Different Bla-g T cell antigens dominate responses in asthma versus rhinitis subjects.

BACKGROUND AND OBJECTIVE: The allergenicity of several German cockroach (Bla-g) antigens at the level of IgE responses is well established. However, less is known about the specificity of CD4+ TH responses, and whether differences exist in associated magnitude or cytokine profiles as a function of disease severity. METHODS: Proteomic and transcriptomic techniques were used to identify novel antigens recognized by allergen-specific T cells. To characterize different TH functionalities of allergen-specific T cells, ELISPOT assays with sets of overlapping peptides covering the sequences of known allergens and novel antigens were employed to measure release of IL-5, IFNγ, IL-10, IL-17 and IL-21. RESULTS: Using these techniques, we characterized TH responses in a cohort of adult Bla-g-sensitized subjects, either with (n = 55) or without (n = 17) asthma, and nonsensitized controls (n = 20). T cell responses were detected for ten known Bla-g allergens and an additional ten novel Bla-g antigens, representing in total a 5-fold increase in the number of antigens demonstrated to be targeted by allergen-specific T cells. Responses of sensitized individuals regardless of asthma status were predominantly TH 2, but higher in patients with diagnosed asthma. In asthmatic subjects, Bla-g 5, 9 and 11 were immunodominant, while, in contrast, nonasthmatic-sensitized subjects responded mostly to Bla-g 5 and 4 and the novel antigen NBGA5. CONCLUSIONS: Asthmatic and nonasthmatic cockroach-sensitized individuals exhibit similar TH 2-polarized responses. Compared with nonasthmatics, however, asthmatic individuals have responses of higher magnitude and different allergen specificity.

Circulating TSLP associates with decreased wheezing in non-atopic preschool children: data from the URECA birth cohort.

BACKGROUND: Mouse models of atopic march suggest that systemic, skin-derived thymic stromal lymphopoietin (TSLP) mediates progression from eczema to asthma. OBJECTIVE: We investigated whether circulating TSLP is associated with eczema, allergic sensitization, or recurrent wheezing in young children. METHODS: A prospective analysis of the relationship between plasma levels of TSLP to allergic sensitization and recurrent wheezing was conducted in the birth cohort from the Urban Environment and Childhood Asthma (URECA) study. Plasma TSLP levels were measured at 1, 2, and 3 years of age and analysed for correlation with clinical parameters in each of the three years. Only those children with consecutive samples for all three years were included in this analysis. RESULTS: We detected TSLP in 33% of 236 children for whom plasma samples were available for all three years. Overall, a consistently significant association was not found between TSLP and eczema or allergic sensitization. With regard to recurrent wheezing, children with detectable TSLP at one year of age were significantly less likely to experience recurrent wheezing by 3 years compared with those children without detectable TSLP, but this was only seen in children without aeroallergen sensitization at 3 years (P < 0.01). CONCLUSIONS AND CLINICAL RELEVANCE: Contrary to our expectations, circulating TSLP was not significantly associated with eczema, allergen sensitization, or recurrent wheezing during the first three years of life. Early presence of circulating TSLP was significantly associated with reduced incidence of recurrent wheeze in those children not sensitized to aeroallergen. These findings suggest a possible underlying distinction between pathogenesis of developing atopic vs. non-atopic recurrent wheeze.

Longitudinal relationship of early life immunomodulatory T cell phenotype and function to development of allergic sensitization in an urban cohort.

BACKGROUND: Immunomodulatory T cells are thought to influence development of allergy and asthma, but early life longitudinal data on their phenotype and function are lacking. OBJECTIVES: As part of the Urban Environment and Childhood Asthma (URECA) study, we investigated the development of immunomodulatory T cell phenotype and function, and characterized their relation to allergic disease progression from birth through to 2 years of age. METHODS: Immunomodulatory T cell phenotype and function in cord blood mononuclear cells (CBMC) and peripheral blood mononuclear cells (PBMC) at 1 and 2 years of age were characterized by analysing CD25(bright) and FoxP3(+) expression, proliferative responses and cytokine production. The relation of immunomodulatory T cell characteristics to allergic sensitization and disease at 1- and 2-years of age was investigated. RESULTS: The proportion of CD4(+)CD25(bright) and CD4(+)CD25(+)FoxP3(+)T cells (n = 114, 83, 82 at birth, 1- and 2-years respectively) increased significantly, whereas there were no significant changes in the suppressive function of CD25(+)T cells (n = 78, 71, 81 at birth, 1- and 2-years respectively). Birth immunomodulatory T cell characteristics were not related to subsequent allergic sensitization or disease. However, increases in the numbers of CD4(+)CD25(bright) cells and their ability to suppress lymphoproliferative responses at 1 year of age were associated with reduced allergic sensitization at 1 (P = 0.03) and 2 (P = 0.02) years of age. Production of the anti-inflammatory cytokine IL-10 by CD25(+)T cells appeared to mediate this protective suppressive function. In contrast, by 2 years of age, we observed the emergence of a positive association of CD4(+)CD25(+) FoxP3(+) T cell numbers with allergic sensitization (P = 0.05) and eczema (P = 0.02). CONCLUSIONS AND CLINICAL RELEVANCE: These findings suggest that the relationship between immunomodulatory T cell subsets, allergic sensitization and eczema is developmentally regulated. In the first year of life, CD4(+)CD25(+) IL-10 producing T cells are associated with a reduced incidence of allergic sensitization. Once allergic sensitization or eczema is established, CD4(+)CD25(+)FoxP3(+)T-reg cells expand to potentially counteract the allergic inflammatory response. Understanding the relationship between development of immunoregulatory T cells and early onset atopy could lead to new preventive strategies for allergic diseases.

Umbilical cord plasma 25-hydroxyvitamin D concentration and immune function at birth: the Urban Environment and Childhood Asthma study.

BACKGROUND: Recent studies have reported conflicting data on the association between maternal intake of vitamin D during pregnancy and asthma. OBJECTIVE: To assess the influence of prenatal vitamin D status on immune function at birth. METHODS: In an inner-city birth cohort of 568 newborns, 520 of whom had at least one atopic parent, we measured the umbilical cord (UC) plasma concentration of 25-hydroxyvitamin D (25(OH)D) and the cytokine responses of UC blood mononuclear cells (UCMCs) to stimuli including phytohaemagglutinin (PHA), lipopolysaccharide (LPS), and peptidoglycan. In a subset, the UCMC expression of regulatory T cell markers and the suppressive activity of CD4(+) CD25(+) UCMCs were measured. Results The 25th, 50th, and 75th percentiles of UC plasma 25(OH)D level were 15.0, 20.2, and 25.6 ng/mL, respectively. Most cytokine responses of UCMC were not correlated with UC 25(OH)D concentration; however, IFN-γ release after LPS stimulation was weakly positively correlated with UC 25(OH)D concentration (r=0.11, P=0.01). PHA responses were not significantly correlated with 25(OH)D concentration. The UC plasma 25(OH)D concentration was inversely related to the number of CD25(+) (r=-0.20, P=0.06), CD25(Bright) (r=-0.21, P=0.05), and CD25(+) FoxP3 (r=-0.29, P=0.06) cells as a proportion of CD4(+) T cells in UC blood (r=-0.26, P=0.04) but not to the suppressive activity of CD4(+) CD25(+) cells (r=0.17, P=0.22). CONCLUSION AND CLINICAL RELEVANCE: UC 25(OH)D concentration was not correlated with most UCMC cytokine responses to multiple stimuli. There was a suggestion of a weakly positive correlation with IFN-γ release after LPS stimulation. The proportions of CD25(+) , CD25(Bright) , and CD25(+) FoxP3 cells to total CD4(+) T cells were inversely correlated with UC 25(OH)D concentration. Our findings suggest that higher vitamin D levels at birth may be associated with a lower number of T-regulatory cells. Vitamin D status in utero may influence immune regulation in early life.

Allergen-specific IgE as a biomarker of exposure plus sensitization in inner-city adolescents with asthma.

BACKGROUND: Relationships among allergen-specific IgE levels, allergen exposure and asthma severity are poorly understood since sensitization has previously been evaluated as a dichotomous, rather than continuous characteristic. METHODS: Five hundred and forty-six inner-city adolescents enrolled in the Asthma Control Evaluation study underwent exhaled nitric oxide (FE(NO)) measurement, lung function testing, and completion of a questionnaire. Allergen-specific IgE levels and blood eosinophils were quantified. Dust samples were collected from the participants' bedrooms for quantification of allergen concentrations. Participants were followed for 12 months and clinical outcomes were tracked. RESULTS: Among sensitized participants, allergen-specific IgE levels were correlated with the corresponding settled dust allergen levels for cockroach, dust mite, and mouse (r = 0.38, 0.34, 0.19, respectively; P < 0.0001 for cockroach and dust mite and P = 0.03 for mouse), but not cat (r = -0.02, P = 0.71). Higher cockroach-, mite-, mouse-, and cat-specific IgE levels were associated with higher FE(NO) concentrations, poorer lung function, and higher blood eosinophils. Higher cat, dust mite, and mouse allergen-specific IgE levels were also associated with an increasing risk of exacerbations or hospitalization. CONCLUSIONS: Allergen-specific IgE levels were correlated with allergen exposure among sensitized participants, except for cat. Allergen-specific IgE levels were also associated with more severe asthma across a range of clinical and biologic markers. Adjusting for exposure did not provide additional predictive value, suggesting that higher allergen-specific IgE levels may be indicative of both higher exposure and a greater degree of sensitization, which in turn may result in greater asthma severity.

Risk factors for asthma morbidity and mortality in a large metropolitan city.

Morbidity and mortality due to asthma continues to increase despite advances in understanding the pathophysiology and treatment of the disease. We evaluated the potential risk factors for asthma morbidity and mortality in a large metropolitan city (St. Louis, MO) using small area geographic analysis. We found that the risk of hospitalization for children with asthma was 8.4 times greater (95% confidence interval [CI] 7.0-9.9) in lower socioeconomic zip code areas and 5.3 times greater (95% CI 4.7-5.9) in those zip codes with a higher percentage of African Americans. Similarly, the risk of death due to asthma was 6.4 times greater in the lower socioeconomic zip code areas (95% CI3.4-12.1). Lower socioeconomic status and African American race are strong risk factors for hospitalization and mortality from asthma. Public policy and healthcare resources need to be organized and directed more efficiently to this population.

Structural basis for recognition of the translocated intimin receptor (Tir) by intimin from enteropathogenic Escherichia coli.

Intimin is a bacterial adhesion molecule involved in intimate attachment of enteropathogenic and enterohaemorrhagic Escherichia coli to mammalian host cells. Intimin targets the translocated intimin receptor (Tir), which is exported by the bacteria and integrated into the host cell plasma membrane. In this study we localized the Tir-binding region of intimin to the C-terminal 190 amino acids (Int190). We have also determined the region's high-resolution solution structure, which comprises an immunoglobulin domain that is intimately coupled to a novel C-type lectin domain. This fragment, which is necessary and sufficient for Tir interaction, defines a new super domain in intimin that exhibits striking structural similarity to the integrin-binding domain of the Yersinia invasin and C-type lectin families. The extracellular portion of intimin comprises an articulated rod of immunoglobulin domains extending from the bacterium surface, conveying a highly accessible 'adhesive tip' to the target cell. The interpretation of NMR-titration and mutagenesis data has enabled us to identify, for the first time, the binding site for Tir, which is located at the extremity of the Int190 moiety.

Structural studies on the effects of the deletion in the red cell anion exchanger (band 3, AE1) associated with South East Asian ovalocytosis.

We have carried out a solution-state NMR study of synthetic peptides patterned on the first membrane span of normal human band 3, and the same region of the mutant band 3 present in Southeast Asian ovalocytosis (SAO) which has a nine amino acid deletion. In 1:1 (v/v) chloroform/methanol, the 42 residue normal peptide (R389-K430) consisted of three helical regions. The slow solvent exchange of backbone amide protons revealed the helix from P403 to A416 was more stable than the "cytoplasmic" N-terminal helix from P391 to A400. These helices were separated by a sharp bend at P403, which is probably located at the boundary between the cytoplasmic domain and the first transmembrane span. The SAO deletion (A400-A408) removed the bend at P403, to leave a stable helix from P391 to A416 containing the residuum of the normal first transmembrane helix and with a hydrophobic turn replaced by a polar turn in the SAO peptide. Insertion of fragments of normal band 3 and band 3 SAO into microsomal membranes was investigated using a cell free translation system. A fragment composed of the cytoplasmic domain and the putative first membrane domain of normal band 3 (B3(1)) inserted stably into the membrane. However, the corresponding fragment of band 3 SAO [SAO(1)] did not integrate stably into membranes. Our results suggest that in SAO band 3, the region of the first membrane span of normal band 3 does not integrate properly into the membrane because it lacks a sufficiently long hydrophobic segment, and the deletion also disrupts a conserved structural subdomain at the membrane surface.

Spectroscopic studies of the interaction of Ca2+-ATPase-peptides with dodecyl maltoside and its brominated analog.

The transmembrane sector of sarcoplasmic reticulum Ca2+-ATPase comprises ten putative transmembrane spans (M1-M10) in current topology models. We report here the structure and properties of three synthetic peptides with a single Trp representing the M6 and M7 regions implicated in Ca2+ binding: peptide M6 (amino acid residues 785-810), peptide M7-L (amino acid residues 808-847) corresponding to loop 6-7 and the majority of span M7, and peptide M7-S (amino acid residues 818-847) which contains a shorter version of loop 6-7 than M7-L. After uptake of the peptides in the hydrophobic environment of dodecyl maltoside micelles, the peptides gain a significant amount of secondary structure, as indicated by their CD spectra. However, the alpha-helical content of M6 is lower than would be expected for a classical transmembrane segment. For M7-L peptide, the L6-7 loop is subject to specific proteolytic cleavage by proteinase K, as in intact Ca2+-ATPase. The formation of the peptide-detergent complexes was followed from the resulting fluorescence intensity changes, either enhancement using n-dodecyl beta-D-maltoside or quenching using the recently introduced brominated analog of n-dodecyl beta-D-maltoside: 7,8-dibromododecyl beta-maltoside [de Foresta, B., Legros, N., Plusquellec, D., le Maire, M. & Champeil, P. (1996) Eur J. Biochem. 241, 343-354]. Our results indicate that M7-L and M7-S are completely taken up by the detergent micelles. In contrast, the M6 peptide, which is highly water soluble, is more loosely associated with the detergent, as is also demonstrated by size-exclusion chromatography. The location of Trp in micelles was evaluated from the quenching observed in mixed micelles of n-dodecyl beta-D-maltoside/7,8-dibromododecyl beta-maltoside, using tryptophan octyl ester and solubilized Ca2+-ATPase as reference compounds. We conclude that W832 in M7 appears to be located near the surface of the micelle, in agreement with its membrane interfacial localization predicted in most Ca2+-ATPase topology models. In contrast, our data suggest that W794 in M6 has a deeper insertion in the micelle although not to the extent predicted by current models of Ca2+-ATPase and the rather short alpha-helix span of M6 may lead to exposure of a significant part of the C-terminal of this peptide to the micelle surface. The results are discussed in relation to the proposed roles of these membrane segments in active transport of Ca2+ ions, in particular, the demonstration that M6 does not behave as a classical transmembrane helix may be correlated with the evidence, from site-directed mutagenesis, that this transmembrane segment should be essential in Ca2+ binding.

NMR solution structure of a cytoplasmic surface loop of the human red cell anion transporter, band 3.

The membrane domain of the human red cell anion transport protein, band 3, is too large to be studied by solution nuclear magnetic resonance spectroscopy (NMR), and its amphiphilic nature requires the use of detergents for solubilization. An alternative approach is to divide the protein into smaller (trans-membrane or surface loop) domains for NMR study. We report the structure of a 46-residue synthetic peptide that corresponds to the cytoplasmic surface loop connecting the putative 12th and 13th trans-membrane spans (residues 796-841) in the 14 span model of band 3. This peptide was shown by circular dichroism (CD) to be 38% helical in 30% trifluoroacetic acid. Two regions of helix (one close to the N-terminus of the peptide and one close to the C-terminus of the peptide) were identified by NMR. Long-range nuclear Overhauser effect (NOE) cross-peaks showed the two helices to be in near proximity. The helices were separated by a proline-rich loop that exhibited local order but was mobile with respect to the rest of the peptide. We discuss how the NMR structure of this loop fits the current models of band 3 structure and topology and the results of recent mutagenesis experiments. A cyclic version of this peptide was synthesized and studied by CD, but NMR studies were not possible due to the low solubility of this peptide.

Solution structure of the ATF-2 recognition site and its interaction with the ATF-2 peptide.

The effect of leucine zipper proteins binding to the DNA recognition site is controversial. Results from crystallography, gel and solution methods have led to opposite conclusions about the conformation of the DNA in the complex. The role of the DNA binding site in the recognition process and in the gene induction mediated by transcription factors needs to be investigated further. In this article the self-complementary 16 bp oligodeoxynucleotide (CATGTGACGTCACATG)2, which contains the cAMP response element recognised by numerous transcription factors of the leucine zipper family, has been examined free from proteins and in its interaction with the mammalian activating transcription factor 2. The recognition process has been investigated by circular dichroism analysis, which has revealed conformational changes in both DNA and protein upon binding. The solution structure of the 16mer, important in order to define the effects induced by binding of leucine zipper proteins and the intrisic bending properties of DNA, has been determined from NMR data using direct refinement against NOE intensities, analysis of scalar coupling constants and restrained molecular dynamics calculations. Final structures starting from the A and B forms of DNA agreed to a pairwise root mean square deviation (r.m.s.d.) of 1.04 +/- 0.3 A (0.7 +/- 0.2 A to the average) for all atoms. The terminal base pairs were less well determined, and the pairwise deviation of the 12 core bp was 0.83 +/- 0.27 A (0.55 +/- 0.19 A to the average). The final structures are within the B-family with an average helical twist of 36+/-2 degrees. No significant intrinsic DNA bend is shown in the activating transcription factor regulatory site. However, there are substantial deviations from the canonical B-DNA (r.m.s.d. = 3.6 A) in the core of the molecule, associated with relatively large base inclinations.

Conformational properties of the prion octa-repeat and hydrophobic sequences.

We have used circular dichroism to study synthetic peptides from two important regions of the prion protein: the N-terminal octa-repeat domain and a highly conserved hydrophobic section. Our results show that the octa-repeat sequence in free solution can adopt a non-random, extended conformation with properties similar to the poly-L-proline type II left-handed helix. We also show that the conformation can be changed by temperature, organic solvents (e.g. acetonitrile) and on binding to phospholipid vesicles. We compared CD data from two peptides corresponding to the hydrophobic region between residues 106 and 136 which contained either methionine or valine at position 129. This variation represents a common polymorphism in humans which has been shown to influence predisposition towards iatrogenic and sporadic CJD. There was no detectable difference between the CD spectra of these peptides irrespective of the solvent conditions we used.

Cutaneous presentation of juvenile chronic myelogenous leukemia: a diagnostic and therapeutic dilemma.

Annular, erythematous, circinate plaques were the first manifestation of juvenile chronic myelogenous leukemia (JCML) in an otherwise healthy 2.5-year-old boy who had had these lesions since 6 months of age. The lesions showed an atypical hematopoietic infiltrate on biopsy. Biopsy of a bone marrow specimen and peripheral blood smear were normal six months before leukemic transformation. At 3 years of age the boy developed splenomegaly, thrombocytopenia, and petechiae, and a bone marrow aspirate and cell marker studies were regarded as consistent with, if not diagnostic of, JCML. Four previous cases of cutaneous leukemic infiltrate associated with JCML have been published. Our patient had recurring urticarial-like plaques for two years before the initial bone marrow finding of JCML. Given the poor prognosis and progressively evolving course of JCML, it may be appropriate to consider therapy before bone marrow changes, based on the presence of the cutaneous eruption with the appropriate findings on skin biopsy and an elevated fetal hemoglobin.

Further characterization of the acid-soluble phosphoprotein (SDS/PAGE apparent molecular mass of 22 kDa) in rat fat-cells by peptide sequencing and immuno-analysis: effects of insulin and isoprenaline.

1. Earlier studies have shown that exposure of fat-cells to insulin results in the rapid increased phosphorylation of an acid-soluble protein which migrates as a doublet on SDS/PAGE with an apparent molecular mass of close to 22 kDa; agents such as isoprenaline, which increase cell concentrations of cyclic AMP, also increase phosphorylation, but to a lesser extent [Belsham, Brownsey, Hughes and Denton (1980) Diabetologia 18, 307-312; Diggle and Denton (1992) Biochem. J. 282, 729-736]. 2. The protein has been purified from rat epididymal adipose tissue, and the sequences of six tryptic peptides were determined. All six peptides are present in the deduced sequence of a protein of similar properties, designated PHAS-I by Hu, Pang, Kong, Velleca and Lawrence [(1994) Proc. Natl. Acad. Sci. U.S.A. 91, 3730-3734]. Hence the proteins are the same or extremely similar. 3. A rabbit anti-peptide antibody has been raised against one of the peptides (AGGDESQFEMD). The antibody was found to be highly specific for the phosphorylated and non-phosphorylated forms of the acid-soluble 22 kDa protein in Western blots and by immunoprecipitation. Studies with the antibody preparation have shown that both phosphorylated and non-phosphorylated forms of the protein appear to be exclusively located in the cytoplasm, and that exposure of cells to isoprenaline causes increased phosphorylation of the same acid-soluble 22 kDa protein as does insulin treatment. 4. Western blots carried out with the antibody preparation indicate that the protein is also present in other insulin-sensitive tissues, including liver, skeletal muscle, heart and brown adipose tissue. The protein was also detected in lung and spleen, but not brain and kidney. It is concluded that the protein may play an important role in some of the actions of insulin.

Lactoferricin, a new antimicrobial peptide.

Lactoferricin B (LF-B) is a peptide derived from acid-pepsin digestion of bovine lactoferrin, which has antimicrobial properties. In order to assess the antimicrobial spectrum of LF-B and its possible in vivo uses, the minimum inhibitory and microbicidal concentrations of pure lactoferricin B were determined for a range of bacterial species and under varying conditions of growth including growth phase and size of the inoculum, pH and ionic strength of the medium. Lactoferricin B was bactericidal against a wide range of bacteria and Candida albicans. Proteus spp., Pseudomonas cepacia and Serratia spp. were resistant. The bactericidal activity of LF-B was inhibited by increasing ionic strength and bacterial inoculum and at acid pH. The activity of lactoferricin B was completely inhibited by the addition of 5% whole cow's milk and was reduced in the presence of increasing concentrations of mucin. These results indicate the potential of LF-B to reduce the numbers of organisms in a simple medium, but raise doubts about its role in vivo because of its sensitivity to changes in physical variables. It may be that lactoferricin exerts a transient antimicrobial effect at mucosal surfaces.

Identification of novel phosphorylation sites in the beta-subunit of translation initiation factor eIF-2.

Initiation factor eIF-2 (a trimer of subunits alpha, beta and gamma) attaches the initiator Met-tRNA to the ribosome during the initiation of translation in eukaryotic cells. Both the alpha and beta subunits can be phosphorylated although the sites in the beta-subunit have not previously been fully identified. Here we identify the sites at which eIF-2 beta is phosphorylated in vitro by three well-characterised protein kinases, casein kinase-2 (which phosphorylates serine residues-2 and -67), protein kinase C (serine-13) and cAMP-dependent protein kinase (serine-218). This constitutes an essential prerequisite for studying the phosphorylation of eIF-2 beta in vivo. Indeed, we present evidence that at least one of these sites (serine-67) is phosphorylated in reticulocytes. The major kinase activity against eIF-2 beta in reticulocyte lysates appears in CK-2 and protein phosphatase-2A is the principal enzyme responsible for dephosphorylation of eIF-2 beta phosphorylated by this kinase.

The solution structures of the first and second transmembrane-spanning segments of band 3.

We have studied the structures of synthetic peptides which correspond to the proposed first and second membrane-spanning segments of the human red cell anion transporter (band 3). The peptides, which were acetylated at their N-termini and amidated at the C-termini, comprise the 20 amino acids of residues 405-424 and 21 amino acids of residues 436-456 of the human band 3 sequence. The solution structures of the peptides in trifluoroethanol were studied by two-dimensional NMR spectroscopy. Characteristic NOEs were observed indicating that the peptides adopted a predominantly alpha-helical structure in trifluoroethanol solution. Dynamical simulated annealing using the program XPLOR was employed for the structure calculations. The amide exchange rates in trifluoroethanol have also been measured and are consistent with an alpha-helical structure for the peptides.

Crisis in asthma care.

Reports of increases in both hospitalizations and deaths due to asthma have provided a sense of crisis in asthma care. This article examines issues concerning this sense of crisis. The authors review current trends in prevalence, morbidity, hospitalization, and mortality from asthma and examine possible reasons for changes that have occurred. A review of data suggesting that asthma can result in irreversible, chronic airway obstruction is presented. Finally, the authors discuss the role of the primary care physician in the management of asthma.