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Biomedical subjects

L Hammarström

Publications and source records attributed to L Hammarström.

At least 19 recordsLinked to original sources
PubMed1992

Shared HLA class II-associated genetic susceptibility and resistance, related to the HLA-DQB1 gene, in IgA deficiency and common variable immunodeficiency.

Most cases of selective IgA deficiency (IgA-D) and common variable immunodeficiency (CVID) occur sporadically. However, familial clustering is not uncommon, and the two disorders can occur within the same family. We have previously described positive associations with three DR-DQ haplotypes as well as a strong negative association with DRw15,DQw6,Dw2 in IgA-D. Different amino acids at position 57 of the HLA-DQ beta chain were found to be related to susceptibility and resistance to IgA-D. Now we have found identical, although somewhat weaker, positive and negative DR-DQ associations in a large group of CVID patients (n = 86), as well as the same associations with codon 57 of the DQB1 gene. In addition, we have confirmed our earlier observations in an independent group of IgA-D individuals (n = 69), and in sib-pair analysis we have found linkage of the genetic susceptibility to IgA-D to the HLA class II region. In IgA-D individuals not carrying the three overrepresented DR-DQ haplotypes, the same positive association with a non-aspartic acid residue at position 57 of the HLA-DQ beta chain was seen. The previously reported associations with deletions of the HLA class III genes C4A (fourth component of complement) and CYP21P (steroid 21-hydroxylase pseudogene) were, in our groups of immunodeficient individuals, statistically secondary to the association with the DQB1 allele 0201. The shared HLA class II associations in the two humoral immunodeficiencies support the hypothesis that IgA-D and CVID are related disorders. Disease susceptibility and resistance are most closely associated with a gene(s) within the DR-DQ region, alleles of the DQB1 locus being candidate genes.

Alleles↗
PubMed1992

Analysis of human IgA subclasses by in situ hybridization and combined in situ hybridization/immunohistochemistry.

In this report we describe a method for the analysis of the cellular expression of the two human IgA subclasses by in situ hybridization (ISH). The technique permits the detection of specific mRNA in individual cells using 35S-labeled oligonucleotide probes without any detectable cross-hybridization between the subclasses. This method was applicable both on cytospin preparation of peripheral blood mononuclear cells as well as in formalin-fixed, paraffin-embedded tissue sections. Furthermore, we describe a combined ISH/immunohistochemistry technique for the simultaneous detection of IgA subclass mRNA and protein at the single cell level. Examination of tissue sections from tonsils revealed a striking localization of labeled cells within the germinal center of some of the lymphoid follicles. The implications of this novel finding and the development of the method are discussed.

B-Lymphocytes↗
PubMed1992

Transcription of unrearranged Ig H chain genes in human B cell malignancies. Biased expression of genes encoded within the first duplication unit of the Ig H chain locus.

Analysis of the H chain class switch recombination events on the productive and nonproductive alleles of several human B cell lines has demonstrated that, in the majority of cases, the two loci had rearranged different CH genes. The absence of a strict correlation between the two rearrangement events has been interpreted in favor of a stochastic switching mechanism in human B cells. Based on the accessibility model for the H chain class switch, we have considered an alternative explanation, namely, that transcriptional activation of more than one CH gene could render more than one isotype accessible for recombination. In order to test this possibility, we have stimulated a number of IgM-bearing B cell tumors and analyzed the transcriptional response of their unrearranged C gamma and C alpha H chain genes at the Ig class level by Northern hybridization and at the subclass level by RNA-RNA solution hybridization. Our data show that human clonal B cell populations can simultaneously express germ-line transcripts of both gamma and alpha genes. Our data also demonstrate a bias in the expression of the different isotypes in the B cell chronic lymphocytic leukemias analyzed, with the genes present with the first duplication unit of the H chain locus (gamma 3, gamma 1, and alpha 1) being expressed almost exclusively. These findings indicate that transcriptional activation of large chromosomal regions containing more than one CH gene could render all the genes available for recombination and, therefore, provide an explanation for the asymmetry in the rearrangement events that have previously been described in human B cell tumors. The possible relevance of our findings to the molecular mechanism of the H chain class switch is discussed.

B-Lymphocytes↗
PubMed1992

Regulation of C gamma 3 expression. Role of switch in the allotype-associated variation of human serum IgG3 levels.

Serum IgG3 levels are associated with G3m allotypes in humans. However, the molecular basis of this association has not been understood. In this study we have analyzed the biologic half-life, the secretion, the cell surface expression, the cytoplasmic content, and the mRNA expression of different allotypes. The biologic properties of the allotypes did not differ. However, the frequency of cells with membrane IgG3, cytoplasmic IgG3, and C gamma 3 mRNA was decreased in donors with a low serum IgG3, whereas the level of C gamma 3 mRNA expression in individual cells did not differ among cells of the different allotypes. As these findings indicated a pretranscriptional control of C gamma 3 expression, genomic DNA from donors with different allotypes were also studied. Despite the absence of gross, allotype-related differences in the I gamma 3 regions, we favor an upstream cis-element influencing C gamma 3 switching as the most likely explanation for variations in IgG3 serum levels.

Animals↗
PubMed1992

Immunoglobulin production in severe combined immunodeficient (SCID) mice reconstituted with human peripheral blood mononuclear cells.

Immunodeficient C.B-17 scid/scid (SCID) mice were reconstituted with human peripheral blood mononuclear cells and analyzed for humoral immunity. The majority of adoptively transferred animals had serum levels of 1-4 mg/ml of human IgG 8-12 weeks after i.p. reconstitution with 20 x 10(6) PBMC, whereas the IgM and especially IgA concentrations were considerably lower. The half-lives of human IgG, IgM, and IgA in SCID mice were 12 days, 36, and 23 hours, respectively. Furthermore, IgA was rapidly secreted into bile indicating that the low IgA concentration was mainly caused by a high turnover rate. IgG subclass distribution in mouse serum was similar to that found in the donor serum. Irradiation with 3 Gy prior to adoptive transfer resulted in increased levels of human IgG early after reconstitution, whereas both IgM and IgA concentrations were impaired. A polyclonal serum Ig pattern was found 4 weeks after transfer of human cells later frequently followed by a predominance of oligoclonal bands. Unexpectedly, oligoclonal bands were also found using donors with a negative Epstein-Barr virus serology. Human cells were found to reside in the peritoneal cavity for several months. Within 2 weeks of reconstitution, human cells were also identified in lymphoid structures in the vicinity of the liver hilus with a later spread to other lymphoid organs. Homing of human cells to skin and gut was not seen.

Animals↗
PubMed1992

Involvement of both HLA and Ig heavy chain haplotypes in human IgA deficiency.

Immunoglobulin-A deficiency (IgA-D) is the most common human Ig class deficiency with an estimated frequency of approximately 1 in 500 in the Swedish population. We investigated the immunoglobulin heavy chain constant region gene segments (IGHC) in 103 individuals with IgA-D and the immunoglobulin heavy chain variable region gene segments (IGHV) in 20 of these, in order to identify a possible molecular basis of the defect. No deletions of IGHV gene segments of the VH2, VH5, and VH6 families or the IGHG genes were observed. In the IGHC, there were, however, differences in the restriction fragment length polymorphism frequencies of IGHG genes where the Bam HI haplotype "H2" [IGHGP, 10 kilobases (kb), IGHG2, 25 kb; and IGHG4, 9.0 kb] was overrepresented. The mean serum levels of IgG4 and IgE were significantly lower in individuals (both IgA-D subjects and healthy controls) homozygous for the H2 haplotype than in individuals homozygous for the H1 haplotype (IGHGP, 8.8 kb, IGHG2, 13.5 kb, and IGHG4, 9.4 kb). IgA-D subjects homozygous for HLA DQB1*0201 (DQw2), a marker that has previously been reported to show a strong association with IgA deficiency, showed a similar reduction of serum levels of IgG4 and IgE as compared with DQB1*0201 negative IgA-D subjects. These findings suggest that the two loci found to be associated with IgA deficiency may act via a common pathway.

Blotting, Southern↗
PubMed1992

Monitoring of mite Dermatophagoides farinae allergen-specific IgG and IgG subclass distribution in patients on immunotherapy.

House dust mite D. farinae and Der f II-specific IgG and IgG subclass responses were evaluated in 32 adults with perennial rhinitis undergoing immunotherapy for 1 year by means of IgG-RAST and ELISA. The ELISA method, which is based on subclass-specific monoclonal antibodies, could detect 0.5-1.5 ng/ml of specific antibodies. D. farinae and Der f II-specific IgG4 antibodies increased continuously as immunotherapy proceeded, while total IgG and IgG1 antibodies reached a plateau value 6 months after the start of immunotherapy, followed by a slow decrease during maintenance therapy. During the early phase of treatment the concentration of IgG1 and IgG4 antibodies rose, even though the increase of IgG4 antibodies dominated. The positive clinical outcome as measured by the decrease in conjunctival sensitivity was associated with an increased ratio of specific IgG4/IgG1 antibodies as well as the magnitude of the IgG4 subclass response. Quantitation of IgG subclass antibodies in patients undergoing immunotherapy may be of some clinical value, but the clinical usefulness needs to be demonstrated for each type of allergen and possibly also for each assay system.

Adult↗
PubMed1992

Effects of phosphonoformic acid and 1-hydroxyethylidene-1,1-bisphosphonate (HEBP) on distribution of tetracycline in the developing rat molar.

Tetracycline was used as a marker to study the effect of phosphonoformic acid and 1-hydroxyethylidene-1,1-bisphosphonate (HEBP) on the mineralization of the developing dental hard tissues. Groups of young rats were given a single subcutaneous injection of tetracycline and at the same time were injected with a single dose of either phosphonoformic acid or HEBP (10 mg P/kg b.w.). Alternatively, rats were injected with the tetracycline after different time intervals from the phosphonate injection. Rats were sacrificed at intervals ranging from 1 to 4 days. Frozen-sections were obtained at the level of the maxillary first molar and prepared for light and fluorescence microscopy. The results of the present study indicate that the distribution pattern of tetracycline in the developing dental hard tissues is greatly affected by the pathologic changes induced by phosphonoformic acid and HEBP. Both drugs caused similar changes in the pattern of tetracycline uptake in the developing enamel. There seems to be a direct relation between the presence of developmental defects of enamel and the degree of discoloration induced by tetracycline. Aberrations in the mineralization of dentin were caused only by HEBP. As demonstrated by this study, HEBP is capable of inducing a provisional inhibitory effect on dentin mineralization.

Ameloblasts↗
PubMed1992

Oral conditions in individuals with selective immunoglobulin A deficiency and common variable immunodeficiency.

Saliva and serum samples were collected from 36 individuals with selective immunoglobulin A deficiency (IgAd) and 23 patients with common variable immunodeficiency (CVI). The oral examination included registration of the teeth, Russell's periodontal index (PI), pocket formation, and salivary flow rate in both unstimulated and stimulated saliva. No differences were found in salivary flow rate, number of teeth, or pocket depth when donors with IgAd or CVI were compared to age and sex matched controls. However, mucosal manifestations of lichenoid type were more frequent in both types of immunoglobulin deficient individuals. An increased PI was also seen in CVI patients. Increased serum IgG and salivary IgM levels were found in the IgAd population.

Adolescent↗
PubMed1992

Herpesvirus serology, aberrant specific immunoglobulin G2 and G3 subclass patterns and Gm allotypes in individuals with low levels of IgG3.

One objective of this study was to determine whether IgG3-deficient individuals have an increased frequency of reactivated herpesvirus infections. Serum titres to Epstein-Barr virus (EBV) and human herpesvirus-6 were examined in 10 healthy and in 10 symptomatic persons with serum IgG3 < 0.1 g/l. Atypical titres were found in 16% of the IgG3-deficient individuals. Reactivations of these viruses thus do not seem common in IgG3 deficiency. Antigen-specific IgG responses were also determined. A lowered frequency of IgG3 to an EBV-derived peptide was found only in symptomatic, IgG3-deficient individuals. Levels of IgG2 to a bacterial polysaccharide were lowered in the same group, despite normal serum levels of total IgG2. A functional IgG2 deficiency may contribute to symptoms in IgG3 deficiency. The G3(g) allotype, known to be associated with low total IgG3, dominated in IgG3-deficient persons (13/17) independently of presence or absence of symptoms. A linkage of G3(g) to the G2(n) negative allotype, associated with low IgG2, was equally common irrespective of symptoms. G3(g) and absence of G2(n) seem to be one prerequisite for most of IgG3 deficiency combined with low specific IgG2.

Antibodies, Viral↗
PubMed1992

Class and subclass-associated specificity differences of anti-gliadin antibodies from mucosa and serum.

The class and subclass distribution of antibodies against gliadin in intestinal lavage fluid, saliva and serum was investigated in individuals with coeliac disease. Serum antibodies against gliadin were mainly or even exclusively of the IgA1 subclass. In intestinal lavage fluid and saliva, antibodies of both IgA1 and IgA2 subclasses were found. In patients with and without IgA deficiency, an IgG response was detected both in serum and intestinal lavage fluid with a predominance of IgG1 in selected patients. Specific IgG2, IgG3 and IgG4 antibodies were also detected in intestinal lavage fluid, while no specific IgG2, IgG3 or IgG4 antibodies were found in serum, suggesting a local production of specific IgG antibodies. In Western blot analysis, intestinal lavage fluid and serum IgA antibodies reacted against gliadin components with a MW between 33,000 and 42,000. Serum IgA1 antibodies directed against a gliadin component with a MW slightly higher than 42,000 were also observed. Specific IgG and IgM antibodies in both the secretion and serum against gliadin components with a MW between 33,000 and 42,000 were also detected. This study shows that mucosa-derived gliadin-specific IgA and IgG antibodies may be produced even when there is an absence of specific antibodies of the corresponding immunoglobulin subclass in serum. Furthermore, the specificity of serum and intestinal lavage fluid anti-gliadin IgA1 antibodies may differ.

Antibody Specificity↗
PubMed1992

Factors regulating and modifying dental root resorption.

A comparison is made between the resorption of bone and the resorption of the mineralized tissues of teeth. The structure and function of osteoclasts are described well as the factors that regulate their activity. The cells resorbing the dental mineralized tissues are of the same cell type as osteoclasts. The dental tissues are covered by cementoblasts or odontoblasts which differ from the osteoblasts in that they do not respond to hormones and cytokines that stimulate bone resorption. Root resorption therefore seem to require damage of the cementoblastic layer in combination with necrosis or inflammation or replacement of the cementoblastic layer by osteoblasts. The root resorption that occurs at the shedding of the primary teeth is induced in a different way possibly by substance(s) from the reduced enamel epithelium. There seems to be no systematic study on the frequency and extension of root resorption in association with inflammatory or neoplastic conditions. It is suggested that dentigerous cysts and some epithelial tumors induce root resorption in the same way as the erupting tooth. The mechanisms by which some other tumors or tumor-like conditions cause root resorption are essentially unknown.

Animals↗
PubMed1991

Ig H chain variable and C region genes in common variable immunodeficiency. Characterization of two new deletion haplotypes.

Common variable immunodeficiency, a disorder characterized by diminished antibody production, manifests clinically as an increased susceptibility to bacterial infections. We have investigated the Ig H chain V and C region gene segments in 33 patients with common variable immunodeficiency, to identify the possible role these genes may have in the molecular basis of the defect. No major deletions were recognized for the VH gene segments of the VH2, VH5, and VH6 families, nor were there any differences in the RFLP patterns of mu- or alpha- switch regions or of C gamma genes. Two new deletion haplotypes were identified for the C region genes, the first encompassing C gamma 1 on a different haplotype from the C gamma 1 deletion described previously, and the second a novel deletion encompassing both C gamma 2 and C gamma 4. Based on these and previously described deletions in the IGHC region, we postulate that homologous regions are involved in the deletion process and that other new deletions likely exist in the population.

Chromosome Deletion↗
PubMed1991

Home treatment of hypogammaglobulinaemia with subcutaneous gammaglobulin by rapid infusion.

Intramuscular and intravenous gammaglobulin treatment for hypogammaglobulinaemia is often associated with systemic adverse reactions in some patients. Subcutaneous infusions of gammaglobulin are usually given at a slow rate. To assess the safety of home treatment with subcutaneous gammaglobulin, rapid infusions (34-40 ml/h) given by small portable pumps were used to treat twenty-five patients with hypogammaglobulinaemia. Fifteen patients had previously had adverse reactions to intramuscular or intravenous gammaglobulin treatment. After the patients had been taught how to use the pumps during 6 months of treatment in hospital, in which they initially received 100 mg of an intramuscular gammaglobulin preparation/kg per week, they went on to use the pumps at home or at work. So far, the patients have given themselves 3232 rapid subcutaneous infusions (2308 in home therapy). A median pre-infusion serum IgG concentration of 8.1 g/l resulted after 6 months of treatment. There were only 30 (0.93%) mild systemic adverse reactions; there were fewer reactions with subcutaneous gammaglobulin than with previously given intramuscular injections (n = 21, p less than 0.001) or intravenous infusions (n = 9, p less than 0.001) in this group of patients. Overall, the patients spent 0.2 days a year in hospital due to respiratory tract infections. The findings show that the method for subcutaneous administration is very easy to learn and is appreciated by the patients; moreover, the infusions can be given much faster than previously reported without any pronounced local reaction.

Adolescent↗
PubMed1991

Antigenicity of mouse monoclonal antibodies. A study on the variable region of the heavy chain.

Mouse monoclonal antibodies (Mabs) against human tumour antigens are currently used in therapy, but up to 50% of the patients receiving treatment form anti-Mab antibodies thus reducing the efficiency of the treatment. One attempt to minimize the immunogenicity of the mouse Mabs is to "humanize" them by replacing the constant part of the molecule with the human equivalent by genetic engineering. However, this does not reduce the immunogenicity of the variable part of the antibody. Some variable regions may be expected to be less antigenic than others. We therefore compared consensus sequences for the 11 mouse VH families with the human VH sequences published so far. Theoretical antigenicity predictions (hydrophilicity, flexibility, surface accessibility and relative antigenicity) were made and two families; VH I(J558) and VH XI (CP5 B5-3) were predicted to be immunogenic by all four methods. One family, VH X (MRL-DNA4), was not predicted to be immunogenic by any of the four methods. The residues predicted to form antigenic epitopes in the two families VH II (Q52) and VH III (36-60) are predicted not to be exposed on the surface of the antibody molecule and may therefore not be immunogenic.

Animals↗