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M Kanariou

Publications and source records attributed to M Kanariou.

14 recordsLinked to original sources
PubMed2001

Mutation in the class II trans-activator leading to a mild immunodeficiency.

The expression of MHC class II molecules is essential for all Ag-dependent immune functions and is regulated at the transcriptional level. Four trans-acting proteins control the coordinate expression of MHC class II molecules: class II trans-activator (CIITA), regulatory factor binding to the X box (RFX)-associated protein; RFX protein containing ankyrin repeats, and RFX5. In humans, defects in these genes result in MHC class II expression deficiency and cause combined immunodeficiency. Most patients with this deficiency suffer from severe recurrent infections that frequently lead to death during early childhood. We investigated three sisters, now ages 21, 22, and 24 years, in whom MHC-II deficiency was detected. Even though the eldest sibling was asymptomatic and the other two had only mild immunodeficiency, none of the three class II isotypes was expressed on T cell blasts, fibroblasts, EBV B cell lines, or epidermal dendritic cells. Residual HLA-II expression was detected in fresh PBMC. Somatic complementation identified the disease as CIITA deficiency. A homozygous T1524C (L469P) substitution was found in the coding region of the CIITA cDNA and was shown to be responsible for the defect in MHC-II expression. This missense mutation prevents the normal functioning of MHC-II but does not lead to the nuclear exclusion of the L469P CIITA. Transfection experiments demonstrated that the CIITA L469P mutant had residual MHC class II trans activation activity, which might explain the unusual clinical course of the patients studied. This study shows that an attenuated clinical phenotype or an asymptomatic clinical course can be observed in patients despite a profound defect in the expression of MHC class II genes. The frequency of the inherited MHC class II deficiency might thus be underestimated.

Adolescent↗
PubMed2001

Analysis of Btk mutations in patients with X-linked agammaglobulinaemia (XLA) and determination of carrier status in normal female relatives: a nationwide study of Btk deficiency in Greece.

Bruton's tyrosine kinase (Btk) is a nonreceptor tyrosine kinase, critical for B-cell development and function. Mutations that inactivate this kinase were found in families with X-linked agammaglobulinaemia (XLA). In this study the Btk gene was analyzed in 13 registered Greek patients with XLA phenotype originated from 12 unrelated families, in order to provide a definite diagnosis of the XLA. The structure of Btk was analyzed at the cDNA level using the recently developed method, NIRCA (Non-Isotopic-Rnase-Cleavage-Assay). Alterations were detected in all patients and sequencing analysis confirmed the results and defined six novel XLA-associated Btk mutations (three missense mutations: C337G, L346R, L452P; one nonsense mutation: Y392X, and two frameshift alterations: c1211-1212delA, c1306-1307insA). Having defined the genetic alteration in the affected males of these families, the information was used to design polymerase chain reaction (PCR) primers and the Btk segments containing the mutated sequences were amplified from peripheral blood derived genomic DNA of potential female carriers. The PCR products were directly sequenced and carrier status was determined in 12 out of 16 phenotypically normal females analyzed. This protocol can be used once the nature of the Btk mutation has been defined in one of the affected males and provides a convenient, simple and reliable way to determine the carrier status of other female family members. Molecular genetic analysis constitutes a determinative tool for the definitive diagnosis of XLA and may allow accurate carrier and prenatal diagnosis for genetic counselling.

Adolescent↗
PubMed2001

Lymphocyte alterations after prolonged sunlight exposure.

BACKGROUND: It has been suggested that prolonged exposure to sunlight may induce systemic or local immune alterations, which may facilitate the development of skin cancer and, perhaps, non-Hodgkin's lymphona. The effects of prolonged sunlight exposure on peripheral blood cells were studied. METHODS: Leukocytes and lymphocyte subpopulations of 12 volunteers aged 10-45 were investigated before and after a 3-week summer holiday in seaside resorts in Greece. Lymphocyte phenotypes were estimated using monoclonal antibodies and flow cytometry. RESULTS: There were no significant differences with respect to total numbers of T cells, T-helper/inducer, T-suppressor/cytotoxic, B cells or HLA-Dr+ cells. However, we have found evidence of lymphocyte stimulation, reflected in an increase in cells expressing the interleukin-2 receptor (IL-2R) and, more specifically, an increase in the T cells expressing IL-2R and HLA-Dr antigens. An increase in natural killer cells has also been noticed. CONCLUSIONS: These findings suggest that prolonged intense exposure to sunlight may be associated with immunostimulation, rather than immunosuppression.

Adolescent↗
PubMed1999

Insulin dependent diabetes mellitus (IDDM) and autoimmune thyroiditis in a boy with a ring chromosome 18: additional evidence of autoimmunity or IDDM gene(s) on chromosome 18.

A 4 year 3 month old boy with insulin dependent diabetes mellitus (IDDM), autoimmune thyroiditis, slight mental retardation, facial dysmorphism, and a de novo ring chromosome 18 (deletion 18q22.3-18qter) is described. This unique association of defects could represent a chance association. Alternatively, the clinical features could be the result of the chromosomal aberration. If so, one could speculate that a gene or genes on chromosome 18 might act as a suppressor or activator of the autoimmune process by itself or in concert with other IDDM loci.

Blood Chemical Analysis↗
PubMed1998

Absence of Bruton's tyrosine kinase (Btk) mutations in patients with acute myeloid leukaemia.

Bruton's tyrosine kinase (Btk) is a non-receptor protein tyrosine kinase (PTK) that is expressed in all haemopoietic lineages except mature T cells and plasma cells. Despite the broad range of expression. mutations that inactivate this molecule affect primarily the development of the B-cell lineage. As a PTK, Btk could potentially be involved directly or indirectly in the processes that relate to the malignant transformation of all the cell lineages where this molecule is expressed. Previous studies have failed to demonstrate mutations in patients with B-cell origin acute lymphoblastic leukaemia (ALL). We have utilized a recently developed method that enables the rapid and convenient detection of mutations at the cDNA level, namely, the non-isotopic RNase cleavage assay (NIRCA) to analyse Btk sequences from 27 patients with different types of acute myeloid leukaemia (AML). The only alteration that we observed was a polymorphism at position 2031. This polymorphism has already been seen in previous studies. Furthermore, using the same methodology, we identified the Btk mutations in six XLA (X-linked agammaglobulinaemia) patients. Our results, although they do not exclude the involvement of Btk mutations in the development or progression of some type of AML, nevertheless suggest that such mutations do not constitute a major co-factor in the development of myeloid malignancies.

Acute Disease↗
PubMed1997

Serum immunoglobulin G subclasses in healthy infants and children in Greece.

Serum concentrations of immunoglobulin IgG1, IgG2, IgG3 and IgG4 were determined by radial immunodiffusion in a sample of 414 healthy Greek children, who were admitted to the major Teaching Hospital for Children in Athens for minor surgical operations. Statistical analysis was performed by multiple regression after logarithmic transformation of the immunoglobulin values. There was a statistically significant increase of IgG3 with age, whereas IgG1, IgG2 and IgG4 levels reached a turning point at the age of five years. Older than 5 years male children were found to have marginally higher IgG4 levels than females. Low socioeconomic class was positively and significantly associated (9% increase) with IgG1 levels only among the older age group. History of frequent infections was associated with a 16% increase of IgG1 levels in the younger (less than 5 years) (p = 0.01) and with a 47% increase of IgG4 among the older age group (p = 0.03). Atopic history was associated with a 16% increase of IgG1 in the younger (p = 0.02). The findings of the present study provide an insight on the determinants and the clinical significance of IgG subclass levels among children.

Adolescent↗
PubMed1996

Exon-scanning mutation analysis of the ATM gene in patients with ataxia-telangiectasia.

Using a polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) assay, which amplifies individually all coding exons of the ATM gene deficient ataxia-telangiectasia (A-T), we have analyzed 10 patients with A-T for ATM mutations. Mutation were detected in 9 patients. We describe the first ATM mutation in the splice junction found in the 5' splice site of intron 17, leading to exon skipping. However, most mutations were small deletions or insertions resulting in premature termination of the translation product. The development of DNA-based methods for detection of unknown mutations and further characterization of ATM mutation pattern will facilitate identification of A-T carriers and assessment of their cancer risk.

Ataxia Telangiectasia↗
PubMed1995

Factors influencing serum immunoglobulin E levels in Greek children.

Serum levels of immunoglobulin E (IgE) were determined by enzyme immunoassay in 414 Greek infants and children of both sexes, 1 month to 14 years old. The children were admitted to the "Aghia Sophia" Teaching Hospital for Children (Athens, Greece) for surgical corrections of minor anatomic abnormalities, but they were otherwise healthy. Statistical analysis was performed through multiple regression after logarithmic transformation of the immunoglobulin values. IgE levels increased significantly by about 80% per year up to the age of 5 years, without noticeable impact of age on these levels thereafter. History of allergic disease showed a significant positive association with serum levels of IgE in both younger (less than 5 years) and older children. History of frequent infections was positively associated with IgE levels, although the relation was statistically significant only in the older age group, IgE levels in Greek children appear to be higher than the corresponding levels of children living in northern Europe, but much lower than those of children in Southeast Asia, a fact that may reflect different exposure level during childhood to infections known to influence IgE levels.

Adolescent↗
PubMed1995

Age patterns of immunoglobulins G, A & M in healthy children and the influence of breast feeding and vaccination status.

Serum levels of immunoglobulins G, A and M were determined by nephelometry in 414 infants and children aged 1 month to 14 years. The children were admitted to "Aghia Sophia" Teaching Hospital for Children for surgical corrections of minor anatomical abnormalities, but they were otherwise healthy. Statistical analysis was performed through multiple regression after logarithmic transformation of the immunoglobulin values. Immunoglobulin G (IgG) levels increased significantly by 18% per year until the age of 5 years and by 2% per year thereafter. Among children less than 5 years old, IgG levels tended to increase significantly with the number of doses of either DTP or Sabin vaccine. Immunoglobulin A (IgA) levels increased significantly by 27% until the age of 7 years and by 4% thereafter. Among children less than 7 years old, history of breast feeding was significantly associated with higher levels of IgA. Vaccination with either DTP or Sabin was associated with elevation of IgA levels among younger and, to a lesser extent, older children, but the elevations did not reach statistical significance. Immunoglobulin M (IgM) levels increased rapidly during the first 12 months of life and very slowly thereafter and they were significantly higher among girls. Among children less than one year old, there was evidence that vaccination with either DTP or Sabin was associated with elevated IgM levels, although the differences were not statistically significant possibly because of small numbers of infants in the study sample.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Hypogammaglobulinaemia associated with normal or increased IgM (the hyper IgM syndrome): a case series review.

The clinical and immunological aspects of 16 children with the syndrome of hypogammaglobulinaemia associated with normal or increased IgM (the hyper IgM syndrome) and their responses to treatment are reviewed. Increased concentrations of IgM, neutropenia, and recurrent infections could usually be controlled by antimicrobial and intravenous immunoglobulin treatment. Together with the bacterial infections characteristic of hypogammaglobulinaemia, these patients often developed opportunistic infections, including Pneumocystis carinii pneumonia, often presenting in the first year of life. The occurrence of sclerosing cholangitis, neurological complications, and neutropenia may be a result of an underlying cell mediated immune deficiency, autoimmunity, or infection. Despite a high incidence of opportunistic infections, immunological investigations did not show any abnormality of T cell function. These findings are discussed in the light of the recent demonstration that the lack of expression of a T lymphocyte activation antigen is the molecular basis of the X linked form of the disorder.

Agammaglobulinemia↗
PubMed1989

Immunosuppression by immunoglobulin deaggregation is not effective in reducing the anti-xenogeneic immunoglobulin response: experimental and clinical studies.

A major complication of in vivo monoclonal antibody therapy in patients with cancer is the host's immune response to the administered xenogeneic immunoglobulin. We have performed parallel clinical and experimental studies to investigate the possibility that deaggregation of the therapeutic monoclonal antibody might render it non-immunogenic, or even tolerogenic, as has been suggested in several animal studies. Deaggregation of xenogeneic immunoglobulin has been shown by others to induce non-responsiveness in some ('susceptible') but not in other ('resistant') strains of mice. We have used an improved deaggregation method of size exclusion chromatography connected to FPLC and have developed a sensitive ELISA detection system to determine whether highly purified human immunoglobulin G (hIgG) monomers could be tolerogenic even to 'resistant' mice. However, our data show that all preparations of hIgG are immunogenic to 'resistant' mice, and that although deaggregation does significantly reduce the anti-hIgG response to 'susceptible' strains, tolerance is not induced. Concomitant administration of cyclosporin A and deaggregated hIgG had a additive effect in reducing the murine anti-hIgG secondary response. In clinical studies of patients with ovarian cancer who received in vivo immunotherapy with either iodine-131 (not aggregated) or yttrium-90 (aggregated) HMFG1 mouse monoclonal antibody, no significant difference was found between the immune responses to aggregated and non-aggregated murine immunoglobulin G. Our data suggest that deaggregation alone is unlikely to be useful in controlling the human anti-murine immunoglobulin G response in our outbred patient population, although in combination with an immunosuppressant it may be more effective.

Animals↗
PubMed1989

Immunosuppression with cyclosporin A alters the thymic microenvironment.

The effect of cyclosporin A (CyA) immunosuppression on the murine thymic microenvironment and T lymphocyte development has been analysed using monoclonal antibodies to epithelial and lymphocyte subpopulations, macrophages and major histocompatibility complex (MHC) class II antigens in immunohistochemistry and flow cytometry. The major microenvironmental target for CyA-induced damage was the thymic medulla, where a reduction in all epithelial cell subsets, dendritic cells and macrophages was observed. In contrast, the thymic cortex appeared essentially normal. CyA had no detectable effect on the intensity of microenvironmental expression of MHC class II molecules in either cortex or medulla, although the number of MHC class II positive medullary cells was reduced after CyA treatment. CyA also had a differential effect on the thymic lymphocyte populations where there was little change in the Thy-1 bright, CD5 dull, CD4+, CD8+ cortical thymocytes but a depletion of the Thy-1 dull, CD5 bright, CD4 or CD8 single-positive medullary cells. This lymphocyte loss may be due partly to increased migration from thymus to spleen and other peripheral lymphoid organs, and partly to a block in the differentiation stage from cortical to medullary lymphocyte. The thymic microenvironment and lymphocyte subpopulations recover rapidly after cessation of CyA treatment, although there may be longer term functional defects resulting from the CyA-induced injury.

Animals↗
PubMedDate not supplied

Detection of 22q11.2 deletion among 139 patients with Di George/Velocardiofacial syndrome features.

Cytogenetic and FISH analysis was performed in 139 patients to detect the pathognomonic of Di George/ Velocardiofacial syndrome (DGS/VFCS) deletion 22q11.2. An abnormal karyotype was revealed in 2/139 cases (47, XXY and 46, XX, 2p+). A deletion was found in 17/139 (12.2%) patients (14 males/ 3 females), inherited in 3 (2 maternal and 1 paternal). Patients with 22q11.2 deletion exhibited facial dysmorphic features (82%), congenital heart defects (70%), immunological problems (47%), multiple congenital anomalies (64%), hypocalcemia (47%), mental retardation/learning difficulties (35%), cleft palate/velopharyngeal insufficiency (23.5%), seizures/hypotonia (23%) and growth retardation (12%). Among 56/139 patients with detailed available clinical data, the 22q11.2 deletion was confirmed in all cases with hypocalcemia and in over half of the cases with multiple congenital anomalies, immunological problems and hypotonia/seizures (70%, 60% and 57%, respectively). Genetic reevaluation of 39 patients without the 22q11.2 deletion contributed to the classification of 14 (37%) under different syndromes, emphasizing the need for stricter referral criteria.

Adolescent↗