Predictors of Poor Asthma Control in European Adults

Asthmatics in the community suffer morbidity due to poor asthma control. The Global Initiative for Asthma (GINA) guidelines established minimum goals for the management of asthma. Our objective was to quantify the demographic and clinical factors associated with asthma control in adult asthmatics. A population sample of asthmatics 16 years and older was obtained by random digit dialing in seven European countries (France, Germany, Italy, The Netherlands, Spain, Sweden, and United Kingdom), and asthma control was quantified according to daytime and nighttime symptoms, severe episodes, and limits on daily activities due to asthma. Among the 2050 adult current asthmatics surveyed, 35% had good asthma control (0 or 1 GINA goals failed), 40% had moderate asthma control (2 or 3 GINA goals failed), and 25% had poor asthma control (4 or 5 GINA goals failed). Fewer subjects with poor than those with good asthma control had ever received a lung function test, and significantly fewer patients with poor asthma control had been taught by a doctor or nurse how to use their peak flow meter. When questioned about the underlying cause of asthma, only 7.8% of asthmatics mentioned airway inflammation, and only 17.6% stated that inhaled corticosteroids were the most effective medication for reducing airway inflammation. There was more use of quick relief bronchodilator medications in the past 4 weeks among patients with poor asthma control. Asthma management practices and the knowledge, attitudes, and behavior of adult asthmatics in the general population are associated with the degree of asthma control.     

Monogenic polyautoimmunity in primary immunodeficiency diseases

Primary immunodeficiency diseases (PIDs) consist of a large group of genetic disorders that affect distinct components of the immune system. PID patients are susceptible to infection and non-infectious complications, particularly autoimmunity. A specific group of monogenic PIDs are due to mutations in genes that are critical for the regulation of immunological tolerance and immune responses. This group of monogenic PIDs is at high risk of developing polyautoimmunity (i.e., the presence of more than one autoimmune disease in a single patient) because of their impaired immunity. In this review, we discuss the mechanisms of autoimmunity in PIDs and the characteristics of polyautoimmunity in the following PIDs: IPEX; monogenic IPEX-like syndrome; LRBA deficiency; CTLA4 deficiency; APECED; ALPS; and PKCδ deficiency.     

Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy

The discovery of the autoimmune regulator (AIRE) protein and the delineation of its critical contributions in the establishment of central immune tolerance has significantly expanded our understanding of the immunological mechanisms that protect from the development of autoimmune disease. The parallel identification and characterization of patient cohorts with the monogenic disorder autoimmune polyendocrinopathy‐candidiasis‐ectodermal dystrophy (APECED), which is typically caused by biallelic AIRE mutations, has underscored the critical contribution of AIRE in fungal immune surveillance at mucosal surfaces and in prevention of multiorgan autoimmunity in humans. In this review, we synthesize the current clinical, genetic, molecular and immunological knowledge derived from basic studies in Aire‐deficient animals and from APECED patient cohorts. We also outline major advances and research endeavors that show promise for informing improved diagnostic and therapeutic approaches for patients with APECED.     

Predictors of Poor Asthma Control in European Adults

Asthmatics in the community suffer morbidity due to poor asthma control. The Global Initiative for Asthma (GINA) guidelines established minimum goals for the management of asthma. Our objective was to quantify the demographic and clinical factors associated with asthma control in adult asthmatics. A population sample of asthmatics 16 years and older was obtained by random digit dialing in seven European countries (France, Germany, Italy, The Netherlands, Spain, Sweden, and United Kingdom), and asthma control was quantified according to daytime and nighttime symptoms, severe episodes, and limits on daily activities due to asthma. Among the 2050 adult current asthmatics surveyed, 35% had good asthma control (0 or 1 GINA goals failed), 40% had moderate asthma control (2 or 3 GINA goals failed), and 25% had poor asthma control (4 or 5 GINA goals failed). Fewer subjects with poor than those with good asthma control had ever received a lung function test, and significantly fewer patients with poor asthma control had been taught by a doctor or nurse how to use their peak flow meter. When questioned about the underlying cause of asthma, only 7.8% of asthmatics mentioned airway inflammation, and only 17.6% stated that inhaled corticosteroids were the most effective medication for reducing airway inflammation. There was more use of quick relief bronchodilator medications in the past 4 weeks among patients with poor asthma control. Asthma management practices and the knowledge, attitudes, and behavior of adult asthmatics in the general population are associated with the degree of asthma control.     

Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation

Intrathymic expression of tissue-specific antigens (TSAs) by medullary thymic epithelial cells (Mtecs) leads to deletion of autoreactive T cells. However, because Mtecs are known to be poor antigen-presenting cells (APCs) for tolerance to ubiquitous antigens, and very few Mtecs express a given TSA, it was unclear if central tolerance to TSA was induced directly by Mtec antigen presentation or indirectly by thymic bone marrow (BM)-derived cells via cross-presentation. We show that professional BM-derived APCs acquire TSAs from Mtecs and delete autoreactive CD8 and CD4 T cells. Although direct antigen presentation by Mtecs did not delete the CD4 T cell population tested in this study, Mtec presentation efficiently deleted both monoclonal and polyclonal populations of CD8 T cells. For developing CD8 T cells, deletion by BM-derived APC and by Mtec presentation occurred abruptly at the transitional, CD4high CD8low TCRintermediate stage, presumably as the cells transit from the cortex to the medulla. These studies reveal a cooperative relationship between Mtecs and BM-derived cells in thymic elimination of autoreactive T cells. Although Mtecs synthesize TSAs and delete a subset of autoreactive T cells, BM-derived cells extend the range of clonal deletion by cross-presenting antigen captured from Mtecs.     

Novel AIRE mutations and P450 cytochrome autoantibodies in Central and Eastern European patients with APECED

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare recessive disorder that results in several autoimmune diseases due to the mutations in the AIRE (autoimmune regulator) gene. APECED patients develop several autoimmune endocrine disorders and are characterized by the high titer autoantibodies to organ-specific antigens such as the steroidogenic P450 cytochromes. So far, 38 mutations have been identified in the AIRE gene. We report here the genetic and autoantibody analysis of 27 APECED patients of Eastern and Central European origins and one Egyptian patient. From 54 analyzed APECED chromosomes, eight mutations were detected, four of which (T16M, W78R, IVS1_IVS4, 30-53dup23bp) are novel. The most prevalent reason for APECED in these populations was the occurrence of R257X (36 chromosomes) that has been described earlier as a common and recurrent mutation in several other populations. The analysis of humoral immunity to steroidogenic P450 cytochromes by the immunoblotting of E. coli expressed antigens in the 18 APECED patients showed that 67%, 44%, and 61% of the Eastern and Central European APECED patients had autoantibodies to P450c17, P450c21, and P450scc, respectively.     

The autoimmune regulator gene (AIRE) is strongly associated with vitiligo

Background  Vitiligo is an autoimmune disorder that occurs with greatly increased frequency in the rare recessive autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy syndrome (APECED) caused by mutations of the autoimmune regulator ( AIRE ) gene on chromosome 21q22·3. We have previously detected an association between alopecia areata and single nucleotide polymorphisms (SNPs) in the AIRE gene.
Objectives  To report the findings of an extended study including haplotype analysis on six AIRE polymorphisms ( AIRE C–103T, C4144G, T5238C, G6528A, T7215C and T11787C) in vitiligo, another APECED-associated disease.
Methods  A case–control analysis was performed.
Results  Results showed a strong association between AIRE 7215C and vitiligo [ P  = 1·36 × 10⁻⁵, odds ratio (OR) 3·12, 95% confidence interval (CI) 1·87–5·46]. We found no significant association with the other polymorphisms individually. However, haplotype analysis revealed that the AIRE haplotype CCTGCC showed a highly significant association with vitiligo ( P  = 4·14 × 10⁻⁴, OR 3·00, 95% CI 1·70–5·28). To select the most informative minimal haplotypes, we tagged the polymorphisms using SNP tag software. Using AIRE C–103T, G6528A, T7215C and T11787C as tag SNPs, the haplotype AIRE CGCC was associated with vitiligo ( P  = 0·003, OR 2·49, 95% CI 1·45–4·26).
Conclusions  The link between vitiligo and AIRE raises the possibility that defective skin peripheral antigen selection in the thymus is involved in the changes that result in melanocyte destruction in this disorder.