Search

Objective. This study describes morbidity attributable to wheezing illness in a multi-ethnic sample of low-income infants younger than age 2, and examines biological, environmental, and psychosocial correlates of morbidity indexes. Method. Infants 9 to 24 months old, considered at risk for developing asthma on the basis of having had 3 or more health care contacts with documented wheezing, received comprehensive evaluations as part of an environmental intervention study. Baseline evaluations with the infants, their families, and their home environments focused on biological, environmental, and psychosocial factors that would potentially increase asthma risk for the children. At study entry, prior morbidity attributable to wheezing illness was assessed with caregiver reports of symptom frequency and severity and medication use, caregiver quality of life, and medical record documentation of hospitalizations and emergency department (ED) visits. Results. Forty-six percent of the infants had 1 or more hospitalizations and 59% had 2 or more ED visits since birth for wheezing illness. Foreign-born Hispanic families had significantly more ED visits for their children's wheezing illness than US-born Hispanic families, whites, or blacks, although they used fewer controller medications and they reported less illness severity. Multivariate analyses showed 3 biological factors, respiratory syncytial virus, elevated child IgE, and cockroach allergen in the home, were independently associated with hospitalizations within this sample. Similar analyses showed that ED visits were not associated with biological variables, but rather with caregivers with single parent status and smokers. Caregiver reports of wheezing illness severity were correlated with ED visits, but not with hospitalizations. Severity ratings were higher for children of mothers with asthma and for those whose caregivers had higher anxiety and stress. The only correlate of caregiver ratings of poor quality of life was high caregiver anxiety. Conclusions. Ethnic and immigrant status was an important factor in morbidity attributable to infant wheezing illness. In addition to respiratory infection, both allergic processes and social variables were associated with morbidity as measured by health care utilization. Caregiver reports of illness severity were significantly correlated with psychosocial factors., ABBREVIATIONS. ED, emergency department; CAPS, Childhood Asthma Prevention Study; CQoL, Caregiver Quality of Life; RSV, respiratory syncytial virus; SD, standard deviation; IgE, immunoglobulin E. This study examines the correlates of [...]

VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) INDUCES REMODELING AND ENHANCES TH2-MEDIATED SENSITIZATION AND INFLAMMATION IN THE LUNG Lee CG, Link H, Baluk P, et al. Nat Med. 2004;10: 1095-1103 Purpose of [...]

VIRAL-INDUCED T HELPER TYPE 1 RESPONSES ENHANCE ALLERGIC DISEASE BY EFFECTS ON LUNG DENDRITIC CELLS Dahl ME, Dabbagh K, Liggitt D, Kim S, Lewis DB. Nat Immunol. 2004;5:337-343 Purpose of [...]

Purpose of the Study. To identify a central asthma susceptibility gene in the large chromosome 5q23-35 region that has been linked to asthma and atopy, using mouse models of asthma. Study Population. Congenic inbred mouse strains: 1) selected for genetic variance in only the chromosomal region homologous to the human chromosome 5q region (mouse chromosome 11), and 2) in which fundamental features of atopic asthma (eg, TH-2-biased immune responses and enhanced bronchial hyperresponsiveness [BHR]) can be induced. Methods. A positional cloning approach was taken to identify and map the genetic locus on mouse chromosome 11 that protected against the induction of TH-2 immune responsiveness and BHR. Using this information, the human homolog to the asthma susceptibility locus in mice was identified, as were genes in this region. The functional consequences of polymorphisms in these genes were then studied in the mouse models. Results. A single gene locus in mouse chromosome 11 was associated with both TH-2 immune responsiveness and BHR. Called Tapr (T cell and airway phenotype regulator), the human homolog to this region was mapped to human chromosome 5q33.2 and found to contain a Tim (T cell membrane glycoproteins with conserved immunoglobulin variable domain and mucin domains) family of genes. Both TIM-1 and TIM-3 gene expression were strongly associated TH-1-TH-2 differentiation and BHR. Additionally, the human homolog of TIM-1 is a cellular receptor for the hepatitis A virus (HAV). Conclusions. Tim genes plays an important role in allergic T cell responses, BHR, and asthma susceptibility. Reviewers' Comments. Genetic studies have discovered candidate genes for asthma susceptibility on chromosomes 5, 6, 11, 12, and 14. Chromosome 5q23-35 region has recently received the most attention because this region includes a large number of cytokine and control protein genes that have been associated with asthma, including the TH-2 cytokine cluster (interleukin [IL]-4, IL5, and IL-13), [beta]-adrenergic receptor, IL-12p40 and IL-9. However, a single asthma susceptibility gene in this region has not yet been conclusively identified. This study identified a novel gene cluster of Tim genes in mouse and man, in which polymorphisms were associated with both TH-2 cytokine production and BHR in mouse asthma models. One particularly intriguing aspect of this finding is that human TIM-1 is the HAV receptor. Several recent studies in Italy and the United States by Matricardi and colleagues have associated serologic evidence of previous HAV infection with less allergen sensitization and asthma. The authors of this article postulate that an interaction of HAV with TIM-1 may reduce TH-2 differentiation and the subsequent risk of asthma and allergy. Studies of the immune-modulating effect of HAV via the TIM-1 gene in humans, and the influence of TIM-1 polymorphisms on this effect, are required to confirm this hypothesis. For more information, please see an editorial comment by Wills-Karp titled "Asthma Genetics: Not for the TIMid?" by on page 1095-1096 in the same issue of Nature Immunology, and a review article by Umetsu et al titled "Asthma: An Epidemic of Dysregulated Immunity" in Nature Immunology (2002;3: 715-720)., McIntire JJ, Umetsu SE, Akbari O, et al. Nature Immunol. 2001;2:1109-1116 AKALUCK THATAYATIKOM, MD ANDREW H. LIU, MD Denver, [...]

Purpose of the Study. To investigate the potential counterregulatory role of lipoxin A4 (LXA4) and lipoxin A4 receptors (ALX) in allergic pulmonary inflammation and bronchial hyperresponsiveness (BHR) in asthma. Methods. In a murine model of allergic asthma, pulmonary inflammation and BHR with administration of a lipoxin A4 analog (LXa) was studied. Transgenic mice expressing human LXA4 receptors were also studied. Results. LXa, administered intravenously after allergen sensitization and before airways allergen exposure, significantly reduced both BHR and allergic pulmonary inflammation, including eosinophils, lymphocytes, interleukin (IL)-5, IL-13, eotaxin, and cysteinyl leukotrienes. Similar findings were observed in transgenic mice that constitutively expressed human LXA4 receptors. Conclusions. Lipoxin A4 and its analog offer a novel therapeutic approach to the treatment of BHR and pulmonary inflammation in asthma. Reviewers' Comments. Lipoxins are endogenously produced eicosanoids with antiinflammatory actions. LXA4, the best-studied member of this family, has antiinflammatory activities in in vitro and in vivo model systems. Its antiinfiammatory actions include downregulation of proinfiammatory cytokines and chemokines involved in neutrophil and eosinophil trafficking, inhibition of cytokine-stimulated metalloproteinase activity and cell proliferation, and stimulation of macrophage clearance of apoptotic cells from an inflammatory focus. LAX4 has recently been shown to interfere with cysteinyl leukotriene (cysLT)-mediated inflammation by competitively binding the cysLT1 receptor. This and another recent study (Bonnas C, et al, Am J Respir Crit Care Med. 2002;165:1531-1535) reveal the therapeutic potential of LXA4 in asthma. Other potential applications of LAX4 are for topical use as an antiinflammatory agent for inflammatory skin conditions (Schottelius AJ, et al, J Immunol. 2002;169:7063-7070). Given the efficacy of the compound, LAX4 may be a compelling alternative to corticosteroids in certain clinical settings. A commentary on this study, titled "Good Lipids for Asthma" by Peters-Golden on pages 931-932 of the same issue, and an article titled "Lipoxins: Revelations on Resolution" by McMahon et at in Trends in Pharmacological Sciences (2001;22:391-395) are suggested for further review., Levy BD, De Sanctis GT, Devchand PR, et al. Nature Med. 2002;8:1018-1023 AKALUCK THATAYATIKOM, MD ANDREW H. LIU, MD Denver, [...]

Purpose of the Study. To identify novel genetic polymorphisms associated with bronchial hyperresponsiveness (BHR) in asthma. Study Population. Four hundred sixty white affected sib-pair families from the United States and the United Kingdom with current asthma. Methods. A genetic linkage analysis was performed for current asthma and BHR. Case-control, transmission disequilibrium, and haplotype analyses were conducted to identify the gene(s) most commonly associated with asthma. Novel genes of interest were identified by a combination of public data mining, complementary DNA (cDNA) library screening, direct cDNA selection, and reverse transcriptase-polymerase chain reaction (RT-PCR). Results. Positional cloning revealed a novel genomic region of interest on chromosome 20p13. Ultimately, polymorphisms in the ADAM33 gene were linked to asthma and BHR. ADAM 33 is a complex metalloproteinase with numerous diverse functions that is expressed in lung fibroblasts and bronchial smooth muscle, but not bronchial epithelial cells. The alleles in ADAM 33 that were associated with an increased susceptibility to asthma were common, ranging from 20% to 95%. Conclusions. Allelic variation in the ADAM33 gene may underlie lower airways dysfunction in asthma, including BHR and airway remodeling. Reviewers' Comments. What are the genetic predispositions to asthma? In this study, current asthma and BHR were linked to a new category of molecules. ADAM proteins are a subfamily of matrix metalloproteinases. They have diverse posttranslational cellular functions, capable of regulating myogenic fusion, proteolysis, cell adhesion, and cell signaling. Their proteolytic functions include the shedding of cell-surface cytokine and cytokine receptors that are involved in inflammation, cell proliferation, and cell death. How the linkage of the ADAM33 gene to asthma and BHR and its expression in human lung fibroblasts and bronchial smooth muscle relates to asthma is not clear. It is speculated that ADAM33 expression may be a primary cause of fibroblast proliferation, and their differentiation into myofibroblasts and smooth muscle, leading to subepithelial fibrosis, smooth muscle hyperplasia and increased matrix deposition, underlying BHR, and airway remodeling. For more information on this subject, please see a brief editorial, titled "Inherit the Wheeze" by Drazen and Weiss, that accompanies this article on pages 383-384 of the same issue, and a review article, titled "ADAM-33 Surfaces as an Asthma Gene," by Shapiro and Owen in the New England Journal of Medicine (2002;347:936-938)., Van Eerdewegh P, Little RD, Dupuis J, et al. Nature. 2002;418:426-430 AKALUCK THATAYATIKOM, MD ANDREW H. LIU, MD Denver, [...]

Purpose of the Study. To identify the genes for familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS). Study Population. Three families with FCAS and 1 family with MWS. Methods. Genomic DNA isolation, identification of coding region, DNA sequencing, and mutation detection. Protein prediction programs were also performed. Results. Four distinct mutations of the CIAS1 Gene on chromosome 1q44 were identified. The gene encodes a newly identified protein called cryopyrin. Conclusion. Mutations of the CIAS1 Gene encoding cryopyrin cause at least two distinct but similar cold-sensitive diseases, including FCAS and MWS. Reviewers' Comments. This exciting discovery has led to the identification of a new protein, aptly named "cryopryin," that links cold temperature exposure to inflammation. In this report, mutations of the cryopyrin gene were identified in family members with 2 rare autosomal dominant conditions that are "autoinflammatory" disorders (ie, conditions with recurrent inflammatory symptoms in the absence of autoantibodies): FCAS and MWS. Recently, FCAS--also known as familial cold urticaria and familial polymorphous cold eruption--has been well-described by the same authors. The FCAS clinical picture includes: skin rash (100%), arthralgia (96%), fever (93%), conjunctivitis (84%), disease onset in the first 6 months of life (95%), an average time delay between cold exposure and the onset of symptoms of 2.5 hours, and an average episode duration of 12 hours (Hoffman HM, et al. J Allergy Clin Immunol. 2001; 108:615-620). In contrast, MWS leads to progressive sensorineural deafness, amyloidosis of the kidneys and other organs, fevers, chills, rigors, malaise, and chronic recurrent urticaria. The reason for the 2 distinct clinical entities associated with mutations in the same gene still need to be explored. For more discussion, see a brief editorial entitled "A fever gene comes in from the cold" by Kastner and O'Shea on pages 241-242 of the same issue. Hoffman HM, Mueller JL, Broide DH, et al. Nature Genet. 2001;29:301-305, AKALUCK THATAYATIKOM, MD ANDREW H. LIU, MD Denver, [...]

Purpose of the Study. To identify susceptibility loci for atopic dermatitis. Study Population. A total of 839 individuals from 199 families in Germany, Italy, Sweden, and the Netherlands with moderate to severe atopic dermatitis with at least 2 affected siblings. Methods. A genome-wide linkage study for atopic dermatitis and immune evidence of atopy (ie, serum evidence of either specific allergen sensitization by CAP-radioallergosorbent test or elevated immunoglobulin E levels). Results. Chromosome 3q21 was strongly linked with atopic dermatitis and immune evidence of atopy. Conclusions. Atopic dermatitis and immune evidence of atopy have been linked to the same locus on chromosome 3q21. Reviewers' Comments. Previous genetic studies of atopic diseases have revealed different chromosome linkages to a variety of atopic disease features. Candidate genes in chromosome 3q21 include costimulatory signals for T lymphocyte activation, CD80, and CD86. Therefore, the finding of a major susceptibility locus for atopic dermatitis on chromosome 3q21 supports a pivotal role of T cell costimulatory signals in mediating allergic inflammation. A larger genetic cohort study of atopic dermatitis in the future will reveal other important loci with affecting and contributing of the disease William Cookson and colleagues also recently published a genome screen for atopic dermatitis and have identified additional atopic dermatitis linkages with chromosomes 1q21, 17q25, 20p (Nature Genet. 2001;27:372-373). Interestingly, Cookson's linkages are closely coincident with some major psoriasis loci previously reported. Furthermore, the 3q21 linkage to atopic dermatitis found by Lee has also been linked with psoriasis. Therefore, Lee's and Cookson's studies imply that similar genetic susceptibilities influence both atopic dermatitis and psoriasis. Lee YA, Wahn U, Kehrt R, et al. Nature Genet. 2000;26: 470-473, AKALUCK THATAYATIKOM, MD ANDREW H. LIU, MD Denver, [...]

Presents an abstract of the research paper `Immunoprophylaxis of Allergen-Induced Immunoglobulin E (IgE) Synthesis and Airway Hyperresponsiveness in Vivo by Genetic Immunization,' by C.H. Hsu et al published in a 1996 issue of `Nature Medicine.'

Presents an abstract of the study titled `Mutations of Jak-3 Gene in Patients with Autosomal Severe Combined Immune Deficiency (SCID),' by P. Macchi, A. Villa, et al, published in the 377th volume 1995 issue of `Nature.'

Reviews the article `Identification of Herpesvirus-Like DNA Sequences in Aids-Associated Kaposi's Sarcoma,' by Y. Chang et al, published in the 1994 issue of `Science.' Evidence supporting the role of a previous unknown herpesvirus as an infectious agent associated with Kaposi's Sarcoma (KS).

Reviews articles about efforts to determine the degree of HIV infection of lymphoid tissues at various stages of HIV disease, published in the 1993 issue of `Nature.' `HIV Infection Is Active and Progressive in Lymphoid Tissue During the Clinically Latent Stage of Disease,' by G. Pantaleo et al; `Massive Covert Infection of Helper T Lymphocytes and Macrophages by HIV During the Incubation...' by J. Embretson et al.

Presents a summary of the research article `Interleukin-2 Receptor Gamma Chain Mutation Results in X-Linked Severe Combined Immunodeficiency in Humans,' by M. Nogucki, H. Yi et al, published in a 1993 issue of `Cell.' Role of interleukin-2 receptor gamma chain in X-linked severe combined immunodeficiency.

Presents a study that restores functional immunoglobulin synthesis to defective B lymphocytes from a patient with X-linked agammaglobulinemia through cell fusion. Methodologies; Findings and conclusion of the study.

Presents an abstract of the study `Functional Requirements for Class I MHC in Central Nervous System Development and Plasticity,' by G.S. Huh, L.M. Boulanger, H. Du and colleagues, published in a 2000 issue of `Science.'

Studies the diversity of the T lymphocyte repertoire during the course of HIV-1 infection and after combination antiretroviral therapy. Methods; Results; Conclusions.

Presents information on a study which evaluated the kinetics of immune reconstitution after triple combination therapy for HIV-infected patients. Methods; Results; Conclusions.

Reviews the article `Cystic Fibrosis Heterozygote Resistance to Cholera Toxin in the Cystic Fibrosis Mouse Model,' by S.E. Gabriel et al, published in the 1994 issue of `Science.' Fluid accumulation in the bowels of mice exposed to cholera toxin and cystic fibrosis transmembrane regulator (CFTR).

Reviews the article `Isolation of a Novel Gene Mutated in Wiskott-Aldrich Syndrome,' by J.M.J. Derry et al, published in the 1994 issue of `Cell.' Wiskott-Aldrich syndrome (WAS), an x-linked recessive disorder associated with severe thrombocytopenia, eczema and bloody diarrhea; Description of the isolation of a novel gene called WAS Protein (WASP).

Reviews the article `Allergen Immunotherapy Decreases Interleukin-4 Production in CD4+ T Cells from Allergic Individuals,' by H. Secrist et al, published in the 1994 issue of `Journal of Experimental Medicine.' Possible mechanism for the beneficial effects of allergen immunotherapy; Production of interleukin-4.

Reviews the article `Abolition of Anaphylaxis by Targeted Disruption of the High-Affinity Immunoglobulin E (IgE) Receptor Alpha Chain,' by D. Dombrowicz, V. Flamand et al, published in the 1994 issue of `Cell.' Mast cells and basophils; Assessment of the relative role of the high-affinity IgE receptor.

Presents a summary of the research articles `Deficient Expression of a B Cell Cytoplasmic Tyrosine Kinase in Human X-Linked Agammaglobulinemia,' by S. Tsukada et al, published in a 1993 issue of `Cell,' and `The Gene Involved in X-Linked Agammaglobulinemia is a Member of the SRC Family of Protein-Tyrosine Kinases,' by D. Vetrie et al, published in a 1993 issue of `Nature.'

Presents a summary of research articles on the genetic aspects of X-linked hyper-immunoglobulin M syndrome. Includes `CD40 Ligand Gene Defects Responsible for X-Linked Hyper-IgM Syndrome,' by R.C. Allen et al, published in a 1993 issue of `Science'; `Defective Expression of T-Cell CD40 Ligand Causes X-Linked Immunodeficiency With Hyper-IgM,' by U. Korthauer et al, published in a 1993 issue of `Nature.'