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Biomedical subjects

B J Zegers

Publications and source records attributed to B J Zegers.

At least 19 recordsLinked to original sources
PubMed2001

Serum IgG subclasses levels in paediatric patients with pneumonia.

OBJECTIVES: To determine the IgG subclass levels of patients admitted to Harare Central Hospital paediatric wards with pneumonia. DESIGN: A cross sectional study. SETTING: Harare Central Hospital, Departments of Immunology and Paediatrics, University of Zimbabwe; Department of Paediatric Immunology, University of Utrecht, The Netherlands. SUBJECTS: 56 paediatric patients. MAIN OUTCOME MEASURES: IgG subclass profiles of children with pneumonia. RESULTS: Of the 56 children tested, 40 (71%) had antibodies to human immunodeficiency virus (HIV). The levels of IgG1 and IgG3 subclasses were significantly higher in HIV antibody positive children (p < 0.001, p < 0.01 respectively) than in those without detectable HIV antibodies in their sera. There was no significant relationship between IgG subclass levels and the presence of HIV p24 antigen. Furthermore, age and gender also had no significant influence on the levels of IgG subclasses in this population. CONCLUSION: High levels of IgG1 and IgG3, but not IgG2 and IgG4, occur frequently in children with pneumonia and are associated with the presence of HIV antibodies.

Child↗
PubMed2000

Identification of six novel WASP gene mutations in patients suffering from Wiskott-Aldrich syndrome.

Mutation in the gene encoding the Wiskott-Aldrich Syndrome protein (WASP) has been identified as the genetic defect responsible for WAS, an X-linked primary immunodeficiency disease characterized by eczema, thrombocytopenia, and recurrent infections. In this study, the WASP gene of 7 unrelated patients with classical WAS of Dutch descent was examined by single-strand conformation polymorphism and sequence analysis. We have identified 6 novel mutations that involve nonsense mutations (196C-->A, 344C-->T), or small deletions (553delG, 768del19, IVS8+1delGTGA, 911delT), all of which result in predicted truncation of WASP protein synthesis.

Alternative Splicing↗
PubMed1999

Impaired IgG antibody production to pneumococcal polysaccharides in patients with ataxia-telangiectasia.

Various factors seem to be etiologic in the susceptibility to sinopulmonary infections in ataxia-telangiectasia (A-T) patients, i.e., low serum and salivary IgA, low serum IgG2, and even aspiration of saliva. S. pneumoniae is a common pathogen responsible from pulmonary infections and impaired antibody response to polysaccharide antigens is seen in patients with IgG2 and IgA deficiency as well as patients with CVID and WAS. We studied IgG-type antibody production to six pneumococcal serotypes in 29 A-T patients by ELISA before and 3-4 weeks after pneumococcal vaccine. The response was considered positive when the antibody titer was >10 U/ml but weak when the titer was 10-20 U/ml. Twenty-two of 29 (76%) patients did not respond to any of the serotypes, 5 (17%) showed a positive response to one serotype, 1 (3.4%) to two serotypes, and 1 (3.4%) to four serotypes. With conversion to gravimetric units (ng IgG/ml) and >1800 ng/ml (300 ng Ab N/ml) considered a positive response, 5 of 29 (17.2%) patients showed a positive response (300 ng ab N/ml) to two or fewer serotypes. All patients tested produced IgG antibody to tetanus toxoid. Sixteen of 27 (59.3%) patients had low IgG2 and four (14.8%) had low IgG3 levels, while 18 (62.1%) of 29 patients had low serum IgA. No correlation was found either between serum Ig isotype levels and antipolysaccharide antibody response or between susceptibility to infection and antibody production. The mechanism responsible for disturbed antipolysaccharide (TI-2 antigen) antibody production in patients with A-T needs to be investigated. It may provide additional information on the function of the ATM gene product and be helpful in clarifying the role of B cells and contribution of T cells in TI-2 responses.

Adolescent↗
PubMed1999

Pneumococcal conjugate vaccine primes for polysaccharide-inducible IgG2 antibody response in children with recurrent otitis media acuta.

Children with frequent recurrent episodes of otitis media may have a deficient IgG2 antibody response to polysaccharide antigens. Five otitis-prone children were vaccinated with heptavalent pneumococcal conjugate vaccine. While all had an IgG1 antibody response to all pneumococcal serotypes included in the conjugate vaccine, the IgG2 response, especially to serotypes 6B, 9V, 19F, and 23F, was poor. However, vaccination with a 23-valent polysaccharide vaccine 6 months after conjugate vaccination induced an 11.5- to 163-fold increase in IgG2 anti-polysaccharide antibody titers. Thus, an IgG2 polysaccharide antibody deficiency can be overcome by priming with a pneumococcal conjugate vaccine followed by a booster with a polyvalent polysaccharide vaccine.

Antibodies, Bacterial↗
PubMed1999

Regulatory T cells in the antibody response to Haemophilus influenzae type b polysaccharide.

An in vitro culture system for the induction of an antipolysaccharide response was used to study the cellular interactions which determine the magnitude and nature of this B-lymphocyte response. Healthy adult volunteers were vaccinated with the Haemophilus influenzae type b polysaccharide (PRP)-tetanus toxoid (TT) conjugate vaccine. Optimal in vitro anti-PRP and anti-TT antibody responses were obtained when B cells were cultured with equal amounts of T cells. The in vitro response is antigen dependent and antigen specific. Culturing with PRP mixed with TT in the presence of T cells induces the highest number of anti-PRP antibody-secreting cells (ASC) (128.4 x// 15.9 [geometric mean x// standard deviation] immunoglobulin M [IgM] anti-PRP ASC/10(6) cells; 9.3 x// 7.6 IgG anti-PRP ASC/10(6) cells). Culturing without T cells induced no anti-PRP ASC; culturing with only PRP, in the presence of T cells, yielded low numbers of anti-PRP ASC (3.7 x// 5.2 IgM anti-PRP ASC/10(6) cells and 1.2 x// 2.2 IgG anti-PRP ASC/10(6) cells). Transwell studies showed that the requirements for the antibody response against the polysaccharide are different from those of an antiprotein response. Cytokines formed as a consequence of contact between protein-specific B and T cells were on their own not sufficient to activate TT-specific B cells (8.4 x// 1.4 anti-TT ASC/10(6) cells); direct contact between T and B cells appeared to be an absolute requirement. However, physical contact between B and T cells in one compartment of the Transwell system resulted in the release of soluble factors able to stimulate B cells in the other compartment to secrete antipolysaccharide antibodies (164 x// 1.6 anti-PRP ASC/10(6) cells).

Adult↗
PubMed1999

Serum immunoglobulin levels in paediatric patients with pneumonia.

OBJECTIVE: To determine levels of serum immunoglobulins IgG, IgM and IgA in patients admitted with pneumonia to Harare Central Hospital paediatric wards. DESIGN: A cross sectional pilot study. SETTING: Harare Central Hospital, Department of Immunology, University of Zimbabwe; Department of Paediatrics, University of Zimbabwe; Immunology Laboratory, University of Utrecht (The Netherlands). SUBJECTS: 71 paediatric patients. MAIN OUTCOME MEASURES: Immunoglobulin profiles for children with pneumonia. RESULTS: Of the 71 children tested, 43 had high IgG levels of between two and half and five times the upper end of the normal age-matched reference range. While the same 43 children with high IgG had similarly elevated levels of IgM, only 25 of them had elevated IgA levels. Of this group of 43 children with hypergammaglobulinaemia, all but one, had antibodies to human immunodeficiency virus (HIV), 50% of whom had detectable levels of p24 antigen in their sera. A small minority, 4% of the 71 patients, had very low levels of total immunogloblins. CONCLUSIONS: High levels of total immunoglobulins occur frequently in children with pneumonia and are associated with the presence of HIV 1/2 antibodies and also p24 antigen.

Child↗
PubMed1998

[Invasive infection with Haemophilus influenzae type b in spite of complete vaccination].

Five patients, 4 boys and 1 girl aged 13-41 months, developed invasive Haemophilus influenzae type b (Hib) disease (2 epiglottitis, 3 meningitis) despite full (or at least 3 times) vaccination. At admission as well during convalescence, 3 out of 5 had IgG anti Hib antibody levels < or = 5 U/ml. Serum immunoglobulin levels, including IgG subclasses, as well as complement were normal in all cases. In 2 of the 3, booster vaccinations with Hib conjugate vaccine elicited adequate antibody titres. Since the incorporation of the conjugated Hib polysaccharide tetanus toxoid vaccine (HibTT) in the National Vaccination Programme in the Netherlands, the number of invasive infections caused by Hib has dropped significantly. Causes of Hib conjugate vaccine failures are mostly unknown. In about one-third of the cases serum immunoglobulin levels are deficient, most often IgG2 or IgM. Susceptibility to Hib infection is in part also genetically determined. In the follow-up of Hib vaccine failures, anti Hib antibody titres should be determined. Booster vaccinations may be necessary.

Antibodies, Viral↗
PubMed1997

T helper 2 cytokines induce preproenkephalin mRNA expression and proenkephalin A in human peripheral blood mononuclear cells.

We investigated the regulatory influence of several cytokines on the expression of preproenkephalin (PPE) mRNA in human peripheral blood mononuclear cells (PBMC). By use of a quantitative reverse-transcriptase-polymerase chain reaction (RT-PCR), we demonstrate that the T helper 2 cytokines IL-4 and IL-10 are more potent in upregulating PPE mRNA expression in human PBMC than the T helper 1 cytokines IL-2 and gamma-IFN. In addition, TGF-beta is also an effective inducer of PPE mRNA. TGF-beta, IL-4 and IL-10 increase the cytoplasmatic concentration of met-enkephalin in PBMC. Secretion of met-enkephalin in the culture supernatant of IL-4- or IL-10-stimulated PBMC could not be observed, but proenkephalin A-derived met-enkephalin containing peptides could be demonstrated. IL-4 and IL-10 do not induce PPE mRNA via the same pathways. We could observe that PKA is involved in IL-4 mediated PPE mRNA induction, whereas IL-10 apparently uses another route.

Cells, Cultured↗
PubMed1997

T cell subsets and T cell function in cartilage-hair hypoplasia.

Cartilage hair hypoplasia is a rare autosomal recessive form of short-limbed dwarfism associated with a cellular immunodeficiency. In eight patients, the authors studied the presence of T cell subsets and in vitro T cell function in order to address the basis for the immunological disorder. Both the proliferative response to phytohaemagglutinin (PHA) and the PHA-induced IL2 production were 60% lower compared with controls (P = 0.007 and 0.005, respectively). The impaired proliferative response could not be restored by addition of IL-2. This result is in accordance with a decrease in the percentage of activated T cells expressing the p55 subunit of the IL-2 receptor complex (CD25). The results define more precisely that T cells from cartilage hair hypoplasia patients are defective in the transition from the G0 to the G1 phase of the cell cycle. Furthermore, the data demonstrate that several CHH patients show a reduced proportion of CD45RA+ 'naive' T cells. However, the in vitro impairment of T cell function cannot solely be explained by imbalance between 'naive' and 'memory' T cells. Although CHH patients with a history of recurrent respiratory tract infections showed the most aberrant in vitro immune parameters, a clear relationship between clinical data and in vitro parameters could not be established for the whole patient group.

Adult↗
PubMed1997

Identification of novel Bruton's tyrosine kinase mutations in 10 unrelated subjects with X linked agammaglobulinaemia.

Mutations of the Bruton's tyrosine kinase (Btk) gene cause X linked agammaglobulinaemia (XLA). This inherited immunodeficiency disease causes an arrest in B cell differentiation of pre-B cells to mature B cells. In this study we report the characterisation of mutations in the Btk gene in 10 unrelated XLA families. The screening approach we used was based on reverse transcriptase PCR and direct cycle sequencing of the amplified products followed by analysis of the observed mutations at the level of genomic DNA. The single strand confirmation polymorphism (SSCP) technique was used for assessment of the carriers in some of these families. Various mutations throughout the coding gene were observed, including missense and nonsense mutations, a deletion, and several splicing defects. None of the mutations except one has been previously described. There were three point mutations resulting in a single amino acid substitution. One of these missense mutations was observed in a conserved region of the PH domain, the other two were found in the src homology domain 2 that is involved in phosphotyrosyl peptide binding. Two mutations were single base pair substitutions resulting in premature stop codons. In four patients abnormal Btk transcripts were found that were the result of aberrant splicing. One small deletion was observed causing a frameshift and a secondary premature termination signal. Characterisation of the mutations responsible for XLA allowed us to diagnose the disease conclusively and identify the phenotypically normal female carriers.

Adolescent↗
PubMed1997

T and B cell development in pituitary deficient insulin-like growth factor-II transgenic dwarf mice.

Treatment of mice with IGF-I stimulates T and B cell development. We showed that overexpression of IGF-II in transgenic FVB/N mice only stimulated T cell development. In the present study, we further addressed the in vivo effects of IGF-II in the absence of IGF-I to get more insight into the potential abilities of IGF-II to influence T and B cell development. To this end, we studied lymphocyte development in IGF-II transgenic Snell dwarf mice that are prolactin, GH and thyroid-stimulating hormone deficient and as a consequence show low serum IGF-I levels. We showed that T cell development was stimulated to the same extent as in IGF-II transgenic FVB/N mice. Furthermore, IGF-II increased the number of nucleated bone marrow cells and the number of immature B cells without having an effect on the number of mature B cells in spleen and bone marrow. Our data show that IGF-II has preferential effects on T cell development compared with B development, and that these preferential effects also occur in the absence of measurable IGF-I levels.

Animals↗
PubMed1996

Human T cell repertoire generation in the absence of MHC class II expression results in a circulating CD4+CD8- population with altered physicochemical properties of complementarity-determining region 3.

In this study, we have investigated the impact of deficient MHC class II expression on the use of TCRBV6 and TCRBJ gene elements, and on the pattern of amino acid incorporation exhibited in the N1-D-N2 segments of the third complementarity-determining region (CDR3) of these TCRBV6 rearrangements. To this end, we have analyzed circulating T cells from three, nonrelated MHC class II-deficient (bare lymphocyte syndrome (BLS)) patients and three MHC class II-expressing family members. The patients and healthy controls exhibited similar, nonrandom usage profiles of TCRBV6 and TCRBJ gene elements in both the CD4+CD8- and the CD4-CD8+ subsets of peripheral blood T cells. No statistically significant differences between patients and controls were detected in the length of CDR3, or in the amount of non-germline modification at the sites of recombination. However, detailed analysis of the TCRBV6 rearrangements derived from the CD4+CD8- subsets from the BLS patients revealed patterns of amino acid incorporation into the N1-D-N2 region of CDR3 that resulted in altered charge and hydropathicity properties of the presumed Ag binding site. In this way, we have been able to demonstrate that human T cell repertoire development in the absence of MHC class II expression results in a circulating CD4+CD8- T cell population bearing TCRs with altered CDR3 profiles. Such altered profiles are likely to be a direct reflection of the lack of MHC class II-mediated selection processes in these BLS patients.

Amino Acid Sequence↗
PubMed1996

Autoreactivity to human heat-shock protein 60 predicts disease remission in oligoarticular juvenile rheumatoid arthritis.

OBJECTIVE: To determine whether T lymphocyte reactivity to endogenous human hsp60 plays a regulatory role in the course of oligoarticular juvenile rheumatoid arthritis (JRA). METHODS: A prospective, longitudinal study of T cell reactivity to HSP in 15 patients with newly diagnosed HLA-B27 negative oligoarticular JRA was performed. Results were compared with those in a group of 20 patients with newly diagnosed polyarticular or systemic JRA or with acute arthritis caused by other systemic diseases or viral infections, as well as with those in a group of 9 healthy control subjects. RESULTS: In 86% of the patients with oligoarticular JRA (13 of 15), significant T lymphocyte proliferative responses to hsp60 were found in peripheral blood mononuclear cells and/or synovial fluid mononuclear cells within 3 months after the onset of arthritis. Only 5% of the patients in the rheumatologic disease control group (1 of 20) showed such positivity. All patients with oligoarticular JRA and positive responses to human hsp60 developed a remission of their disease within 12 weeks. During this period of remission, blood samples were taken from 8 patients and showed significantly lower and even negative responses to hsp60, compared with active disease, when all 8 patients had good responses. CONCLUSION: The results show that significant proliferative responses to human hsp60 can be found early in the course of oligoarticular JRA. Furthermore, these responses correlate with disease activity in such a manner that T cell reactivity to human hsp60 seems to be associated with disease remission.

Adolescent↗
PubMed1996

Ontogency of the responses of human peripheral blood T cells to glucocorticoids.

The inhibitory effect of steroids such as dexamethasone on the immune response of adults has been widely documented. Little is known, however, about the effect of these agents on the developing immune system in newborns. The present study describes the ontogeny of the sensitivity of peripheral blood T cells to dexamethasone during the first year of life. Cord blood T cells of preterm or term infants appear to be extremely sensitive to inhibition of the proliferative response. This high sensitivity of cells to dexamethasone can still be observed in the first 2 weeks after birth. Subsequently, the sensitivity to dexamethasone inhibition of T-cell proliferation gradually decreases. At 1 year of age, the adult response pattern has been acquired.

Adult↗
PubMed1996

IGF-I potentiates interleukin-2 production in human peripheral T cells.

IGF-I stimulates the proliferation and differentiation of many cell types. In the case of T cells, IGF-I has been described to potentiate mitogen-induced DNA synthesis. We have addressed the working mechanism of IGF-I on T cell proliferation by measuring the effects of IGF-I on various stages of T cell activation. We found that IGF-I augmented the phytohaemagglutinin- and anti-CD3-induced interleukin-2 (IL2) production of human peripheral T cells before they enter the S phase of the cell cycle. Furthermore, the addition of IGF-I did not influence DNA synthesis of IL2-dependent growing T cells.

Adult↗