Atopic dermatitis is associated with a functional mutation in the promoter of the C-C chemokine RANTES.

Up-regulation of C-C chemokine expression characterizes allergic inflammation and atopic diseases. A functional mutation in the proximal promoter of the RANTES gene has been identified, which results in a new consensus binding site for the GATA transcription factor family. A higher frequency of this allele was observed in individuals of African descent compared with Caucasian subjects (p < 0.00001). The mutant allele was associated with atopic dermatitis in children of the German Multicenter Allergy Study (MAS-90; p < 0.037), but not with asthma. Transient transfections of the human mast cell line HMC-1 and the T cell line Jurkat with reporter vectors driven by either the mutant or wild-type RANTES promoter showed an up to 8-fold higher constitutive transcriptional activity of the mutant promoter. This is the first report to our knowledge of a functional mutation in a chemokine gene promoter. Our findings suggest that the mutation contributes to the development of atopic dermatitis. Its potential role in other inflammatory and infectious disorders, particularly among individuals of African ancestry, remains to be determined.

Linkage analysis of Dermatophagoides pteronyssinus-specific IgE responsiveness with polymorphic markers on chromosome 6p21 (HLA-D region) in Caucasian families by the transmission/disequilibrium test. Collaborative Study on the Genetics of Asthma (CSGA).

BACKGROUND: Recently, we have obtained evidence for linkage between Der p 1-specific IgE antibodies and markers on chromosome 6p21 (HLA-D region) in a genome-wide screening in Caucasian families recruited as a part of the Collaborative Study on the Genetics of Asthma (CSGA). OBJECTIVE: Specific IgE antibodies toward different Dermatophagoides pteronyssinus (Der p) polypeptides were detected by immunoblotting analysis, and the transmission/disequilibrium test (TDT) was performed between specific IgE responsiveness toward each different Der p polypeptide and markers on chromosome 6p21 to better clarify the genetic contribution of HLA-D genes. METHODS: We studied 299 individuals in 45 Caucasian families participating in the CSGA. Serum samples from 137 individuals that showed elevated specific IgE antibodies toward the Der p crude allergen (> -0.5 log IU/mL) by ACCESS immunoassay were subjected to immunoblotting analysis. TDT was conducted between the presence of specific IgE antibodies toward each of 12 different Der p polypeptides and 4 polymorphic markers on chromosome 6p21. RESULTS: The 196-bp allele of D6S1281 and the 104-bp allele of DQCAR showed significant excess transmission to specific IgE responders toward a particular Der p polypeptide (120 kd, 55 kd, 45 kd, or 37 kd). In contrast, the 200-bp allele of D6S1281 and the 204-bp allele of D6S291 showed significantly decreased transmission to specific IgE responders toward a particular Der p polypeptide (120 kd, 90 kd, 52 kd, or 45 kd). Deviation from the expected 50% transmission in heterozygous parents was statistically significant after correcting for multiple comparisons. CONCLUSION: This study supported our previous findings that genes on chromosome 6p21 (HLA-D region) may influence the expression of Der p-specific IgE responsiveness in this Caucasian population. Our results, however, reveal the complexity of genetic regulations of Der p-specific IgE responsiveness by HLA-D genes, suggesting the strong influence of non-HLA loci and perhaps environmental factors for the development of Der p-specific IgE responsiveness.

Inadequate outpatient medical therapy for patients with asthma admitted to two urban hospitals.

PURPOSE: To determine the patterns of chronic outpatient management in urban patients with moderate and severe asthma, and to assess medical practice adherence to the Guidelines for the Diagnosis and Management of Asthma from the National Asthma Education Program (NAEP). PATIENTS AND METHODS: This is a cross-sectional survey of adult patients with asthma admitted to the general medical services at the Johns Hopkins Medical Institutes (Johns Hopkins Hospital and Johns Hopkins Bayview Medical Center) Baltimore, Maryland. Subjects were 101 adults admitted with an asthma exacerbation from February 1992 through January 1993. Using a validated questionnaire, these subjects were surveyed within 48 hours of admission concerning their chronic outpatient medical management and the measures patients or their physicians took to alleviate symptoms during the asthma exacerbation leading to hospitalization. RESULTS: The average asthma admission rate in the past year for this group of patients was 2.5, indicative of moderate to severe disease. Less than half of these patients had been prescribed inhaled anti-inflammatory therapy. Of the patients who had previously been shown the metered dose inhaler technique by a health care professional, 11% could perform all components of this technique correctly. Only 28% of patients had been given an action plan by their physician in the event of an acute exacerbation. Sixty percent of patients who contacted their physician during the exacerbation that preceded admission had no changes made in their treatment regimen. In those whose exacerbation lasted at least 24 hours, the average beta-agonist metered dose inhaler use during the 24 hour prior to admission was 44.8 +/- 7.8 puffs (mean +/- standard error of the mean). Older age, (current smoking, and race (black) were the most significant correlates of inhaled beta-agonist use during this period. CONCLUSIONS: This is the first documentation of multiple problems in conforming with the standards of care delineated by the NAEP as they relate to the outpatient management of inner-city patients with moderate to severe asthma in the United States. In this population of patients with asthma, management was characterized by underutilization of anti-inflammatory therapy, inability to use inhalation devices properly, inadequate communication between patient and physician of an action plan to be utilized in the event of an acute exacerbation and inadequate physician intervention during the acute stages of the exacerbation. There was also overutilization of inhaled beta-agonists during exacerbations. It is imperative that these aspects of management, for which the NAEP has set standards of care, are addressed as part of the effort to reduce asthma morbidity in the urban United States.

Relationship among asthma, serum IgE levels and skin test sensitivity to inhaled allergens.

In two groups of subjects, we have shown that increased high total serum IgE levels (with and without age and sex correction) are significantly associated with the asthmatic phenotype, as diagnosed by a physician. This association was confirmed by discriminant analyses; as compared to variables such as specific sensitivity to allergens and smoking history, age- and sex-corrected log[total serum IgE] was the best predictor of the status of physician-diagnosed asthma in these subjects. Additionally, we observed significantly increased skin test sensitivity to house dust allergens in asthmatics. These findings support previous studies showing that high total serum IgE levels and IgE-mediated sensitivity to house dust allergens are associated with the presence of asthma.

Human immune responsiveness to Lolium perenne pollen allergen Lol p III (rye III) is associated with HLA-DR3 and DR5.

A well-characterized allergen of Lolium perenne (perennial rye grass) pollen, Lol p III, has been used as a model antigen to study the genetic control of the human immune response. Associations between HLA type and IgE or IgG antibody (Ab) responsiveness to Lol p III were studied in two groups of skin-test-positive Caucasoid adults (N = 135 and 67). We found by nonparametric and parametric analyses that immune responsiveness to Lol p III was significantly associated with HLA-DR3 and DR5. No association was found between any DQ type and immune responsiveness to Lol p III. Geometric mean IgE or IgG Ab levels to Lol p III were not different between B8+, DR3+ subjects and B8-, DR3+ subjects, showing that HLA-B8 had no influence on the association. Lol p III IgG Ab data obtained on subjects after grass antigen immunotherapy showed that 100% of DR3 subjects and 100% of DR5 subjects were Ab+. A comparison of all the available protein sequences of DRB gene products showed that the first hypervariable region of DR3 and DR5 (and DRw6), and no other region, contains the sequence Glu9-Tyr-Ser-Thr-Ser13. Our observations are consistent with the possibility that immune responsiveness to the allergen Lol p III is associated with this amino acid sequence in the first hypervariable region of the DR beta 1 polypeptide chain.

A genetic-epidemiologic study of human immune responsiveness to allergens in an industrial population. III. Environmental influences on skin sensitivity and total serum IgE in a stratified random sample.

We quantitated puncture skin-test responses to 6 standardized, high-quality-inhalant allergen extracts in 320 adults - a stratified random sample, equally distributed between the sexes and among all decades between 20 and 60 years. For each subject, the 'average' IgE-mediated skin sensitivity to the entire panel of allergens (Allergy Index) was calculated. We evaluated correlations between log[total serum IgE]levels and Allergy Index versus quantitative measures of several environmental variables, including infection in childhood, residential history and smoking history. Age, sex and month bled were also included in these analyses. Although many significant intercorrelations were found among these variables, subsequent analyses by stepwise multiple regression showed that log[total IgE], age and smoking history were the best predictors of the Allergy Index and that the Allergy Index and sex were the best predictors of log[total IgE]. The negative relationship between smoking and skin-test responsiveness may reflect a tendency for allergic people to avoid the irritative effects of smoking on respiration. Our analyses, which simultaneously evaluated the effects of age, sex, Allergy Index and smoking history on log[total IgE]levels, did not support other studies which concluded that smoking significantly increases total serum IgE levels.