healthy controls (both, P<0.001). For asthma detection, the best cutoff values of angle ß and FeNO were observed at 189.3° and 22 parts per billion, respectively. The area under the ROC curve for the combination of angle ß and FeNO improved to 0.91 (95% confidence interval [CI], 0.87-0.95) from 0.80 (95% CI, 0.75-0.86; P<0.001) for angle ß alone and 0.86 (95% CI, 0.82-0.91; P=0.002) for FeNO alone. In addition, the combination enhanced sensitivity with no significant decrease in specificity. CONCLUSION: These data suggest that the combined use of the curvilinearity of the MEFV curve and FeNO is a useful tool to differentiate between children with and without atopic asthma.

Combined use of fractional exhaled nitric oxide and bronchodilator response in predicting future loss of asthma control among children with atopic asthma.

BACKGROUND AND OBJECTIVE: Recognition of patients at risk of asthma exacerbation is important for future asthma care and improved outcome. The aim of the present study was to see whether measurements of bronchodilator response (BDR) and fractional exhaled nitric oxide (FeNO) in combination provide prognostic information superior to either measurement alone in children with atopic asthma. METHODS: A total of 201 atopic children aged 8-16 years with intermittent or mild persistent asthma were included. Pulmonary function tests including BDR and FeNO were serially monitored 10 times or more over 2 years when subjects were not receiving controller medications. After completion of monitoring, 1-year observation for a loss of asthma control was performed. RESULTS: During the monitoring period, positive BDRs (≥12% in forced expiratory volume in 1 s (FEV1 ) from pre-bronchodilator value) and FeNO higher than 35 parts per billion (ppb) were observed at least once in 59% and 77% of participants. When analysed as continuous variables, both BDR (hazard ratio (HR): 1.21; 95% CI: 1.04-1.41; P = 0.014) and FeNO (HR: 1.27; 95% CI: 1.09-1.49; P = 0.003) were associated with increased risks for a control loss. Compared with patients showing either positive BDRs (HR: 3.19; 95% CI: 1.05-9.64) or FeNO higher than 35 ppb (HR: 4.70; 95% CI: 1.68-13.11), patients with both findings (HR: 7.08; 95% CI: 2.57-19.49) had greater risks for a control loss. CONCLUSION: These data support that combined use of BDR and FeNO measurements can modify predictive risk obtained from either measurement alone.

House dust mite-specific immunoglobulin E and longitudinal exhaled nitric oxide measurements in children with atopic asthma.

PURPOSE: House dust mite (HDM) has been suggested to be the most important aeroallergen responsible for atopic asthma in Korea. We aimed to investigate that specific IgE antibodies to HDM and other common indoor aeroallergens contribute differently to total serum IgE and show different relationships with longitudinal fractional exhaled nitric oxide (FeNO) measurements in Korean atopic asthmatic patients. METHODS: A total of 193 children aged 8 to 16 years with intermittent or mild persistent atopic asthma were recruited. Sera were assayed for total IgE and specific IgE antibodies to HDM and other common indoor allergens. FeNO was serially measured 10 times or more over 2 years when subjects were not receiving controller medications. RESULTS: In 152 children who completed the study, IgE antibodies to specific HDM were more prevalent than those to other common indoor aeroallergens. In addition, IgE antibody titers to HDM were the strongest contributor to total IgE increases. Furthermore, only HDM-specific IgE antibody titer significantly correlated with maximum FeNO (r=0.21, P=0.029) and the rate of FeNO higher than 21 parts per billion (ppb) (r=0.30, P=0.002). Eight patients (5%) were found to have maximum FeNO of 21 ppb or less, suggesting the presence of a low FeNO phenotype among atopic asthmatic patients. CONCLUSION: The quantity of HDM-specific IgE antibody provides a possible explanation for increases of total IgE and significantly correlates with the amount and frequency of FeNO increases in Korean atopic asthmatic patients.

Association of longitudinal fractional exhaled nitric oxide measurements with asthma control in atopic children.

OBJECTIVES: We sought to determine whether longitudinal measurements of FeNO are informative for future loss of asthma control in children with atopic asthma. METHODS: One hundred seventy-eight patients aged 8-16 years with atopic asthma were enrolled. FeNO and lung functions were serially monitored 10 times or more over 2 years when subjects were not receiving controller medications. After completion of monitoring, 1-year observation on the occurrence of loss of asthma control was performed and associations of loss of asthma control with spirometric and FeNO measurements were analyzed. RESULTS: Loss of asthma control occurred during observation periods in 110 (76%) of 145 patients who completed the study. Of all monitored parameters including airway reactivity, the highest FeNO of serial measurements (H-FeNO) (adjusted odds ratio (aOR), 1.21; 95% CI, 1.08-1.36) and the rate of FeNO levels higher than 21 ppb (R21FeNO) (aOR, 1.06; 95% CI, 1.01-1.11) were the only independent predictors of upcoming control loss in the multiple logistic regression analysis. In receiver-operator characteristic curve analysis, H-FeNO > 37 ppb and R21FeNO > 20% demonstrated 91% and 88% sensitivity for a future loss of asthma control at the cost of low specificity (60% and 65%, respectively). In contrast, H-FeNO > 47 ppb and R21FeNO > 41% gave 96% and 88% specificity, but these sacrificed sensitivity to 70% and 72%, respectively. CONCLUSIONS: Our data show that both amount and frequency of a FeNO increase during longitudinal monitoring are helpful in predicting asthma control status.

Measurements of fractional exhaled nitric oxide in pediatric asthma.

Exhaled nitric oxide (NO) has been extensively investigated as a noninvasive marker of airway inflammation in asthma. The increased NO expression induced by inflammatory mediators in airways can be monitored easily in exhaled air from asthmatic children. Based on the relationship between the increased NO expression and eosinophilic airway inflammation, fractional exhaled nitric oxide (FeNO) measurements become an important adjunct for the evaluation of asthma. In addition, the availability of portable devices makes it possible to measure FeNO more easily and frequently in the routine pediatric practice. Despite various confounding factors affecting its levels, FeNO can be applicable in diagnosing asthma, monitoring treatment response, evaluating asthma control, and predicting asthma exacerbations. Thus, although pulmonary function tests are the standard tools for objective measurements of asthmatic control, FeNO can broaden the way of asthma monitoring and supplement standard clinical asthma care guidelines.

Increased cow's milk protein-specific IgG4 levels after oral desensitization in 7- to 12-month-old infants.

BACKGROUND: Cow's milk protein (CMP)-specific IgG4 responses and the efficacy of oral desensitization in infants with cow's milk allergy (CMA) warrant more clarification. OBJECTIVE: To explore whether CMP-specific IgG4 responses develop during infancy and whether regular CM exposure is efficacious for inducing a CMP-specific IgG4 response accompanying CM desensitization in 7- to 12-month-old infants. METHODS: CM-specific IgE and CMP (α-lactalbumin, ß-lactoglobulin, and casein)-specific IgG4 levels were measured in 262 CM-sensitized children. Of these, 31 infants 7 to 12 months old with challenge-proved CMA were randomly assigned to oral desensitization or an elimination diet and evaluated 6 months later. RESULTS: CMP-specific IgG4 levels in 7- to 12-month-old infants were higher than in those younger than 6 months but comparable to those in children older than 12 months. CMP-specific IgG4 levels in 7- to 12-month-old infants with CMA were significantly lower than in those without CMA. Fourteen of 16 patients receiving oral desensitization could accept daily doses of 200 mL of CM, whereas all but 3 dropout patients receiving the elimination diet still showed allergic symptoms at the follow-up food challenge. In patients who became desensitized, CM-specific IgE levels were lower than at baseline, whereas CMP-specific IgG4 levels were significantly increased. In patients receiving the elimination diet, CM-specific IgE and CMP-specific IgG4 levels remained unchanged. CONCLUSION: CMP-specific IgG4 responses did not develop sufficiently in 7- to 12-month-old infants with CMA. Oral desensitization in 7- to 12-month-old infants with CMA was associated with the upregulation of CMP-specific IgG4 responses accompanying the alleviation of CMA symptoms.

Fractional exhaled nitric oxide and forced expiratory flow between 25% and 75% of vital capacity in children with controlled asthma.

PURPOSE: Fractional exhaled nitric oxide (FeNO) and forced expiratory flow between 25% and 75% of vital capacity (FEF(25-75)) are not included in routine monitoring of asthma control. We observed changes in FeNO level and FEF(25-75) after FeNO-based treatment with inhaled corticosteroid (ICS) in children with controlled asthma (CA). METHODS: We recruited 148 children with asthma (age, 8 to 16 years) who had maintained asthma control and normal forced expiratory volume in the first second (FEV(1)) without control medication for ≥3 months. Patients with FeNO levels >25 ppb were allocated to the ICS-treated (FeNO-based management) or untreated group (guideline-based management). Changes in spirometric values and FeNO levels from baseline were evaluated after 6 weeks. RESULTS: Ninety-three patients had FeNO levels >25 ppb. These patients had lower FEF(25-75)% predicted values than those with FeNO levels ≤25 ppb (P<0.01). After 6 weeks, the geometric mean (GM) FeNO level in the ICS-treated group was 45% lower than the baseline value, and the mean percent increase in FEF(25-75) was 18.% which was greater than that in other spirometric values. There was a negative correlation between percent changes in FEF(25-75) and FeNO (r=-0.368, P=0.001). In contrast, the GM FeNO and spirometric values were not significantly different from the baseline values in the untreated group. CONCLUSION: The anti-inflammatory treatment simultaneously improved the FeNO levels and FEF(25-75) in CA patients when their FeNO levels were >25 ppb.

Utility of fractional exhaled nitric oxide (F(E)NO) measurements in diagnosing asthma.

BACKGROUND: To facilitate the use of fractional exhaled nitric oxide (F(E)NO) as a clinical test, F(E)NO measurements need more clarification. AIM: We sought to evaluate the yield of F(E)NO measurement for the diagnosis of asthma and identify the determinants of F(E)NO in children. METHODS: Two hundred forty five consecutive steroid-naïve patients aged 8-16 years with symptoms suggestive of asthma were included. Children were evaluated using F(E)NO measurements, questionnaires, skin prick tests, spirometries, and methacholine challenge tests. RESULTS: Asthma was diagnosed in 167 children. The sensitivity, specificity, and positive (PPV) and negative predictive values (NPV) of F(E)NO measurements for the diagnosis of asthma at the best cutoff value of 22 ppb were 56.9%, 87.2%, 90.5%, and 48.6%, respectively. At a cutoff value of 42 ppb, specificity and PPV were all 100% but at the cost of very low sensitivity (23.4%) and NPV (37.9%). Both atopy and asthma were identified as independent risk factors associated with high F(E)NO. The association of asthma with high F(E)NO was found only in atopic children because F(E)NO was low in non-atopic children regardless of asthma status. Although highest F(E)NO was observed in atopic asthmatic patients, 28% of these patients had F(E)NO values lower than 22 ppb. CONCLUSION: Atopic asthmatic patients with low F(E)NO values and non-atopic asthmatic patients were responsible for false-negative cases that might contribute to low sensitivity of F(E)NO measurements in diagnosing asthma. High specificity of F(E)NO measurements may help identify patients with atopic asthma among subjects with respiratory symptoms.

Tuberculous pericarditis presenting as multiple free floating masses in pericardial effusion.

Pericarditis is a rare manifestation of tuberculosis (Tb) in children. A 14-yr-old Korean boy presented with cardiac tamponade during treatment of pulmonary tuberculosis. He developed worsening anemia and persistent fever in spite of anti-tuberculosis medications. Echocardiography found free floating multiple discoid masses in the pericardial effusion. The masses and exudates were removed by pericardiostomy. The masses were composed of pink, amorphous meshwork of threads admixed with degenerated red blood cells and leukocytes with numerous acid-fast bacilli, which were confirmed as Mycobacterium species by polymerase chain reaction. The persistent fever and anemia were controlled after pericardiostomy. This is the report of a unique manifestation of Tb pericarditis as free floating masses in the effusion with impending tamponade.

Effect of Lactobacillus sakei supplementation in children with atopic eczema-dermatitis syndrome.

BACKGROUND: Probiotics have been suggested to be useful in children with atopic eczema-dermatitis syndrome (AEDS). OBJECTIVE: To assess the clinical effect of Lactobacillus sakei supplementation in children with AEDS. METHODS: In a double-blind, placebo-controlled trial, children aged 2 to 10 years with AEDS with a minimum SCORing of Atopic Dermatitis (SCORAD) score of 25 were randomized to receive either daily L sakei KCTC 10755BP or daily placebo supplementation for 12 weeks. Changes in SCORAD scores and serum chemokine levels from baseline were evaluated. RESULTS: Eighty-eight children were enrolled, and 45 were allocated to probiotic treatment. Seventy-five children completed the study, with 4 dropouts in the probiotic group and 9 in the placebo group. At week 12, SCORAD total scores adjusted by pretreatment values were lower after probiotic treatment than after placebo treatment (P = .01). There was a 31% (13.1-point) improvement in mean disease activity with probiotic use compared with a 13% (5.2-point) improvement with placebo use (P = .008). Significant differences in favor of probiotic treatment were also observed in proportions of patients achieving improvement of at least 30% and 50%. Compared with placebo, probiotic administration was associated with lower pretreatment-adjusted serum levels of CCL17 and CCL27 (P =.03 for both), which were significantly correlated with SCORAD total score (r = 0.59 and 0.63, respectively; P < .001). CONCLUSIONS: Supplementation of L sakei in children with AEDS was associated with a substantial clinical improvement and a significant decrease in chemokine levels, reflecting the severity of AEDS.

Analysis of gamma delta T cell functions in the mouse.

Mouse models of disease and injury have been invaluable in investigations of the functional role of gammadelta T cells. They show that gammadelta T cells engage in immune responses both early and late, that they can function both polyclonally and as peripherally selected clones, and that they can be effector cells and immune regulators. They also suggest that functional development of gammadelta T cells occurs stepwise in thymus and periphery, and that it is governed by gammadelta TCR-signaling and other signals. Finally, they indicate that gammadelta T cell functions often segregate with TCR-defined subsets, in contrast to conventional T cells. From the functional studies in mice and other animal models, gammadelta T cells emerge as a distinct lymphocyte population with a unique and broad functional repertoire, and with important roles in Ab responses, inflammation and tissue repair. They also are revealed as a potentially useful target for immune intervention.

Pathogenesis and clinical manifestations of juvenile rheumatoid arthritis.

Juvenile rheumatoid arthritis (JRA) is the most common rheumatic childhood disease; its onset is before 16 years of age and it persists for at least 6 weeks. JRA encompasses a heterogeneous group of diseases that is classified according to 3 major presentations: oligoarthritis, polyarthritis, and systemic onset diseases. These presentations may originate from the same or different causes that involve interaction with specific immunogenetic predispositions, and result in heterogeneous clinical manifestations. An arthritic joint exhibits cardinal signs of joint inflammation, such as swelling, pain, heat, and loss of function; any joint can be arthritic, but large joints are more frequently affected. Extra-articular manifestations include high fever, skin rash, serositis, and uveitis. The first 2 types of JRA are regarded as T helper 1 (Th1) cell-mediated inflammatory disorders, mainly based on the abundance of activated Th1 cells in the inflamed synovium and the pathogenetic role of proinflammatory cytokines that are mainly produced by Th1 cell-stimulated monocytes. In contrast, the pathogenesis of systemic onset disease differs from that of other types of JRA in several respects, including the lack of association with human leukocyte antigen type and the absence of autoantibodies or autoreactive T cells. Although the precise mechanism that leads to JRA remains unclear, proinflammatory cytokines are thought to be responsible for at least part of the clinical symptoms in all JRA types. The effectiveness of biologic therapy in blocking the action of these cytokines in JRA patients provides strong evidence that they play a fundamental role in JRA inflammation.

Allergic airway hyperresponsiveness-enhancing gammadelta T cells develop in normal untreated mice and fail to produce IL-4/13, unlike Th2 and NKT cells.

Allergic airway hyperresponsiveness (AHR) in OVA-sensitized and challenged mice, mediated by allergen-specific Th2 cells and Th2-like invariant NKT (iNKT) cells, develops under the influence of enhancing and inhibitory gammadelta T cells. The AHR-enhancing cells belong to the Vgamma1(+) gammadelta T cell subset, cells that are capable of increasing IL-5 and IL-13 levels in the airways in a manner like Th2 cells. They also synergize with iNKT cells in mediating AHR. However, unlike Th2 cells, the AHR enhancers arise in untreated mice, and we show here that they exhibit their functional bias already as thymocytes, at an HSA(high) maturational stage. In further contrast to Th2 cells and also unlike iNKT cells, they could not be stimulated to produce IL-4 and IL-13, consistent with their synergistic dependence on iNKT cells in mediating AHR. Mice deficient in IFN-gamma, TNFRp75, or IL-4 did not produce these AHR-enhancing gammadelta T cells, but in the absence of IFN-gamma, spontaneous development of these cells was restored by adoptive transfer of IFN-gamma-competent dendritic cells from untreated donors. The i.p. injection of OVA/aluminum hydroxide restored development of the AHR enhancers in all of the mutant strains, indicating that the enhancers still can be induced when they fail to develop spontaneously, and that they themselves need not express TNFRp75, IFN-gamma, or IL-4 to exert their function. We conclude that both the development and the cytokine potential of the AHR-enhancing gammadelta T cells differs critically from that of Th2 cells and NKT cells, despite similar influences of these cell populations on AHR.