Involvement of eosinophils in the onset of asthma
2007; Elsevier BV; Volume: 121; Issue: 1 Linguagem: Inglês
10.1016/j.jaci.2007.10.002
ISSN1097-6825
AutoresKenji Matsumoto, Mayumi Tamari, Hirohisa Saito,
Tópico(s)Respiratory and Cough-Related Research
ResumoWhen we read medical journals, every article provides new information, usually with surprise and sometimes with disappointment. In the November 2007 issue of the Journal, Lee et al1Lee J.H. Chang H.S. Kim J.H. Park S.M. Lee Y.M. Uh S.T. et al.Genetic effect of CCR3 and IL-5 receptor alpha gene polymorphisms on eosinophilia in asthmatics.J Allergy Clin Immunol. 2007; 120: 1110-1117Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar report a gene-gene interaction of single nucleotide polymorphisms and the haplotypes of CCR3 and the IL-5 receptor α-chain gene (IL5RA), which is associated with the eosinophil count, and they have also identified the effects of these genetic variations on the levels of those proteins in peripheral eosinophils. Although they did not find a positive association between the genetic variations of these molecules and asthma, this article provides allergy researchers with important information regarding the role of eosinophils in asthma.Eosinophils are certainly the most enigmatic cells involved in allergic inflammation. After the first observation in the early 1920s, hundreds of studies showed a positive association between activation of eosinophils and the severity of allergic symptoms.2Gleich G.J. The eosinophil and bronchial asthma: current understanding.J Allergy Clin Immunol. 1990; 85: 422-436Abstract Full Text PDF PubMed Scopus (604) Google Scholar, 3Rothenberg M.E. Hogan S.P. The eosinophil.Annu Rev Immunol. 2006; 24: 147-174Crossref PubMed Scopus (1204) Google Scholar A recent systematic review has indicated that the number of sputum eosinophils is an important clinical marker correlating with disease activity.4Petsky H.L. Kynaston J.A. Turner C. Li A.M. Cates C.J. Lasserson T.J. et al.Tailored interventions based on sputum eosinophils versus clinical symptoms for asthma in children and adults.Cochrane Database Syst Rev. 2007; 18 (CD005603)Google Scholar In addition, elevated serum eosinophil cationic protein levels5Pifferi M. Ragazzo V. Caramella D. Baldini G. Eosinophil cationic protein in infants with respiratory syncytial virus bronchiolitis: predictive value for subsequent development of persistent wheezing.Pediatr Pulmonol. 2001; 31: 419-424Crossref PubMed Scopus (52) Google Scholar and cord blood eosinophilia6Matsumoto K. Shimanouchi Y. Kawakubo K. Oishi N. Wakiguchi H. Futamura K. et al.Infantile eczema at one month of age is associated with cord blood eosinophilia and subsequent development of atopic dermatitis and wheezing illness until two years of age.Int Arch Allergy Immunol. 2005; 137: 69-76Crossref PubMed Scopus (20) Google Scholar were reported to precede wheeze and eczema, respectively. The remaining question is whether the eosinophilia is a cause or just a marker of allergic inflammation in vivo in human beings.One of the definitive methods for proving the involvement of a specific molecule in the onset of a disease is to demonstrate a positive association between genetic polymorphism of the molecule and the prevalence of the disease. A single nucleotide polymorphism, a tiny variation of genetic sequence, modulates the production or the functional properties of the gene product, and shows association with the prevalence of the disease only if the molecule is a cause, not a marker.IL-5 is a critical cytokine that regulates the differentiation, priming, activation, and survival of eosinophils.3Rothenberg M.E. Hogan S.P. The eosinophil.Annu Rev Immunol. 2006; 24: 147-174Crossref PubMed Scopus (1204) Google Scholar To date, only 1 study7Freidin M.B. Puzyrev V.P. Ogorodova L.M. Kobiakova O.S. Kulmanakova I.M. [Polymorphism of interleukins and interleukin receptor genes: population distribution and association with atopic bronchial asthma].Genetika. 2002; 38: 1710-1718PubMed Google Scholar has demonstrated a positive association between a polymorphism of IL5 or IL5RA and asthma, whereas several other studies, including the article by Lee et al,1Lee J.H. Chang H.S. Kim J.H. Park S.M. Lee Y.M. Uh S.T. et al.Genetic effect of CCR3 and IL-5 receptor alpha gene polymorphisms on eosinophilia in asthmatics.J Allergy Clin Immunol. 2007; 120: 1110-1117Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar negated this association.8Hong S.J. Lee S.Y. Kim H.B. Kim J.H. Kim B.S. Choi S.O. et al.IL-5 and thromboxane A2 receptor gene polymorphisms are associated with decreased pulmonary function in Korean children with atopic asthma.J Allergy Clin Immunol. 2005; 115: 758-763Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 9Pereira E. Goldblatt J. Rye P. Sanderson C. Le Souef P. Mutation analysis of interleukin-5 in an asthmatic cohort.Hum Mutat. 1998; 11: 51-54Crossref PubMed Scopus (11) Google Scholar It is notable that in some of those studies, including the article by Lee et al,1Lee J.H. Chang H.S. Kim J.H. Park S.M. Lee Y.M. Uh S.T. et al.Genetic effect of CCR3 and IL-5 receptor alpha gene polymorphisms on eosinophilia in asthmatics.J Allergy Clin Immunol. 2007; 120: 1110-1117Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar a positive association was found between polymorphisms in IL5 or IL5RA and the eosinophil count. In sharp contrast, positive associations have frequently been reported between asthma and polymorphisms of the genes for IL-4, IL-13, and their receptors, even though all 3 of these TH2 cytokines are mapped on the same gene locus, 5q31-33.10Ober C. Hoffjan S. Asthma genetics 2006: the long and winding road to gene discovery.Genes Immun. 2006; 7: 95-100Crossref PubMed Scopus (519) Google ScholarOn the other hand, CCR3, a receptor for RANTES, eotaxin-1, eotaxin-2, eotaxin-3, and monocyte chemoattractant proteins 3 and 4, plays a critical role in the selective recruitment and activation of eosinophils in allergic inflammatory sites.11Wardlaw A.J. Molecular basis for selective eosinophil trafficking in asthma: a multistep paradigm.J Allergy Clin Immunol. 1999; 104: 917-926Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar To date, a couple of reports have demonstrated that polymorphisms of CCR3 or its ligands are associated with asthma,12Shin H.D. Kim L.H. Park B.L. Jung J.H. Kim J.Y. Chung I.Y. et al.Association of eotaxin gene family with asthma and serum total IgE.Hum Mol Genet. 2003; 12: 1279-1285Crossref PubMed Scopus (43) Google Scholar, 13Fukunaga K. Asano K. Mao X.Q. Gao P.S. Roberts M.H. Oguma T. et al.Genetic polymorphisms of CC chemokine receptor 3 in Japanese and British asthmatics.Eur Respir J. 2001; 17: 59-63Crossref PubMed Scopus (26) Google Scholar but such association cannot specify the involvement of eosinophils, because CCR3 is also expressed in basophils, T cells, and dendritic cells.Very recently, IL-5 and eotaxin-2 (CCL24) double-transgenic mouse were shown to develop marked respiratory inflammation with the characteristics of severe asthma.14Ochkur S.I. Jacobsen E.A. Protheroe C.A. Biechele T.L. Pero R.S. McGarry M.P. et al.Coexpression of IL-5 and eotaxin-2 in mice creates an eosinophil-dependent model of respiratory inflammation with characteristics of severe asthma.J Immunol. 2007; 178: 7879-7889PubMed Google Scholar Thus, it should be worth testing whether interaction of these 2 molecules is involved in the onset of asthma. In this context, again, the study by Lee et al1Lee J.H. Chang H.S. Kim J.H. Park S.M. Lee Y.M. Uh S.T. et al.Genetic effect of CCR3 and IL-5 receptor alpha gene polymorphisms on eosinophilia in asthmatics.J Allergy Clin Immunol. 2007; 120: 1110-1117Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar failed to detect any positive associations between asthma and the polymorphisms of IL5RA and CCR3, but interaction of those polymorphisms was clearly associated with the eosinophil count.1Lee J.H. Chang H.S. Kim J.H. Park S.M. Lee Y.M. Uh S.T. et al.Genetic effect of CCR3 and IL-5 receptor alpha gene polymorphisms on eosinophilia in asthmatics.J Allergy Clin Immunol. 2007; 120: 1110-1117Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar Of course, it is important to know whether the association can be replicated in an independent sample. Genetic analyses of the associated variants in different ethnic groups are necessary and desired. Further functional analyses of the genetic variants in eosinophils and other cell types would also be helpful. At least for now, however, it seems unlikely that IL-5 plays critical roles in the onset of asthma.Researchers who are “eosinophiles” will probably read the article by Lee et al1Lee J.H. Chang H.S. Kim J.H. Park S.M. Lee Y.M. Uh S.T. et al.Genetic effect of CCR3 and IL-5 receptor alpha gene polymorphisms on eosinophilia in asthmatics.J Allergy Clin Immunol. 2007; 120: 1110-1117Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar with disappointment, just like 7 years ago when Leckie et al15Leckie M.J. ten Brinke A. Khan J. Diamant Z. O'Connor B.J. Walls C.M. et al.Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response.Lancet. 2000; 356: 2144-2148Abstract Full Text Full Text PDF PubMed Scopus (1640) Google Scholar published an article showing no appreciable clinical efficacy for anti–IL-5 antibody therapy. Then, however, several subsequent studies revealed the presence of tissue-dwelling eosinophils in the lung.16Flood-Page P.T. Menzies-Gow A.N. Kay A.B. Robinson D.S. Eosinophil's role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway.Am J Respir Crit Care Med. 2003; 167: 199-204Crossref PubMed Scopus (736) Google Scholar Thus, although IL-5 was apparently not a good target for the treatment of asthma, those subsequent findings gave new life to the hope that eosinophils could serve as a therapeutic target for asthma.Will the same scenario unfold this time, too? Probably not, because this genetic linkage study by Lee et al1Lee J.H. Chang H.S. Kim J.H. Park S.M. Lee Y.M. Uh S.T. et al.Genetic effect of CCR3 and IL-5 receptor alpha gene polymorphisms on eosinophilia in asthmatics.J Allergy Clin Immunol. 2007; 120: 1110-1117Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar clearly demonstrates a positive association between the interaction of IL5RA and CCR3 and the eosinophil count, and no association between the interaction and asthma. In other words, variations in IL5RA and CCR3 showed no influence on the onset of asthma (and we presume that the eosinophil count does not, either).As described by Bochner,17Bochner B.S. Verdict in the case of therapies versus eosinophils: the jury is still out.J Allergy Clin Immunol. 2004; 113: 3-9Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar the jury is still out regarding the verdict in the case of therapies versus eosinophils, whereas, for the case of eosinophils versus the onset of asthma, the article by Lee et al1Lee J.H. Chang H.S. Kim J.H. Park S.M. Lee Y.M. Uh S.T. et al.Genetic effect of CCR3 and IL-5 receptor alpha gene polymorphisms on eosinophilia in asthmatics.J Allergy Clin Immunol. 2007; 120: 1110-1117Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar failed to demonstrate any involvement of IL-5 in the onset of asthma. However, researchers who are “eosinophiles” should by no means be discouraged, because the possibilities of involvement of eosinophils in the onset of asthma and their involvement in the course of asthma, especially remodeling (ie, potential target for the therapeutic intervention), are separate issues. Indeed, since 2000, various investigators have piled up evidence that eosinophils play important roles, predominantly in the formation of airway remodeling.18Pascual R.M. Peters S.P. Airway remodeling contributes to the progressive loss of lung function in asthma: an overview.J Allergy Clin Immunol. 2005; 116: 477-486Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar New therapeutic strategies that efficiently deplete tissue-dwelling eosinophils will further clarify the importance of eosinophils in the pathogenesis of asthma.Further studies are surely necessary to prove the role of eosinophils or these eosinophil-related molecules by increasing the population or by selecting a certain asthma phenotype having, for example, symptoms related to airway remodeling. However, this study by Lee et al1Lee J.H. Chang H.S. Kim J.H. Park S.M. Lee Y.M. Uh S.T. et al.Genetic effect of CCR3 and IL-5 receptor alpha gene polymorphisms on eosinophilia in asthmatics.J Allergy Clin Immunol. 2007; 120: 1110-1117Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar may provide an efficient method for genetic studies regarding this complex disease. Genetic variations of CCR3 and IL5RA were associated with objective phenotype markers—the protein levels and the number of circulating eosinophils. It is necessary to collect and arrange the numerous pieces of the jigsaw puzzles called asthma, and this study has contributed to that effort. When we read medical journals, every article provides new information, usually with surprise and sometimes with disappointment. In the November 2007 issue of the Journal, Lee et al1Lee J.H. Chang H.S. Kim J.H. Park S.M. Lee Y.M. Uh S.T. et al.Genetic effect of CCR3 and IL-5 receptor alpha gene polymorphisms on eosinophilia in asthmatics.J Allergy Clin Immunol. 2007; 120: 1110-1117Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar report a gene-gene interaction of single nucleotide polymorphisms and the haplotypes of CCR3 and the IL-5 receptor α-chain gene (IL5RA), which is associated with the eosinophil count, and they have also identified the effects of these genetic variations on the levels of those proteins in peripheral eosinophils. Although they did not find a positive association between the genetic variations of these molecules and asthma, this article provides allergy researchers with important information regarding the role of eosinophils in asthma. Eosinophils are certainly the most enigmatic cells involved in allergic inflammation. After the first observation in the early 1920s, hundreds of studies showed a positive association between activation of eosinophils and the severity of allergic symptoms.2Gleich G.J. The eosinophil and bronchial asthma: current understanding.J Allergy Clin Immunol. 1990; 85: 422-436Abstract Full Text PDF PubMed Scopus (604) Google Scholar, 3Rothenberg M.E. Hogan S.P. The eosinophil.Annu Rev Immunol. 2006; 24: 147-174Crossref PubMed Scopus (1204) Google Scholar A recent systematic review has indicated that the number of sputum eosinophils is an important clinical marker correlating with disease activity.4Petsky H.L. Kynaston J.A. Turner C. Li A.M. Cates C.J. Lasserson T.J. et al.Tailored interventions based on sputum eosinophils versus clinical symptoms for asthma in children and adults.Cochrane Database Syst Rev. 2007; 18 (CD005603)Google Scholar In addition, elevated serum eosinophil cationic protein levels5Pifferi M. Ragazzo V. Caramella D. Baldini G. Eosinophil cationic protein in infants with respiratory syncytial virus bronchiolitis: predictive value for subsequent development of persistent wheezing.Pediatr Pulmonol. 2001; 31: 419-424Crossref PubMed Scopus (52) Google Scholar and cord blood eosinophilia6Matsumoto K. Shimanouchi Y. Kawakubo K. Oishi N. Wakiguchi H. Futamura K. et al.Infantile eczema at one month of age is associated with cord blood eosinophilia and subsequent development of atopic dermatitis and wheezing illness until two years of age.Int Arch Allergy Immunol. 2005; 137: 69-76Crossref PubMed Scopus (20) Google Scholar were reported to precede wheeze and eczema, respectively. The remaining question is whether the eosinophilia is a cause or just a marker of allergic inflammation in vivo in human beings. One of the definitive methods for proving the involvement of a specific molecule in the onset of a disease is to demonstrate a positive association between genetic polymorphism of the molecule and the prevalence of the disease. A single nucleotide polymorphism, a tiny variation of genetic sequence, modulates the production or the functional properties of the gene product, and shows association with the prevalence of the disease only if the molecule is a cause, not a marker. IL-5 is a critical cytokine that regulates the differentiation, priming, activation, and survival of eosinophils.3Rothenberg M.E. Hogan S.P. The eosinophil.Annu Rev Immunol. 2006; 24: 147-174Crossref PubMed Scopus (1204) Google Scholar To date, only 1 study7Freidin M.B. Puzyrev V.P. Ogorodova L.M. Kobiakova O.S. Kulmanakova I.M. [Polymorphism of interleukins and interleukin receptor genes: population distribution and association with atopic bronchial asthma].Genetika. 2002; 38: 1710-1718PubMed Google Scholar has demonstrated a positive association between a polymorphism of IL5 or IL5RA and asthma, whereas several other studies, including the article by Lee et al,1Lee J.H. Chang H.S. Kim J.H. Park S.M. Lee Y.M. Uh S.T. et al.Genetic effect of CCR3 and IL-5 receptor alpha gene polymorphisms on eosinophilia in asthmatics.J Allergy Clin Immunol. 2007; 120: 1110-1117Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar negated this association.8Hong S.J. Lee S.Y. Kim H.B. Kim J.H. Kim B.S. Choi S.O. et al.IL-5 and thromboxane A2 receptor gene polymorphisms are associated with decreased pulmonary function in Korean children with atopic asthma.J Allergy Clin Immunol. 2005; 115: 758-763Abstract Full Text Full Text PDF PubMed Scopus (28) Google Scholar, 9Pereira E. Goldblatt J. Rye P. Sanderson C. Le Souef P. Mutation analysis of interleukin-5 in an asthmatic cohort.Hum Mutat. 1998; 11: 51-54Crossref PubMed Scopus (11) Google Scholar It is notable that in some of those studies, including the article by Lee et al,1Lee J.H. Chang H.S. Kim J.H. Park S.M. Lee Y.M. Uh S.T. et al.Genetic effect of CCR3 and IL-5 receptor alpha gene polymorphisms on eosinophilia in asthmatics.J Allergy Clin Immunol. 2007; 120: 1110-1117Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar a positive association was found between polymorphisms in IL5 or IL5RA and the eosinophil count. In sharp contrast, positive associations have frequently been reported between asthma and polymorphisms of the genes for IL-4, IL-13, and their receptors, even though all 3 of these TH2 cytokines are mapped on the same gene locus, 5q31-33.10Ober C. Hoffjan S. Asthma genetics 2006: the long and winding road to gene discovery.Genes Immun. 2006; 7: 95-100Crossref PubMed Scopus (519) Google Scholar On the other hand, CCR3, a receptor for RANTES, eotaxin-1, eotaxin-2, eotaxin-3, and monocyte chemoattractant proteins 3 and 4, plays a critical role in the selective recruitment and activation of eosinophils in allergic inflammatory sites.11Wardlaw A.J. Molecular basis for selective eosinophil trafficking in asthma: a multistep paradigm.J Allergy Clin Immunol. 1999; 104: 917-926Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar To date, a couple of reports have demonstrated that polymorphisms of CCR3 or its ligands are associated with asthma,12Shin H.D. Kim L.H. Park B.L. Jung J.H. Kim J.Y. Chung I.Y. et al.Association of eotaxin gene family with asthma and serum total IgE.Hum Mol Genet. 2003; 12: 1279-1285Crossref PubMed Scopus (43) Google Scholar, 13Fukunaga K. Asano K. Mao X.Q. Gao P.S. Roberts M.H. Oguma T. et al.Genetic polymorphisms of CC chemokine receptor 3 in Japanese and British asthmatics.Eur Respir J. 2001; 17: 59-63Crossref PubMed Scopus (26) Google Scholar but such association cannot specify the involvement of eosinophils, because CCR3 is also expressed in basophils, T cells, and dendritic cells. Very recently, IL-5 and eotaxin-2 (CCL24) double-transgenic mouse were shown to develop marked respiratory inflammation with the characteristics of severe asthma.14Ochkur S.I. Jacobsen E.A. Protheroe C.A. Biechele T.L. Pero R.S. McGarry M.P. et al.Coexpression of IL-5 and eotaxin-2 in mice creates an eosinophil-dependent model of respiratory inflammation with characteristics of severe asthma.J Immunol. 2007; 178: 7879-7889PubMed Google Scholar Thus, it should be worth testing whether interaction of these 2 molecules is involved in the onset of asthma. In this context, again, the study by Lee et al1Lee J.H. Chang H.S. Kim J.H. Park S.M. Lee Y.M. Uh S.T. et al.Genetic effect of CCR3 and IL-5 receptor alpha gene polymorphisms on eosinophilia in asthmatics.J Allergy Clin Immunol. 2007; 120: 1110-1117Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar failed to detect any positive associations between asthma and the polymorphisms of IL5RA and CCR3, but interaction of those polymorphisms was clearly associated with the eosinophil count.1Lee J.H. Chang H.S. Kim J.H. Park S.M. Lee Y.M. Uh S.T. et al.Genetic effect of CCR3 and IL-5 receptor alpha gene polymorphisms on eosinophilia in asthmatics.J Allergy Clin Immunol. 2007; 120: 1110-1117Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar Of course, it is important to know whether the association can be replicated in an independent sample. Genetic analyses of the associated variants in different ethnic groups are necessary and desired. Further functional analyses of the genetic variants in eosinophils and other cell types would also be helpful. At least for now, however, it seems unlikely that IL-5 plays critical roles in the onset of asthma. Researchers who are “eosinophiles” will probably read the article by Lee et al1Lee J.H. Chang H.S. Kim J.H. Park S.M. Lee Y.M. Uh S.T. et al.Genetic effect of CCR3 and IL-5 receptor alpha gene polymorphisms on eosinophilia in asthmatics.J Allergy Clin Immunol. 2007; 120: 1110-1117Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar with disappointment, just like 7 years ago when Leckie et al15Leckie M.J. ten Brinke A. Khan J. Diamant Z. O'Connor B.J. Walls C.M. et al.Effects of an interleukin-5 blocking monoclonal antibody on eosinophils, airway hyper-responsiveness, and the late asthmatic response.Lancet. 2000; 356: 2144-2148Abstract Full Text Full Text PDF PubMed Scopus (1640) Google Scholar published an article showing no appreciable clinical efficacy for anti–IL-5 antibody therapy. Then, however, several subsequent studies revealed the presence of tissue-dwelling eosinophils in the lung.16Flood-Page P.T. Menzies-Gow A.N. Kay A.B. Robinson D.S. Eosinophil's role remains uncertain as anti-interleukin-5 only partially depletes numbers in asthmatic airway.Am J Respir Crit Care Med. 2003; 167: 199-204Crossref PubMed Scopus (736) Google Scholar Thus, although IL-5 was apparently not a good target for the treatment of asthma, those subsequent findings gave new life to the hope that eosinophils could serve as a therapeutic target for asthma. Will the same scenario unfold this time, too? Probably not, because this genetic linkage study by Lee et al1Lee J.H. Chang H.S. Kim J.H. Park S.M. Lee Y.M. Uh S.T. et al.Genetic effect of CCR3 and IL-5 receptor alpha gene polymorphisms on eosinophilia in asthmatics.J Allergy Clin Immunol. 2007; 120: 1110-1117Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar clearly demonstrates a positive association between the interaction of IL5RA and CCR3 and the eosinophil count, and no association between the interaction and asthma. In other words, variations in IL5RA and CCR3 showed no influence on the onset of asthma (and we presume that the eosinophil count does not, either). As described by Bochner,17Bochner B.S. Verdict in the case of therapies versus eosinophils: the jury is still out.J Allergy Clin Immunol. 2004; 113: 3-9Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar the jury is still out regarding the verdict in the case of therapies versus eosinophils, whereas, for the case of eosinophils versus the onset of asthma, the article by Lee et al1Lee J.H. Chang H.S. Kim J.H. Park S.M. Lee Y.M. Uh S.T. et al.Genetic effect of CCR3 and IL-5 receptor alpha gene polymorphisms on eosinophilia in asthmatics.J Allergy Clin Immunol. 2007; 120: 1110-1117Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar failed to demonstrate any involvement of IL-5 in the onset of asthma. However, researchers who are “eosinophiles” should by no means be discouraged, because the possibilities of involvement of eosinophils in the onset of asthma and their involvement in the course of asthma, especially remodeling (ie, potential target for the therapeutic intervention), are separate issues. Indeed, since 2000, various investigators have piled up evidence that eosinophils play important roles, predominantly in the formation of airway remodeling.18Pascual R.M. Peters S.P. Airway remodeling contributes to the progressive loss of lung function in asthma: an overview.J Allergy Clin Immunol. 2005; 116: 477-486Abstract Full Text Full Text PDF PubMed Scopus (268) Google Scholar New therapeutic strategies that efficiently deplete tissue-dwelling eosinophils will further clarify the importance of eosinophils in the pathogenesis of asthma. Further studies are surely necessary to prove the role of eosinophils or these eosinophil-related molecules by increasing the population or by selecting a certain asthma phenotype having, for example, symptoms related to airway remodeling. However, this study by Lee et al1Lee J.H. Chang H.S. Kim J.H. Park S.M. Lee Y.M. Uh S.T. et al.Genetic effect of CCR3 and IL-5 receptor alpha gene polymorphisms on eosinophilia in asthmatics.J Allergy Clin Immunol. 2007; 120: 1110-1117Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar may provide an efficient method for genetic studies regarding this complex disease. Genetic variations of CCR3 and IL5RA were associated with objective phenotype markers—the protein levels and the number of circulating eosinophils. It is necessary to collect and arrange the numerous pieces of the jigsaw puzzles called asthma, and this study has contributed to that effort.
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