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Biomedical subjects

A Fischer

Publications and source records attributed to A Fischer.

At least 91 records · Page 5Linked to original sources
PubMed2002

Primary immunodeficiency diseases: natural mutant models for the study of the immune system.

Primary immunodeficiency diseases represent many natural mutant models for the analysis of many aspects of immunology. Examples dealing with T- and B-cell receptors are herein discussed. They also represent privileged models in medicine, because well characterized monogenic inherited diseases can in some instances be viewed as good targets for gene therapy as shown here for severe combined immunodeficiency (SCID).

Animals↗
PubMed2002

Distribution and function of the peptide transporter PEPT2 in normal and cystic fibrosis human lung.

BACKGROUND: Aerosol administration of peptide based drugs has an important role in the treatment of various pulmonary and systemic diseases. The characterisation of pulmonary peptide transport pathways can lead to new strategies in aerosol drug treatment. METHODS: Immunohistochemistry and ex vivo uptake studies were established to assess the distribution and activity of the beta-lactam transporting high affinity proton coupled peptide transporter PEPT2 in normal and cystic fibrosis human airway tissue. RESULTS: PEPT2 immunoreactivity in normal human airways was localised to cells of the tracheal and bronchial epithelium and the endothelium of small vessels. In peripheral lung immunoreactivity was restricted to type II pneumocytes. In sections of cystic fibrosis lung a similar pattern of distribution was obtained with signals localised to endothelial cells, airway epithelium, and type II pneumocytes. Functional ex vivo uptake studies with fresh lung specimens led to an uptake of the fluorophore conjugated dipeptide derivative D-Ala-L-Lys-AMCA into bronchial epithelial cells and type II pneumocytes. This uptake was competitively inhibited by dipeptides and cephalosporins but not ACE inhibitors, indicating a substrate specificity as described for PEPT2. CONCLUSIONS: These findings provide evidence for the expression and function of the peptide transporter PEPT2 in the normal and cystic fibrosis human respiratory tract and suggest that PEPT2 is likely to play a role in the transport of pulmonary peptides and peptidomimetics.

Acetates↗
PubMed2002

Differential expression of IgG Fc binding protein (FcgammaBP) in human normal thyroid tissue, thyroid adenomas and thyroid carcinomas.

The genetic events involved in thyroid carcinogenesis are still incompletely understood. Several rearrangements and mutations of oncogenes have been implicated in the development of thyroid papillary carcinomas, follicular adenomas and carcinomas. However, none of these molecular alterations is suitable either as a general marker for the diagnosis of thyroid carcinomas or to differentiate between thyroid follicular adenomas and carcinomas. In order to identify new genes with altered expression which could serve as such markers, we analyzed RNA from thyroid tumor and normal tissue using a novel technique called restriction-mediated differential display. Several differentially expressed genes were identified, including the gene for IgG Fc binding protein (FcgammaBP). Differential expression of FcgammaBP was confirmed by quantitative real-time RT-PCR. Our experiments showed that IgG Fc binding protein (FcgammaBP) is differentially expressed in normal thyroid tissue, thyroid adenomas and thyroid carcinomas. While the FcgammaBP gene is constitutively expressed in normal thyroid tissue, its expression is significantly increased in follicular thyroid adenomas and significantly decreased in papillary and follicular thyroid carcinomas. Thus, measurement of the expression levels of FcgammaBP in thyroid biopsies might help to make the otherwise difficult distinction between a thyroid follicular adenoma and a follicular carcinoma.

Adenoma↗
PubMed2002

[Hereditary abnormalities in the immune system: physiology and treatment].

There are multiple genetic abnormalities of the immune system. About one hundred syndromes have been so far described. All of them disturb immune defenses against microorganism invasions and/or the homeostasis of the immune system. Thanks to the advances in genomics, genetic and molecular basis of more than 80 of these conditions, have been unravelled. These achievements provide significant insight into the understanding of many steps of the biology of the immune system, i.e., its development, function and regulation. It is also the basis for the design of molecular diagnostic tools and perhaps for new therapeutics of these severe disorders.

Homeostasis↗
PubMed2001

Treatment of childhood autoimmune haemolytic anaemia with rituximab.

Autoimmune haemolytic anaemia commonly has a severe course in young children, thus requiring multiple immunosuppressive treatments. Five children with refractory idiopathic autoimmune haemolytic anaemia, and one child with the disease after bone-marrow transplantation, were treated with rituximab-a monoclonal antibody against CD20. Tolerance of the treatment was good. However, circulating Bcells were absent and hypogammaglobulinaemia was seen for 9 months after treatment. All patients remained in complete remission 15-22 months after the start of rituximab therapy. Corticosteroids and immunosuppressive drugs were stopped or their dose markedly reduced. We suggest that rituximab could be a valuable treatment for autoimmune haemolytic anaemia, although a long-lasting but transient B-cell deficiency develops.

Anemia, Hemolytic, Autoimmune↗
PubMed2001

The Arabidopsis thaliana genome contains at least 29 active genes encoding SET domain proteins that can be assigned to four evolutionarily conserved classes.

SET domains are conserved amino acid motifs present in chromosomal proteins that function in epigenetic control of gene expression. These proteins can be divided into four classes as typified by their Drosophila members E(Z), TRX, ASH1 and SU(VAR)3-9. Homologs of all four classes have been identified in yeast and mammals, but not in plants. A BLASTP screening of the Arabidopsis genome identified 37 genes: three E(z) homologs, five trx homologs, four ash1 homologs and 15 genes similar to Su(var)3-9. Seven genes were assigned as trx-related and three as ash1-related. Only four genes have been described previously. Our classification is based on the characteristics of the SET domains, cysteine-rich regions and additional conserved domains, including a novel YGD domain. RT-PCR analysis, cDNA cloning and matching ESTs show that at least 29 of the genes are active in diverse tissues. The high number of SET domain genes, possibly involved in epigenetic control of gene activity during plant development, can partly be explained by extensive genome duplication in Arabidopsis. Additionally, the lack of introns in the coding region of eight SU(VAR)3-9 class genes indicates evolution of new genes by retrotransposition. The identification of putative nuclear localization signals and AT-hooks in many of the proteins supports an anticipated nuclear localization, which was demonstrated for selected proteins.

Active Transport, Cell Nucleus↗
PubMed2001

[Prevention and therapy of diabetic foot syndrome. Preventing complications].

Selective prevention and stage-orientated treatment of the diabetic foot syndrome helps to avoid late complications. A prerequisite is good blood sugar control, early use of ACE inhibitors, CSE inhibitors and--based on the vascular situation, with consideration given to indications--platelet aggregation inhibitors. Regular inspection of the feet must be taken seriously. Every diabetic should be taught the rules of behavior in young years. The primary physician is responsible for coordinating further treatment and early referral to specialized foot clinics. In the event of an infection, specific treatment of the usually polymicrobial infection should be initiated. Long-term antibiotic treatment is not to be recommended. Wherever necessary, the calculated antibiotic therapy must be corrected on the basis of the results of antibiotic sensitivity testing of swabs taken from deep tissue (better: exudate from the floor of the wound. In the case of superinfected ulcers, wound debridement by the specialist surgeon is considered a must. Also, late stages of diabetic foot can be successfully managed in specialized centers by "foot-relieving" measures, revascularization, arthrodesis, etc.

Aged↗
PubMed2001

Somatic hypermutation shapes the antibody repertoire of memory B cells in humans.

High-affinity antibodies produced by memory B cells differ from antibodies produced in naive B cells in two respects. First, many of these antibodies show somatic hypermutation, and second, the repertoire of antibodies expressed in memory responses is highly selected. To determine whether somatic hypermutation is responsible for the shift in the antibody repertoire during affinity maturation, we analyzed the immunoglobulin lambda light chain (Iglambda) repertoire expressed by naive and antigen-selected memory B cells in humans. We found that the Iglambda repertoire differs between naive and memory B cells and that this shift in the repertoire does not occur in the absence of somatic hypermutation in patients lacking activation-induced cytidine deaminase (AID). Our work suggests that somatic hypermutation makes a significant contribution to shaping the antigen-selected antibody repertoire in humans.

APOBEC-1 Deaminase↗
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

Effect of selenium and vitamin E deficiency on differential gene expression in rat liver.

To examine the molecular events associated with selenium (Se) and vitamin E (VE) deficiency, we applied cDNA array technology to define the transcriptional response in the liver of Se- and VE-deficient rats. VE deficiency alone did not induce any significant changes in expression profile among the genes evaluated. Se deficiency lead to a down-regulation of Se-dependent cGPx and to an induction of genes, encoding for detoxifying enzymes in liver (cytochrome P450 4B1, UDP-glucuronosyltransferase 1). Combined VE and Se deficiency was characterized by alterations in the expression level of genes encoding for proteins involved in inflammation (multispecific organic anion exporter, SPI-3 serine protease inhibitor) and acute phase response (alpha-1 acid glycoprotein, metallothionein 1). Additionally, a significant down-regulation in the expression level of genes important in the inhibition of apoptosis (defender against cell death 1 protein, Bcl2-L1), cell cycle (G1/S-specific cyclin D1) and antioxidant defense (gamma-glutamylcysteine synthetase catalytic subunit) was demonstrated. The experimental strategy identified several novel Se and VE sensitive genes.

Animals↗
PubMed2001

Interleukin-12 receptor beta1 deficiency in a patient with abdominal tuberculosis.

Two siblings with interleukin-12 receptor beta1 (IL-12Rbeta1) deficiency but different clinical phenotypes were studied. Both are homozygous for an IL12RB1 missense mutation that prevents receptor expression and abolishes cellular responses to IL-12. Transfection of the patients' T cells with wild-type IL12RB1 restored IL-12Rbeta1 expression and function. One patient had the expected phenotype of disseminated bacille Calmette-Guérin (BCG) infection in early childhood, whereas the other did not develop BCG infection, despite 3 inoculations with live BCG. Abdominal tuberculosis was diagnosed in this second patient at age 18 years. To date, neither of them has had clinical disease caused by environmental mycobacteria. These observations show unexpected interfamilial and intrafamilial heterogeneity of the clinical phenotype associated with IL-12Rbeta1 deficiency. The patients may be resistant to BCG but remain vulnerable to Mycobacterium tuberculosis. A diagnosis of IL-12Rbeta1 deficiency should therefore be considered in selected patients with severe tuberculosis, despite their resistance to BCG and a lack of atypical mycobacteriosis.

Abdomen↗
PubMed2001

Primary immunodeficiency diseases: an experimental model for molecular medicine.

Primary immunodeficiency diseases represent a vast array of inherited disorders of the immune system. Major advances in the understanding of genetic basis and molecular mechanisms have occurred within the past 10 years, as a result of the tools of modern genetics. About three quarters of 100 primary immunodeficiency diseases can now be reliably diagnosed with molecular probes. In many cases, gene identification has enabled significant insight into the physiopathology of the related conditions. Therapeutic progress based on protein engineering and possibly gene therapy will also ensue.

Genetic Therapy↗