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K A Deichmann

Publications and source records attributed to K A Deichmann.

31 records · Page 2Linked to original sources
PubMed2000

A European study on the genetics of mite sensitization.

BACKGROUND: Sensitization to mite allergens represents a prominent feature of atopy and an important predictor of bronchial asthma. OBJECTIVE: It was the intention of this study to define genetic loci linked to mite sensitization because these could represent the genetic basis of the important atopic component of asthma. METHODS: We studied a multiethnic white population of 99 families, including 224 sib pairs sensitized to Dermatophagoides pteronyssinus. A genome-wide candidate-region search was performed that covered potential asthma and atopy regions. RESULTS: As for nonparametric linkage (NPL) analysis, 14 of the candidate regions showed evidence for linkage (NPL > 2.0), and 4 of them showed prominent linkage (NPL > 3.0). However, there were substantial ethnic differences. Maximizing the LOD score analysis identified candidate regions with suspected dominant and recessive mode of inheritance. Furthermore, genetic imprinting models provided significant evidence for linkage in the 8p23 region and revealed potential maternal imprinting. The regions found are distinct to those in asthma searches that have been found to be linked to asthma, as well to other inflammatory diseases. In addition, we could not find linkage to the HLA region. By different cutoff points of the phenotype definition, the IL cluster showed evidence of being linked to the degree of sensitization rather than to sensitization per se. CONCLUSION: The results indicate that the genetic basis of the atopic component of asthma is different from that of the inflammatory component. Furthermore, it seems reasonable to assume that specific sensitizations are influenced by distinct genetic variants leading to their initiation versus those leading to their enhancement.

Allergens↗
PubMed2000

Recent advances in understanding how interleukin 13 signals are involved in the pathogenesis of bronchial asthma.

The prevalence of allergic disease has dramatically increased in recent decades, especially in urban and industrialized areas. Allergic diseases are disorders of the immune system, the results of complex interactions among various genetic and environmental factors. Among them, the important role of interleukin 13 (IL-13), a Th2-type cytokine, has recently emerged in the pathogenesis of bronchial asthma. Based on studies using mice, great attention has been paid to the direct effects of IL-13 on bronchial tissues. In this review, we describe recent advances in understanding the signal transduction mechanism of IL-13, the involvement of IL-13 signal-related genes as genetic factors in the pathogenesis of bronchial asthma, and the expression of IL-13 receptor on bronchial tissues. We describe potential strategies for targeting IL-13 signals to improve allergic states.

Animals↗
PubMed1999

Association studies on beta2-adrenoceptor polymorphisms and enhanced IgE responsiveness in an atopic population.

The beta2 adrenergic receptor 2 represents a cell surface receptor responsible for the binding of endogenous catecholamines and their exogenously administered agonists and antagonists, mediating their effects to the interior of the cell. On the basis of these functions, the observed association of two of its polymorphisms, Gly16 and Gln27, with nocturnal- and steroid-dependent asthma has been discussed. It has recently been suggested that Gln27 contributes to IgE variability in families with asthma. The aim of this study was to investigate possible influences of the polymorphisms Arg16Gly and Glu27Gln on IgE levels in families recruited through an atopic index case without regard to the presence of clinical symptoms. We employed linkage analysis in affected sibpairs characterized by elevated total IgE concentrations or sensitization to common inhalant allergens. Furthermore, we tested 258 children for association of any of the polymorphisms with enhanced IgE responsiveness. We could find neither linkage at the locus 5q31 nor significant association of the polymorphisms with elevated total IgE concentrations or specific sensitization. We conclude from our data that the polymorphisms Gln27Glu and Arg16Gly of the beta2-adrenergic receptor do not play a significant role in the pathogenesis of enhanced IgE responsiveness in an atopic population in general.

Alleles↗
PubMed1999

Genetic linkage of HLA-class II locus to mite-specific IgE immune responsiveness.

BACKGROUND: IgE response to common inhalant allergens seems to be the major determinant of the development of atopic rhinitis and asthma but it has been difficult to demonstrate genetic control of the IgE response. OBJECTIVE: To investigate genetic linkage between specific IgE reactions to purified aero-allergens (grass, birch, cat, mite) and the HLA-class II locus. METHODS: DNA-based HLA-class II typing was performed for determination of DRB1, DQB1 and DPB1 alleles. Linkage was studied by the affected sibpair method and the extended transmission disequilibrium test in 100 children from 40 nuclear families selected from a homogeneous population in south-western Germany. RESULTS: Significant linkage of mite-specific IgE response to HLA-DPB (P = 0.00001), HLA-DRB (0.02) and HLA-DQB (P = 0.001) was revealed by sibpair analysis of MHC class II alleles and confirmed by the extended transmission disequilibrium test for HLA-DRB (P = 0.01) and HLA-DPB (P = 0.04). No consistent significant linkage between the HLA-class II locus and IgE response to grass pollen, birch pollen, and cat dander could be demonstrated. CONCLUSION: The findings are consistent with the existence of one or more genes in the HLA-class II region modifying the IgE immune response to common environmental allergens.

Adolescent↗
PubMed1999

The polymorphisms S503P and Q576R in the interleukin-4 receptor alpha gene are associated with atopy and influence the signal transduction.

Interleukin-4 (IL-4) plays a major role in immunoglobulin E (IgE) production. Its signal is conferred to effector cells through binding to the alpha chain of the IL-4 receptor (IL-4Ralpha). We present further evidence for polymorphisms in the IL-4Ralpha gene having an effect on IgE regulation. For two of four common polymorphisms, S503P and Q576R, we found an association with lowered total IgE concentrations (P=0.0008 if occurring together). The polymorphism S503P has not yet been described and is located within the I4R motif of the receptor. In vitro analyses using synthetic peptides of this region showed that the tyrosine kinase Janus kinase 1 (JAK1), as well as IRS-1 and IRS-2 bind to the I4R motif irrespective of the polymorphism or a tyrosine phosphorylation. In vivo immunoassays using T cells of four different groups of individuals (S503/Q576; P503/Q576; S503/R576; P503/R576) revealed that only in case of both polymorphisms the phosphorylation of IRS-1 and IRS-2, but not JAK1 was increased. We found no binding of STAT6 to the I4R synthetic peptides; however, the phosphorylation was reduced in the presence of any of the two polymorphisms, including P503 alone. We discuss possible conformational changes of the receptor leading to the observed effects on the phosphorylation status of IRS-1, IRS-2 and STAT6, in addition to previous findings that Q576R alters STAT6 binding. We conclude that P503 and R576 influence the signal transduction pathways through the IL-4Ralpha, an effect that is magnified by the presence of both polymorphisms. This could explain the observed association effects with lowered total IgE concentrations.

Adolescent↗
PubMed1999

Characterization of the membrane-bound and a soluble form of human IL-4 receptor alpha produced by alternative splicing.

IL-4 plays a major role in IgE production. Its signal is conferred to effector cells through binding to the alpha chain of the membrane-bound human IL-4 receptor (huIL-4Ralpha). Here we present the genomic structure and organization of huIL-4Ralpha. The promotor region shows binding sites for several transcription factors involved in inflammatory processes. HuIL-4Ralpha has been shown to be organized differently to that of mouse IL-4Ralpha. A soluble form of huIL-4Ralpha is produced by alternative splicing of the huIL-4Ralpha gene (shuIL-4Ralpha/splice). Expression of the corresponding mRNA coding for the extracellular part of the receptor and an additional three amino acids is also shown. A second form of huIL-4Ralpha, i.e. shuIL-4Ralpha/prot, is produced by limited proteolysis of the receptor (shedding) and is already known. These results reveal a complex pattern for the regulation of the IL-4 pathway at the receptor level. The patterns of expression of all three receptor proteins as well as their individual meaning in the context of inflammation still have to be elucidated.

Alternative Splicing↗
PubMed1999

The recognition pattern of sequential B cell epitopes of beta-lactoglobulin does not vary with the clinical manifestations of cow's milk allergy.

BACKGROUND: beta-Lactoglobulin (BLG) represents one of the major allergens causing cow's milk allergy (CMA) - a disease with a wide spectrum of clinical symptoms. The aim of this study was to evaluate sequential B cell epitopes of BLG by the Pin-ELISA method. Furthermore, we wanted to investigate a possible association of the IgE recognition patterns in sera of patients with BLG sensitization and the type of clinical reactions following contact with cow's milk. METHODS: Overlapping sequential decapeptides corresponding to the amino acid sequence of BLG were used in Pin-ELISAs specific for human IgE. Tested sera were from 14 individuals with CMA, 8 of them with a history of immediate systemic reactions and 6 with delayed skin reactions following contact with cow's milk. All of them showed specific IgE antibodies to BLG in the CAP-RAST. Control sera were from 5 healthy nonallergic individuals. RESULTS: All sera from BLG-sensitized individuals showed IgE binding with one region of BLG corresponding to amino acids 95-113. Furthermore, individual sera showed reactions with two further regions, 12-27 and 124-135. Inhibition of IgE binding to BLG with one soluble synthetic peptide confirmed the major epitope. No differences were found in the B cell epitope recognition pattern to BLG in the two groups of patients with CMA, characterized by acute systemic or delayed skin reactions. CONCLUSIONS: Using IgE Pin-ELISAs we were able to confirm previously described sequential B cell epitopes of BLG. However, the recognition pattern of one of the major cow's milk allergens is not predictive of the clinical type of reaction.

Amino Acid Sequence↗
PubMed1999

Linkage and association studies of atopy and the chromosome 11q13 region.

The clinical syndrome atopy is largely determined by genetic factors. In 1989, the first linkage of markers within and flanking the chromosomal region 11q13 and atopy was reported. In the following years, the gene coding for the beta chain of the high affinity IgE receptor was localised to this region and two polymorphisms in this gene have been shown to be associated with the atopic phenotype. We investigated two independent populations (population based and outpatient department) with different degrees of clinical symptoms. Using highly polymorphic markers we could find no evidence for linkage or allelic association of this particular genomic region to the atopic phenotype defined by enhanced IgE responsiveness (p>0.05). Neither did we succeed in finding either of the two polymorphisms described, nor could we identify any other polymorphisms within the gene. However, we found weak evidence for linkage in asthmatic sib pairs regarding maternal alleles (p=0.03). We conclude from our data that in our populations the gene for the beta chain of the high affinity IgE receptor is of minor importance for enhanced IgE responsiveness, and that it might influence atopy with clinical signs like asthma through maternally derived alleles.

Adolescent↗
PubMed1998

Linkage and allelic association of atopy and markers flanking the IL4-receptor gene.

BACKGROUND: Atopy, a clinical syndrome characterized by heightened IgE responsiveness, is largely determined by genetic factors. The disease may well be heterogeneous but the mode of inheritance is unknown. Several genes have been named which affected IgE responsiveness. However, results are conflicting reflecting heterogeneity and a complicated inheritance pattern of the atopic syndrome. In 1994 linkage of the 5q32 gene region and elevated total IgE levels were reported, leaving the IL4 gene as a prominent candidate. OBJECTIVES: We were interested in a possible involvement of the IL4-receptor gene in the development of atopy. METHODS: We employed sib-pair linkage analysis using highly polymorphic microsatellite markers within and flanking the IL4 receptor gene in atopic families, characterized for specific sensitization to inhalant allergens and elevated total serum IgE. Allele sizes were determined for all microsatellite probes to allow transmission disequilibrium analysis. RESULTS: We found significant sharing of maternal but not paternal alleles in affected sibs from two independent populations, both of which presented enhanced IgE responsiveness. Linkage and maternal inheritance could be confirmed by transmission disequilibrium analysis. CONCLUSIONS: We conclude from our findings that maternal inheritance of a gene in the chromosome 16p12 region increases the risk for enhanced IgE responsiveness. The most prominent candidate in this region is represented by the IL4 receptor gene.

Adolescent↗
PubMed1998

Two common polymorphisms in the coding part of the CD43 gene are not associated with atopy.

BACKGROUND: Recently linkage and association of the chromosomal region 16p12-11 with enhanced IgE responsiveness have been shown. The gene coding for CD43 (sialophorin) has been localized to this region. Sialophorin represents a major sialoglycoprotein on the surface of human lymphocytes, monocytes and granulocytes. It is supposed to play an important role in human mast cell, T- and B-cell regulation and activation and has been described in connection with immunodeficiency diseases such as the Wiskott-Aldrich syndrome. Therefore, it can be designated as a candidate gene for atopy. METHODS: Using SSCP analysis and direct genomic sequencing, polymorphisms in the CD43 gene have been looked for and their association with atopy has been tested in a population of 260 largely atopic children and young adults. RESULTS: Three common polymorphisms in the coding part of the CD43 gene were found. Two of them are leading to amino acid exchanges, one from argine to cysteine at amino acid position 337 of the mature gene product and one from leucine to phenylalanine at amino acid position 341. Subsequent association studies revealed no obvious influence of R337C or L341F on IgE regulation (p = 0.47 and 0.43), neither in a cognate nor in an uncognate fashion. CONCLUSION: We conclude that CD43 polymorphisms are unlikely to account for the observed linkage effect at 16p12-11. Whether the polymorphisms R337C and L341F adjacent to phosphorylation sites in the intracellular region of the protein alter the normal functioning of CD43 remains to be elucidated.

Adolescent↗
PubMed1989

Characteristics of a multicopy gene family predominantly consisting of processed pseudogenes.

The monoclonal antibody MOC-32 detected a 40 kDa protein in Western blot analysis. Immunological screening of an expression library of human SCLC cells with MOC-32 led to the isolation of overlapping cDNA clones. One of these, cHD4, was 1.0 kbp long and of about the same size as its corresponding mRNA. Preceded by an in phase stop codon, an open reading frame of 885 bp was present in cHD4 and a translational product of only 33 kDa could be calculated. Biochemical and immunological analysis established the relationship between the 40 kDa antigen and the isolated coding sequences and resolved the apparent discrepancy between the calculated molecular weight and the observed electrophoretic mobility. Nucleotide sequence comparison of cHD4 to the EMBL database revealed that cHD4 was nearly identical to a sequence claimed to encode a laminin binding protein. Southern blot and nucleotide sequence analysis indicated the presence of multiple copies of the gene in the human genome. At least five of these appeared to represent processed pseudogenes.

Amino Acid Sequence↗
PubMedDate not supplied

A novel polymorphism in the 5' promoter region of the human interleukin-4 receptor alpha-chain gene is associated with decreased soluble interleukin-4 receptor protein levels.

Interleukin (IL)-4 exerts its biological effects through binding to the IL-4 receptor (IL4R) complex, plays a central role in stimulating B-cell differentiation, and is crucial for the development of T helper 2 cells. Recently, a soluble form of the human IL4R alpha chain (sIL4R alpha), which is produced by alternate mRNA splicing of exon 8, was discovered. sIL4R is thought to play an important role in either enhancing or inhibiting IL-4 signalling. We analyzed the 5' promoter region of the human IL4R alpha-chain gene (IL4RA) of healthy volunteers by DNA sequencing and found three novel single-nucleotide polymorphisms (SNPs; T-890C, T-1914C, C-3223T) and one novel short tandem repeat [(CAAAA)(5-7)-3600]. The two common promoter region SNPs T-1914C and C-3223T as well as six known coding SNPs in the IL4RA gene were genotyped in healthy blood donors by PCR with sequence-specific primers; total sIL4R levels were measured by ELISA. Results revealed a highly significant association of the -3223T variant with lowered sIL4R levels (two-tailed t-test, P=0.0002). Results remained highly significant after Bonferroni adjustment for multiple comparisons (P=0.0017). Moreover, the C-3223T variant was found to be in strong linkage disequilibrium with the extracellular 150V variant (P<0.001), which was recently described to be associated with atopic asthma in a Japanese population. Since this novel IL4RA promoter region SNP is common (allele frequency 29.8%), we conclude that it may be of importance for the genetic regulation of the IL-4 signalling pathway.

Gene Frequency↗