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Biomedical subjects

L Hammarström

Publications and source records attributed to L Hammarström.

At least 127 records · Page 7Linked to original sources
PubMed1995

Genetics of IgA deficiency.

IgA deficiency is the most common humoral defect in man and results in an increased susceptibility to respiratory tract and gastrointestinal infections. Both clinical and genetic data support a close relationship with common variable immunodeficiency, a disease which involves not only IgA and IgG production, but also, in half of the patients, IgM. It is likely that the two disorders represent an allelic condition with a variable expression of a common gene defect which is thought to be involved in the regulation of immunoglobulin class switching. It is possible that a single, autosomally inherited gene with a limited penetrance is responsible for the development of both these defects.

Gene Expression Regulation↗
PubMed1995

Characterization of Haemophilus influenzae isolates from the respiratory tract of patients with primary antibody deficiencies: evidence for persistent colonizations.

A total of 117 consecutive patients with primary antibody deficiencies were followed for up to 5 years with regard to acute respiratory tract infections. Nontypeable Haemophilus influenzae (NTHI) was the sole pathogen in 61% (202/330) of the samples from which a potential pathogen was recovered. Common variable immunodeficiency (CVI) was the most prevalent condition (27/39 patients) in the group where H. influenzae was isolated. In patients where H. influenzae was not found only 9/78 patients had CVI. 49 of these 78 patients had isolated IgG3 or IgA deficiency. Both of these entities seemed to be associated with a lower prevalence of NTHI infections. 13 of 18 patients with at least 2 isolates of NTHI were colonized with the same strain from 3 to 43 months as shown by total genomic DNA-fingerprinting. Recurrent symptomatic infections occurred in these patients despite substitution therapy with gammaglobulins and repeated antibiotic treatments. All but 2 of the 224 H. influenzae isolates were beta-lactamase negative and sensitive to ampicillin. The use of 10 lipopolysaccharide-specific monoclonal antibodies in a whole cell ELISA showed that the LPS-epitopes on the 224 H. influenzae isolates from the hypogammaglobulinemic group were very similar to 499 NTHI isolates from immunocompetent patients with respiratory infections. One may therefore conclude that i) patients with CVI, were prone to be permanently colonized with NTHI, and ii) the colonizing bacteria were ordinary strains showing the same LPS-phenotypes as those strains that cause acute respiratory tract infections in immunocompetent individuals.

Adolescent↗
PubMed1995

C-CAM expression in odontogenesis and tooth eruption.

The distribution of the cell adhesion molecule C-CAM was analyzed during tooth development, eruption and formation of the junctional epithelium in rat molars by immunohistochemistry and in situ hybridization. C-CAM could not be detected during odontogenesis until the late bell stage; then only the mRNA was demonstrated in the odontoblasts and ameloblasts. Prior to eruption, a local increase in C-CAM (mRNA and protein) was observed in the reduced enamel epithelium. During eruption, high C-CAM levels were seen in the fusion zone between the oral epithelium and the reduced enamel epithelium. In the adult rat, C-CAM remained strongly expressed in the junctional epithelium. Our study indicates that C-CAM may play a role in odontogenesis and during formation of the epithelial structures involved in tooth eruption and formation of the junctional epithelium.

Ameloblasts↗
PubMed1995

Coronal dentinal nodules induced by single or multiple injections of HEBP in young rats.

In the developing tooth, the bisphosphonate HEBP causes hypoplasias and hypomineralization of the enamel and dentine as well as inhibition of acellular cementum formation. Here, we describe a novel effect, associated with dentine mineralization. HEBP was administrated to young rats, and the maxillary molars were analyzed histologically. Localized dentinal nodules, protruding towards the pulp, were found in the developing crown of the molars. They occurred in regions, where the mantle dentine was about to mineralize at the time of the injection, and were more frequent at the mesial cusp side. The nodules accumulated mineral, as evidenced by the fluorescence after calcein and tetracyclin labelling. Histologically, the nodules were separated from the enamel by a layer of mantle dentine and were progressively surrounded by predentine and dentine. The nodules were interpreted to contain transport or metabolism intermediates, which were locally accumulated due to the interruption of the mineralization process by HEBP.

Animals↗
PubMed1994

Molecular analysis of IgA deficiency. Evidence for impaired switching to IgA.

The most common form of primary immunodeficiency is IgA deficiency (IgAD). However, the molecular basis of this disease remains elusive. Therefore, to address this issue we made a systematic analysis of the molecular events leading to IgA production. B lymphocytes that produce IgA have undergone somatic rearrangement that joins the switch (S) mu to S alpha region with deletion of the intervening sequences. Examination of the resulting S mu/S alpha junctions in unstimulated PBMC from IgAD patients by nested primer PCR revealed a significant decrease in the number of the S mu/S alpha fragments. To obtain the antisense primers to generate the S mu/S alpha fragments, we sequenced the human S alpha 1 and the downstream region extending to the C alpha 1 locus. Similar to previously reported switch sequences, we also found the S alpha 1 to be predominantly composed of pentameric repeats GAGCT and GGGCT. The decrease in the number of S mu/S alpha fragments is consistent with a profound decrease in the C alpha membrane mRNA expression in unstimulated PBMC, as well as in the C alpha mRNA levels and IgA production in PWM-stimulated PBMC. Sequence analysis of the switch junctions from IgA-producing cell lines, control donors, and an IgAD patient showed direct joining in 8 of 9 cases examined. TGF-beta 1, previously shown to be the switch factor for human and mouse IgA, was also examined. No difference in the TGF-beta 1 mRNA levels in unstimulated PBMC between the control subjects and the IgAD patients were detected. Our findings indicate that the failure to switch to IgA-producing B lymphocytes, or an impaired survival of such cells, may be an important molecular mechanism in IgAD.

Animals↗
PubMed1994

Expression of Bruton's agammaglobulinemia tyrosine kinase gene, BTK, is selectively down-regulated in T lymphocytes and plasma cells.

The gene mutated in the human disease, X-linked agammaglobulinemia (XLA), is related to the Src gene family of cytoplasmic protein-tyrosine kinases and is designated Btk (Bruton's agammaglobulinemia tyrosine kinase; formerly Atk/Bpk; the human gene is denoted BTK, using capital letters according to the kinase nomenclature). We have recently reported that this gene is expressed in B lymphocytes and that the specific mRNA was undetectable in T cells using Northern blotting. Further analyses of different sources of B and T lymphocytes confirmed this pattern. However, BTK transcripts were undetectable in four plasmacytoma lines. Moreover, as virtually normal amounts of BTK transcripts were found in PBMC from two patients carrying a point mutation in BTK, despite low B cell numbers, we anticipated that the gene would also be expressed in cells of other lineages. The erythroleukemia cell line K-562, the promyelocytic line HL-60 and the histiocytic lymphoma line U-937 were found to have BTK mRNA levels comparable to B cells. BTK mRNA was also detected in monocytes from healthy donors as well as in the human immature basophilic cell line KU812, in the human mast cell leukemia cell line HMC-1 and in the CD34 expressing myeloblast KG-1. A similar expression pattern was obtained when BTK protein was analyzed by immunoprecipitation and Western blotting. Using a polymerase chain reaction-based analysis, a small amount (less than 1% of the level in B cells) of BTK mRNA was identified in T lymphocytes. Our findings are compatible with a general expression of the BTK gene in hematopoietic cells, except in T lymphocytes and plasma cells, in which the transcript level is selectively down-regulated.

Agammaglobulinemia↗
PubMed1994

Bioavailability of gamma-globulin after subcutaneous infusions in patients with common variable immunodeficiency.

Replacement therapy, using subcutaneous infusions of gamma-globulin, is being applied increasingly for antibody-deficient patients, as this form of treatment has been found to be related to a very low frequency of adverse systemic reactions. However, the uptake of IgG from subcutaneous tissue may be low, owing to degradation locally, especially for the IgG3 molecule. Therefore, the kinetics of IgG and IgG-subclass concentrations in the sera of 23 patients with common variable immunodeficiency was investigated during 18 months of subcutaneous infusions of gamma-globulin (100 mg/kg/week). Seventeen patients were previously treated with intramuscular injections or intravenous infusions. The mean serum IgG level increased twice in the previously treated patients and four times in the previously untreated patients. A steady state was reached after 6 months if the subcutaneous infusions were given weekly and after 1 week if the patients were given daily infusions for 5 consecutive days and, thereafter, weekly infusions. The fractional catabolic rate of IgG (4.1-5.9% per day) was found to be at the lower limit reported for normal controls, if 100% bioavailability of the infused IgG was assumed. The fractional contents of IgG subclasses in the patients' serum IgG resembled the physiological pattern, with the exception of IgG4, which was not present in the gamma-globulin preparations used. Significantly increased levels of IgG1 and -2 were seen in both previously treated and untreated patients during the treatment.

Administration, Cutaneous↗
PubMed1994

T-cell receptor beta gene rearrangements in leukaemic B-cells from patients with chronic lymphocytic leukaemia: association with chromosome 6 deletions.

Rearrangement of immunoglobulin genes is a characteristic finding in normal B-cells and in leukaemic cells of B-cell origin. In some leukaemic cells simultaneous cross-lineage rearrangement of immunoglobulin- and T-cell receptor (TcR) genes occur. We have analysed TcR beta gene rearrangement in 100 patients with B-cell chronic lymphocytic leukaemia. All samples expressed CD5, CD19 and CD20 and six patients had rearrangements of both immunoglobulin and TcR beta genes. Analysis of gene expression in cells with TcR beta gene rearrangement indicated production of truncated TcR beta transcripts but no expression of the T-cell markers CD3, CD4, CD8, TcR alpha beta or delta on the cell surface. Three of the patients with both Ig and TcR beta rearrangement (50%) were 44 years or younger at diagnosis and cells from three such patients expressed IgG. Three of the six patients had a terminal deletion of the long arm of chromosome 6 with different breakpoints, with or without other chromosomal abnormalities, whereas 6q deletions were found in 4/94 patients without TcR beta gene rearrangement (4.3%) (P = 0.001). This study indicates a correlation between TcR beta gene rearrangement and deletion of chromosome 6q.

Antigens, CD↗
PubMed1994

In vivo expression of human immunoglobulin germ-line mRNA in normal and in immunodeficient individuals.

Previous in vitro studies suggest that transcription of the unrearranged immunoglobulin switch region and its 5' flanking region precedes isotype switching. These transcripts, which are devoid of a variable region, contain unique exons and are called germ-line (GL) mRNA. A crucial point in this regard is whether such transcripts could be detected in vivo, and if their expression correlates with immunoglobulin class switching in health and disease. To understand the in vivo role of this transcriptional activity we have adapted the reverse transcription-polymerase chain reaction (PCR) to analyse the GL transcripts from unstimulated peripheral blood mononuclear cells (PBMC) in healthy individuals and in different immunological diseases. Furthermore, mononuclear cells from different human organs were also analysed. We report here that GL (I alpha, I gamma and I epsilon used to designate the GL mRNA for IgA, IgG and IgE, respectively) mRNA are expressed differentially during ontogeny of B cells. Unexpectedly, no difference of I alpha mRNA expression between the PBMC and the secondary lymphoid organs was detected. Rather, the levels of GL transcripts were correlated to the number of sIgM+ cells. GL mRNA of all three isotypes could be detected in PBMC from healthy donors, whereas there was a decrease of specific GL transcript synthesis in individuals with immunoglobulin deficiency. Furthermore, during the in vivo immune response in a parasitic infection, we could demonstrate an induction of GL I epsilon mRNA during in vivo immune response. Concomitantly, there was also increased synthesis of productive epsilon transcripts. These findings implicate a potential role of GL transcription during in vivo immunoglobulin class switching.

Base Sequence↗
PubMed1994

IgG subclass-associated differences in anti-schistosomal antibody specificity.

Consecutive sera from before and after treatment were collected from 23 patients with a Schistosoma mansoni infection, seven of whom had an early infection. All sera were analysed for IgG1, IgG3 and IgG4 antibody activity against three peptides from the protein Sm 28 GST (24-43, 115-131 and 140-153 aa). In addition, sera from 14 patients, four with an early infection and 10 patients with a chronic infection, were analysed for IgG and IgA antibody activity using seven peptides derived from the protein Sm 28 GST. This molecule has previously demonstrated protective activity against infection in various experimental models. The results are indicative of a subclass-related epitope specificity of the antibodies. Moreover, reactivity to one of the peptides (158-175 aa) was significantly associated with a chronic infectious status.

Adolescent↗
PubMed1994

Disturbances of cementum formation induced by single injection of 1-hydroxyethylidene-1,1-bisphosphonate (HEBP) in rats: light and scanning electron microscopic studies.

With the rat molar as a model, evidence is presented that dentin mineralization influences formation of acellular cementum. Formation of acellular cementum did not occur on the surface of experimentally induced unmineralized dentin. Instead, an atypical hyperplastic cementum was formed. The disturbance in acellular cementum formation was permanent.

Animals↗
PubMed1994

Distribution of protein kinase C alpha and accumulation of extracellular Ca2+ during early dentin and enamel formation.

Activation of the protein kinase C (PKC)-related signal transduction system has been associated with phenotypic expression in a wide variety of cell types. In in vitro studies, it has often been activated by relatively small increases in the Ca2+ concentration ([Ca2+]) in the medium. The studies reported here explored the hypothesis that localized increases in the extracellular [Ca2+] and activation of the PKC-related pathway may be involved in early dentin and enamel formation. Whole-head, freeze-dried sections through the developing molars of 5-day-old rats were evaluated by methods that localized non-crystalline Ca2+. Immunohistochemical methods were adapted for use with the freeze-dried sections, and two monoclonal antibodies were used to localize PKC alpha in the formative cells of the developing teeth. Low concentrations of extracellular Ca2+ were observed in the early, unmineralized dentin in the area of ameloblast differentiation. Increased concentrations occurred at the point of initial dentin mineralization, immediately before the beginning of enamel matrix deposition. PKC alpha was localized in the differentiating odontoblasts, at the beginning of dentin matrix deposition. It was intensely localized in the distal borders of the pre-ameloblasts, and appeared to redistribute in the cells during ameloblast differentiation. These observations suggest that local increases in the extracellular [Ca2+] and the PKC signal transduction pathway may be involved in key inductions in the early stages of dentin and enamel formation.

Ameloblasts↗
PubMed1994

Salivary and serum immunoglobulins in recipients of transplanted allogeneic and autologous bone marrow.

Significantly decreased levels of all classes Ig were found in saliva and serum of 85 patients before and up to 5 years after bone marrow transplantation (BMT). Salivary levels of IgG were increased before BMT in patients that died shortly after transplantation (p = 0.04). Significantly higher secretory IgA (sIgA) levels in saliva were noted in patients with malignant disorders than in those with non-malignant diseases, both before (p = 0.007) and after BMT (p = 0.011). Recipients of autologous marrow had higher levels of salivary sIgA before BMT than recipients of allogeneic bone marrow (p = 0.020). With increased BM cell dose at transplantation, lower levels of salivary IgG and albumin were found. Patients with cytomegalovirus infections after transplantation showed increased salivary IgG levels (p = 0.029). Individuals with chronic GVHD had less salivary IgM one year after BMT (median value 3.2 mg/l, p = 0.04) than those without chronic GVHD (median value 42.6 mg/l). All Ig classes in serum were decreased directly after BMT and later normalized. Salivary levels of all Ig classes except IgD fluctuated post-BMT.

Adolescent↗