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• W2000508860 abstract "To the Editor: Mycoplasma pneumoniae (MP) is an extracellular pathogen that attaches to and destroys ciliated epithelial cells of the respiratory tract.1Waites K.B. Talkington D.F. Mycoplasma pneumoniae and its role as a human pathogen.Clin Microbiol Rev. 2004; 17: 697-728Crossref PubMed Scopus (952) Google Scholar MP infection (MPI) has been shown to be strongly associated with asthma exacerbation, but data suggest it might also be involved in the development of asthma.2Johnston S.L. Martin R.J. Chlamydophila pneumoniae and Mycoplasma pneumoniae: a role in asthma pathogenesis?.Am J Respir Crit Care Med. 2005; 172: 1078-1089Crossref PubMed Scopus (173) Google Scholar Although epidemiologic data indicate a high MPI rate in different populations, some individuals seem to be more susceptible to infection than others. Similarly, asthma does not develop in all infected individuals. As several data indicate, genetic factors must play a role in the susceptibility to the infection and influence the lower respiratory tract response to MPI. RANTES, or CCL5, is one of the most extensively studied chemokines in allergic and infectious diseases.3Koya T. Takeda K. Kodama T. Miyahara N. Matsubara S. Balhorn A. et al.RANTES (CCL5) regulates airway responsiveness after repeated allergen challenge.Am J Respir Cell Mol Biol. 2006; 35: 147-154Crossref PubMed Scopus (27) Google Scholar A polymorphism in the RANTES promoter region (−403 G/A) has been found affecting the transcription of the RANTES gene and in some studies associating with asthma.4Al-Abdulhadi S.A. Helms P.J. Main M. Smith O. Christie G. Preferential transmission and association of the −403 G → A promoter RANTES polymorphism with atopic asthma.Genes Immun. 2005; 6: 24-30PubMed Google Scholar The chemokine receptor CCR5 expressed on monocytes, macrophages, and TH1 cells (but not on TH2 cells) is responsible for transducing the chemotactic response to RANTES. A common 32-bp deletion mutation in the CCR5 gene (CCR5Δ32), which causes truncation and loss of CCR5 receptors on lymphoid cell surfaces, has been described.5Dean M. Carrington M. Winkler C. Huttley G.A. Smith M.W. Allikmets R. et al.Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene.Science. 1996; 273: 1856-1862Crossref PubMed Scopus (2196) Google Scholar Some data indicate an association of the CCR5Δ32 allele with reduced risk of asthma in some populations, whereas in other studies there was no such association for atopy or asthma/wheeze.6Szalai C. Bojszko A. Beko G. Falus A. Prevalence of CCR5delta32 in allergic diseases.Lancet. 2000; 355: 66Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Given the possible roles and interaction of MPI, RANTES, and CCR5 in asthma, it might be hypothesized that polymorphisms, which influence the level of these molecules, might have an effect on the infection, the susceptibility to asthma, or both in patients infected with MP. To test this hypothesis, we investigated the role of MPI in 254 children with physician-diagnosed asthma, comparing them with 260 healthy control subjects, and studied the modifying effects of these polymorphisms on the susceptibility to the disease. The selection criteria and methods for the asthmatic and control patients and some of their clinical and biological characteristics are presented in the Methods section and Table E1 in this article's Online Repository (available at www.jacionline.org). CCR5Δ32 and RANTES −403G/A polymorphisms were determined as described in this article's Online Repository (available at www.jacionline.org). MP-specific antibodies were determined from serum by using SeroMP-IgA and IgG EIA kits (Savyon Diagnostic Ltd, Ashdod, Israel), according to the manufacturer's instructions. Because in this study children with chronic or recurrent MPI were going to be investigated, only children whose IgG positivity was combined with IgA positivity were regarded as positive for MPI. Data were analyzed by using the SPSS 11.0 program (SPSS, Inc, Chicago, Ill). The χ2 test was used to test for differences in allele distribution between the groups. The results were adjusted for age, sex, and in some cases also for atopic status by means of logistic regression analysis to minimize the effect of potentially confounding factors (see this article's Online Repository at www.jacionline.org for more details). In the asthmatic group significantly more children had positive results for MP-specific antibodies than in the control group (31.1% vs 18.1%, P = .0009). As could be expected among the asthmatic patients, significantly more children were atopic than among the control subjects (79.5% vs 23.8%, P < .0001). The 2 groups did not differ in the distributions of genotypes and alleles for the RANTES −403G/A and CCR5Δ32 polymorphisms (see Table E2 in this article's Online Repository at www.jacionline.org). Allelic frequencies for the 2 polymorphisms were compared between MP-seropositive and MP-seronegative individuals to test whether the 2 polymorphisms influence the susceptibility to MPI. The allelic frequency of the CCR5Δ32 allele was significantly higher among MP-seropositive than among MP-seronegative children (18.0% vs 8.6%, respectively; P = .006). A similar ratio could be observed when children homozygous for the CCR5Δ32 allele were considered (homozygote frequencies in seropositive vs seronegative children were 2.4% vs 1.3%, respectively). No significant difference between MP-seropositive and MP-seronegative individuals in the frequency of the RANTES −403A allele was revealed. With multiple logistic regression analyses, we tested whether MPI, the 2 polymorphisms, or the interaction of each polymorphism with MPI were associated with asthma, atopy, or asthma severity (see Table E3 in this article's Online Repository at www.jacionline.org). MPI was significantly associated with asthma (odds ratio [OR], 2.2; 95% CI, 1.5-3.3; P < .0001) and atopy (OR, 2.1; 95% CI, 1.4-3.2; P = .0001), if all subjects were considered, and remained significant when the results were adjusted for age and sex (OR, 2.0; 95% CI, 1.3-3.1; P = .001 and OR, 1.7; 95% CI, 1.1-2.6; P = .01 for asthma and atopy, respectively). However, when asthmatic and nonasthmatic patients were separated, the significant association for atopy disappeared. Because atopic status might influence the effect of MPI on the susceptibility to asthma, the analyses were carried out by adjusting the results also for atopic status. The association between MPI and asthma remained significant (OR, 1.8; 95% CI, 1.2-3.0; P = .005). A significant association was found when MPI∗CCR5Δ32 interaction and asthma were considered (OR, 0.3; 95% CI, 0.2-0.7; P = .002). This result indicates that significantly less MP-seropositive asthmatic patients than MP-seropositive control subjects carry the CCR5Δ32 allele (3.9% vs 12.7%, respectively), which suggests that carrying a defective CCR5 receptor might reduce the susceptibility to asthma in MP-infected children when comparing them with children with similar infection status but carrying only wild-type CCR5. The association remained significant when age, sex, and atopic status were involved in the analysis (OR, 0.3; 95% CI, 0.1-0.6; P = .002). No significant association was found when MPI∗RANTES −403A interaction and asthma, atopy, or asthma severity were considered. The present study shows that in this cohort of children, chronic MPI is associated with physician-diagnosed asthma but also implies that genetic polymorphisms can influence the susceptibility to and effect of the infection. According to our results, children carrying the defective form of the chemokine receptor CCR5 might have a higher susceptibility to chronic MPI when comparing them with children without this mutant allele, whereas infected children with the CCR5Δ32 allele might have reduced risk of asthma development when comparing them with children with the same infection status but without the mutant allele. A causal association between MP and asthma is biologically plausible based on the observations that asthma is a chronic inflammatory disease of the airways and that MPI is known to produce chronic inflammatory damage in the airways. Our results showing that chronic MPI is associated with asthma confirms previous findings,7Martin R.J. Infections and asthma.Clin Chest Med. 2006; 27: 87-98Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar although whether MPI is facilitated by the presence of underlying airway inflammation or whether the organism plays a more direct role in the pathogenesis of asthma is still unresolved. Furthermore, according to these results, it cannot be excluded that MPI might simply lead to a wrong diagnosis of asthma or exacerbate preexisting asthma. The new and most interesting finding of this study is the possible dual role of the chemokine receptor CCR5 in MPI and asthma. It is well known that host defense against intracellular pathogens, such as MP, depends on effective cell-mediated immunity. However, human and animal models also suggest that cytokine and chemokine production might either minimize disease through the enhancement of host defense mechanisms or exacerbate disease through immunologic lesion development. After MPI of the lower respiratory tract, macrophages become activated, begin phagocytosis, and undergo chemotactic migration to the site of infection. T lymphocytes also infiltrate the lung. Both macrophages and T cells express CCR5, suggesting biologically plausible involvement of CCR5 in regulating leukocyte migration to the lungs of infected patients and in clearance of the bacterium. According to these findings, it can be hypothesized that patients with defective CCR5 might have reduced capacity to eliminate or mitigate MPI, rendering infected individuals more susceptible to the development of chronic MPI. Regarding seropositivity, however, similar trends could be observed in both CCR5Δ32 allelic and homozygote frequencies, indicating that carrying no wild-type CCR5 was not associated with extra risk for MPI relative to carriers. It must be noted, however, that the number of homozygotes in this study (8) was too few for a valuable statistical analysis in this respect. The ligands of CCR5 play an important role in the pathogenesis of asthma. Animal studies have identified macrophage inflammatory protein 1α and RANTES as important recruitment factors during allergic airway responses. In vitro, MPI induced RANTES production in small airway epithelial cells, suggesting a possible connection between MPI and asthma.8Dakhama A. Kraft M. Martin R.J. Gelfand E.W. Induction of regulated upon activation, normal T cells expressed and secreted (RANTES) and transforming growth factor-beta 1 in airway epithelial cells by Mycoplasma pneumoniae.Am J Respir Cell Mol Biol. 2003; 29: 344-351Crossref PubMed Scopus (25) Google Scholar Otherwise, the increased IFN-γ production found in CCR5 knockout mice indicates a TH1-dominant cytokine response, which might be protective against the development of allergic inflammation.9Zhou Y. Kurihara T. Ryseck R.-P. Yang Y. Ryan C. Loy J. et al.Impaired macrophage function and enhanced T cell –dependent immune response in mice lacking CCR5, the mouse homologue of the major HIV-1 coreceptor.J Immunol. 1998; 160: 4018-4025PubMed Google Scholar This makes it reasonable to hypothesize that a deletion mutation in the CCR5 receptor, which abolishes the receptor from the cell surface, might be beneficial in asthma or other atopic disorders. Our results might have important implications regarding the potential safety of CCR5-blocking agents now under development for the treatment of HIV/AIDS and being considered for patients with inflammatory disorders, such as rheumatoid arthritis. Prospective studies are needed to evaluate the net effect of such a treatment, including clinical benefits of treating or preventing HIV infection or inflammatory disorders and risks of development of chronic MPI or other infections. In conclusion, this article shows an association between chronic MPI and physician-diagnosed asthma and between the defective chemokine receptor CCR5 variant CCR5Δ32 and chronic MPI. Furthermore, according to our results in this cohort of patients, infected children carrying the CCR5Δ32 allele might have reduced risk of asthma development when compared with wild-type CCR5 carriers. Additionally, this study highlights the possible roles of gene polymorphisms in the immune system in response to bacterial infection. 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• W2000508860 title "CCR5Δ32 mutation, Mycoplasma pneumoniae infection, and asthma" @default.
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