Th-1/Th-2 switch regulation in immune responses to inhaled antigens. Role of dendritic cells in the aetiology of allergic respiratory disease.
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Administration, Inhalation↗
Biomedical subjects
C Macaubas
Publications and source records attributed to C Macaubas.
Development of long-term tolerance versus sensitisation to environmental allergens during the perinatal period.
Evidence is steadily accumulating which indicates that the patterns of T cell reactivity against the environmental antigens that determine the allergen responder phenotype in adulthood are, in many cases, established during infancy. The underlying regulatory processes which determine the nature of long-term immunological memory against these antigens appear to involve a combination of classical high zone and low zone tolerance mechanisms. It appears likely that these T cell responses are initiated before birth via the transplacental transfer of low levels of allergen to which mothers are exposed during pregnancy.
Allergens↗
The complex mutation pattern of a microsatellite.
DQCAR is a (CA)n microsatellite located in the HLA class II region and tightly linked to HLA-DQB1. Previous studies showed a strikingly low level of size variation in DQCAR alleles within an extensive subfamily of HLA-DQ subtypes (DQ1). DQCAR alleles in non-DQ1 subtypes showed a higher degree of size polymorphism. In this study sequence analysis demonstrates that DQ1-associated DQCAR alleles have a single C-->A nucleotide substitution interrupting the CA repeat array. Frequent CA-->GA mutations are also observed in DQ1-associated microsatellites with identical allele sizes. In contrast, DQCAR alleles associated with non-DQ1 haplotypes display a perfect CA repeat sequence and the variation in allele size is attributable only to differences in the number of CA repeats. Our results imply that several mutational mechanisms are involved in the generation of allelic diversity within the same microsatellite locus. The possibility of different mutation rates in the same locus should to be taken into account when using these markers in evolutionary and disease studies.
Alleles↗
TH2-polarized immunological memory to inhalant allergens in atopics is established during infancy and early childhood.
BACKGROUND: There is increasing evidence that the T-cell reactivity to environmental allergens underlying expression of allergic disease in adulthood, develops initially during childhood. However, there is little information available on the kinetics of these early responses, or on the patterns of cytokine production during this period. OBJECTIVE: The purpose of this study was twofold: to obtain further information on the reported differences between responses to food versus inhalant allergens during early childhood, and to ascertain the age-range over which T-cell responses to inhalant allergens become polarized towards the TH2 cytokine profile, in potentially atopic children. METHODS: In vitro cytokine responses to house dust mite (HDM) and egg (OVA) were assessed by semiquantitative RT-PCR in panels of 2- and 5-year-old children and adults; lymphoproliferative responses to OVA were subjected to epitope analysis. RESULTS: At age 2 years IL-4/IL-5 responses to HDM grouped with positive atopic family history, and by age 5 years cytokine responses correlated strongly with individual SPT reactivity to HDM. In contrast, OVA responses were restricted to weak and transient IL-5 signals in the 2-year-old family history positive group. Lymphoproliferation assays performed in parallel indicate a log-scale greater postnatal expansion of T-cell reactivity to the inhalant allergen; preliminary epitope analysis of OVA responses indicate that the number of OVA epitopes recognised decrease during early childhood. CONCLUSIONS: Inhalant allergen-specific in vitro cytokine production associated with positive skin-prick test (SPT) reactions, one of the hallmarks of adult atopy, manifests in children at or before 5 years of age; additionally, cytokine responses in SPT negative 5 year-olds are restricted to IFNgamma, as per normal adults. In contrast, T-cell responses to a typical food allergen appear to be deleted during early childhood.
Age Factors↗
Mutation rate varies among alleles at a microsatellite locus: phylogenetic evidence.
The understanding of the mutational mechanism that generates high levels of variation at microsatellite loci lags far behind the application of these genetic markers. A phylogenetic approach was developed to study the pattern and rate of mutations at a dinucleotide microsatellite locus tightly linked to HLA-DQB1 (DQCAR). A random Japanese population (n = 129) and a collection of multiethnic samples (n = 941) were typed at the DQB1 and DQCAR loci. The phylogeny of DQB1 alleles was then reconstructed and DQCAR alleles were superimposed onto the phylogeny. This approach allowed us to group DQCAR alleles that share a common ancestor. The results indicated that the DQCAR mutation rate varies drastically among alleles within this single microsatellite locus. Some DQCAR alleles never mutated during a long period of evolutionary time. Sequencing of representative DQCAR alleles showed that these alleles lost their ability to mutate because of nucleotide substitutions that shorten the length of uninterrupted CA repeat arrays; in contrast, all mutating alleles had relatively longer perfect CA repeat sequences.
Alleles↗
Extensive polymorphism of a (CA)n microsatellite located in the HLA-DQA1/DQB1 class II region.
A highly polymorphic (CA)n microsatellite marker (DQCAR), located between the DQA1 and the DQB1 genes, was characterized in four ethnic groups. Based on length polymorphism, 12 alleles could be defined. The marker is located 1- to 2-kb telomeric to the DQB1 gene and 10 kb centromeric to the DQA1 gene and was shown to be in tight linkage disequilibrium with HLA-DQ. Analysis of the linkage disequilibrium pattern revealed little additional diversity in DQ1-associated haplotypes. Almost all DQ1 subjects examined were DQCAR 103 or DQCAR 107 (13 and 15 CA repeats, respectively). In contrast, significant haplotypic diversity was observed for most DQ2-, DQ3-, and DQ4-associated haplotypes. These haplotypes often had longer allele sizes (DQCAR > 111, more than 17 CA repeats) and more DQCAR alleles per haplotype. These haplotypes also carried DQCAR alleles of different sizes, even though they bore the same DQA1 and DQB1 alleles, and sometimes the same DRB1 allele as well. These results indicate that DQCAR could be a useful marker to better define disease associations with HLA. Our results are also consistent with the hypothesis that CAR alleles with higher numbers of repeats have higher mutation rates and that recombination within the HLA-DR/DQ region is haplotype dependent.
Alleles↗
DQCAR microsatellite polymorphisms in three selected HLA class II-associated diseases.
DQCAR is a very polymorphic CA repeat microsatellite located between the HLA DQA1 and DQB1 gene. Previous studies have shown that specific DQCAR alleles are in tight linkage disequilibrium with known HLA DR-DQ haplotypes. Of special interest was the fact that haplotypes containing long CA repeat alleles (DQCAR > 111) were generally more polymorphic within and across ethnic groups. In these latter cases, several DQCAR alleles were found even in haplotypes containing the same flanking DQA1 and DQB1 alleles. In this work, three HLA class II associated diseases were studied using the DQCAR microsatellite. The aim of this study was to test if DQCAR typing could distinguish haplotypes with the same DRB1, DQA1 and DQB1 alleles in control and affected individuals. To do so, patients with selected HLA DR-DQ susceptibility haplotypes were compared with HLA DR and DQ matched controls. This included: Norwegian subjects with Celiac disease and the HLA DRB1*0301, DQA1*05011, DQB1*02 haplotype; Japanese subjects with Type 1 (insulin-dependent) Diabetes Mellitus and the HLA DRB1*0405, DQA1*0302, DQB1*0401 haplotype; and French patients with corticosensitive Idiopathic Nephrotic Syndrome and the HLA DRB1*0701, DQA1*0201, DQB1*0202 haplotype. These specific haplotypes were selected from our earlier work to include one haplotype bearing a short DQCAR allele (celiac disease and DR3,DQ2-DQCAR99) and two haplotypes bearing long DQCAR alleles (Diabetes Mellitus and DR4,DQ4-DQCAR 113 or 115 Idiopathic Nephrotic syndrome and DR7,DQ2-DQCAR 111-121). Additional DQCAR diversity was found in both control and patients bearing haplotypes with long CA repeat alleles. The results indicate that DQCAR typing did not improve specificity in combination with high resolution DNA HLA typing as a marker for these three disorders.
Base Sequence↗
DQB1*0602 and DQA1*0102 (DQ1) are better markers than DR2 for narcolepsy in Caucasian and black Americans.
In the present study, we tested 19 Caucasian and 28 Black American narcoleptics for the presence of the human leucocyte antigen (HLA) DQB1*0602 and DQA1*0102 (DQ1) genes using a specific polymerase chain reaction (PCR)-oligotyping technique. A similar technique was also used to identify DRB1*1501 and DRB1*1503 (DR2). Results indicate that all but one Caucasian patient (previously identified) were DRB1*1501 (DR2) and DQB1*0602/DQA1*102 (DQ1) positive. In Black Americans, however, DRB1*1501 (DR2) was a poor marker for narcolepsy. Only 75% of patients were DR2 positive, most of them being DRB1*1503, but not DRB1*1501 positive. DQB1*0602 was found in all but one Black narcoleptic patient. The clinical and polygraphic results for this patient were typical, thus confirming the existence of a rare, but genuine form of DQB1*0602 negative narcolepsy. These results demonstrate that DQB1*0602/DQA1*0102 is the best marker for narcolepsy across all ethnic groups.
Black People↗
Reactivity of renal transplant sera against a 17 kD mononuclear cell antigen.
In recent years, studies have shown that non-HLA antigens can be involved in renal graft rejection. The so called minor antigens have been found to be expressed on a variety of cells, including endothelial cells. With the aim of understanding better the role of minor antigens in graft rejection, we undertook a Western blot screening of sera from patients waiting for or having received grafts from living-related or cadaveric donors. In this study we described the reactivity of these sera against a 17 kD antigen with expression in many different cell types.
B-Lymphocytes↗
Regulation of cytokine production in T-cell responses to inhalant allergen:GATA-3 expression distinguishes between Th1- and Th2-polarized immunity.
BACKGROUND: The precise nature of allergen-specific cytokine responses in atopics versus non-atopics, in particular the 'Th1 polarity' of responses in non-atopics, remains controversial. This is due in part to the relative insensitivity of cytokine detection systems, and associated variations in kinetics of cytokine production and catabolism in in vitro culture systems. As an alternative to cytokine measurement, this study focuses on expression of the transcription factor GATA-3 for analysis of allergen-specific Th cell responses. METHODS: Cord blood mononuclear cells were Th1- or Th2-polarized by culture in IL-12- or IL-4-employing established methods; PBMC from house dust mite (HDM)-sensitive atopics and controls were stimulated overnight with HDM; cytokine production was measured by ELISA and GATA-3 mRNA expression by PCR. RESULTS: Cytokine-driven Th2 polarization of naive T cells is associated with marked upregulation of GATA-3 expression, whereas a reciprocal expression pattern accompanies differentiation towards the Th1 cytokine phenotype. In T cells from HDM skin prick test-positive (HDM-SPT+/HDM-IgE+) volunteers, overnight stimulation results in marked upregulation of GATA-3 expression, compared to an equally marked downregulation of expression in T cells from SPT-/IgE- subjects. In subjects who are HDM-SPT+ but IgE-, GATA-3 expression levels remained relatively stable during culture with HDM. CONCLUSIONS: Upregulation of GATA-3 expression in PBMC is a hallmark of the early phase of Th2 recall responses to specific allergen in atopics. The reciprocal expression pattern observed in HDM-specific recall responses of non-atopics provides independent confirmation of the presence of underlying Th1-like immunity in these subjects. The parallel findings in neonatal T cells suggest that the same approach may be utilized for monitoring the progress of allergen-specific Th1/Th2 memory development during early childhood, and hence in assessment of risk for future allergic disease.
Allergens↗