Transplantation of a lobe of lung from mother to child following previous transplantation with maternal bone marrow.
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Bone Marrow Transplantation↗
Biomedical subjects
A Svejgaard
Publications and source records attributed to A Svejgaard.
Interleukin-2 induces tyrosine phosphorylation and nuclear translocation of stat3 in human T lymphocytes.
An early biochemical event associated with T cell activation through the interleukin-2 receptor (IL-2R) is tyrosine phosphorylation of several intracellular substrates. The exact mechanism by which IL-2 regulates transcription of different genes is presently unknown. Here, we report that stimulation through the IL-2R induced tyrosine phosphorylation and subsequent nuclear translocation of stat3, a newly identified member of the signal transducers and activators of transcription (STAT) family of proteins. In contrast, stat1 proteins were not tyrosine phosphorylated after IL-2 ligation, whereas tyrosine-phosphorylated stat1 proteins (91 and 84 kDa proteins) were translocated to the nucleus following interferon-gamma treatment of HeLa cells. Apart from stat3, another cytoplasmic protein was tyrosine phosphorylated and subsequently translocated to the nucleus in response to IL-2. This protein had an apparent molecular mass of 84 kDa and was not recognized by stat3 or stat1 mAb or antisera. Since IL-2 induced nuclear translocation of the 84 kDa protein and stat3 followed identical kinetics, p84 is a candidate for a new, yet undefined, member of the STAT family. Taken together, we report that IL-2 induces tyrosine phosphorylation and subsequent nuclear translocation of stat3 and an as yet undefined 84-kDa protein in antigen-specific human T cell lines.
Biological Transport↗
A new frequent allele is the missing link in the structural polymorphism of the human mannan-binding protein.
Human mannan-binding protein (MBP) is a serum lectin participating in the innate immune defence. Low MBP concentrations are explained by the dominant action of a point mutation at codon 54 of the MBP gene in Eskimos, partially in Caucasians, but not in Africans. A previously described point mutation at codon 57 was very frequent (0.23) in East Africans, low in Caucasians (0.02), and absent in Eskimos. The African population only conformed to Hardy-Weinberg expectation when assuming the existence of an unknown allele, which was subsequently found as a point mutation at codon 52. This allele appeared with a relatively high frequency (0.05) in both Africans and Caucasians, but was absent in Eskimos. Hardy-Weinberg equilibrium is now seen in the investigated ethnic groups. All cases of MBP deficiency may be explained by these three variants.
Alleles↗
Peptide specificity of anti-myelin basic protein antibodies in patients with acute optic neuritis and the HLA system.
Multiple sclerosis (MS) may be an autoimmune disease, partially caused by autoreactivity to myelin basic protein (MBP) and other central nervous system proteins. Acute optic neuritis (ON) is a frequent first symptom of MS. The role of the HLA system in anti-MBP antibody production in ON was investigated employing a restriction fragment length polymorphism system for genomic HLA-DQ and -DR typing and an immunospot assay for the detection of individual cells secreting antibodies to three different synthetic MBP peptides. Thirty-two out of 40 patients (80%) with ON had cells in cerebrospinal fluid secreting anti-MBP peptide antibodies while this occurred in 10/19 patients with other neurological diseases (53%; mainly in patients with inflammatory diseases in the central nervous system). This difference was statistically significant (P = 0.03). None of the three examined peptides were immunodominant in any patient group. It was found, however, that presence of HLA DR15, which is associated with MS, may be associated further with predominant production of antibodies to the MBP amino acids 63-88 in patients with ON (P = 0.002, corrected for multiple comparisons).
Adult↗
Post-transfusion purpura: a survey of 12 Danish cases with special reference to immunoglobulin G subclasses of the platelet antibodies.
The clinical and immunological data of 12 Danish cases of post-transfusion purpura (PTP) are summarized. All patients but one were women. All except one had thrombocytopenic purpura which occurred 4-11 days after transfusion, usually with a nadir of the platelet count below 10 x 10(9) 1(-1). The typical haemorrhagic symptoms were cutaneous bleedings, melena and haematuria lasting from 3 to 12 days. The time until normalization of platelet count varied from 3 to 50 days after onset. One patient had recurrence of PTP and one patient died due to intracranial haemorrhage. Ten of the HPA-1a negative patients (83%) had platelet-specific HPA-1a antibodies and two HPA-1a positive individuals had anti-HPA-1b antibodies. In 10 patients, HLA antibodies were also detectable and in one patient a delayed haemolytic transfusion reaction due to anti-E was seen. All of seven patients investigated had anti-HPA antibodies of both IgG1 and IgG3 subclasses during the thrombocytopenic period while all of 10 patients had anti-HPA of only the IgG1 subclass after recovery from PTP. Thus, the destruction of autologous platelets in PTP seems to be associated with the presence of anti-HPA of the IgG3 subclass which may be of importance in the pathogenesis of PTP.
Adult↗
HLA and disease associations: detecting the strongest association.
A major aim of HLA and disease association studies is to identify the causative HLA factor truly responsible for the association. This is usually difficult due to the pronounced linkage disequilibrium between most HLA determinants. The causative factor must show the strongest association compared to all other factors. Here we describe a simple analysis which can be used to identify which of two factors, say A and B, shows the strongest association. The basic data for the analysis are the entries of the two-by-four table giving the four phenotypic combinations of A and B in patients and controls, respectively. These data are analyzed in various two-by-two tables involving stratification of each of the two factors against the other. A stronger increase of factor A is established if A is significantly associated with the condition both in B-positives and in B-negatives, when this is not true for B in A-positives and A-negatives. Using simulation with control data, it is demonstrated how linkage disequilibrium may influence secondary associations. The analysis may also be used to investigate interaction between HLA factors, but linkage disequilibrium complicates the interpretation in such cases. The method is exemplified using various published data. Finally, some statistical recommendations are given. Thus, we advise that phenotype (marker) frequencies are generally used instead of gene (i.e. allele, or haplotype) frequencies. The importance of correcting p-values, the levels of significance, and the power of Fisher's exact test are discussed.
Disease Susceptibility↗
Prevalence and predictive value of islet cell antibodies and insulin autoantibodies in women with gestational diabetes.
The objective of the present study was to investigate the predictive value of islet cell antibodies (ICA) and insulin autoantibodies (IAA) for development of diabetes in women with previous gestational diabetes (GDM). Two hundred and forty-one previous diet-treated GDM patients and 57 women without previous GDM were examined 2-11 years after the index pregnancy. In subgroups, plasma from the diagnostic OGTT during index pregnancy was analysed for ICA and IAA. Among the previous GDM patients, 3.7% had developed Type 1 diabetes and 13.7% Type 2 diabetes. Four (2.9%) of the 139 GDM patients tested for ICA were ICA-positive and three of these had Type 1 diabetes at follow-up, as well as three ICA-negative patients. The sensitivity, specificity, and predictive value of ICA-positivity for later development of diabetes were 50%, 99%, and 75%, respectively. None of the women was IAA-positive during pregnancy. In conclusion, the majority of the patients with GDM did not show evidence of ongoing autoimmune destruction of the beta cells during the index pregnancy. However, ICA-positive GDM patients had a high risk of developing Type 1 diabetes later in life.
Autoantibodies↗
Dual role of mannan-binding protein in infections: another case of heterosis?
Human mannan-binding protein (MBP) is a serum lectin that participates in the immune defence by mediating phagocytosis and activation of complement. Variant MBP alleles causing dominant low-serum concentrations have high frequencies in all populations studied, and therefore, low MBP concentrations may confer selective advantages to those individuals carrying the variant alleles. Mycobacterium leprae, the causative agent of leprosy, is an obligate intracellular parasite dependent on phagocytosis to invade host cells. The serum concentrations of MBP in 36 Ethiopian patients (median: 1688 micrograms l-1) with lepromatous or borderline lepromatous leprosy were significantly (P < 0.001) higher than in 26 healthy Ethiopian blood donors (median: 368 micrograms l-1). Only 17% of the patients vs. 58% of the donors (P = 0.0019) had the relatively low MBP concentrations usually associated with variant alleles. Functional studies revealed that M. leprae and M. tuberculosis sonicates bind MBP as strongly as pure mannan. These observations suggest a role for mycobacteria as a selective force in the positive selection of alleles causing low levels of MBP and warrant genetic studies of patients infected with these bacteria.
Candida albicans↗
MHC class II molecules regulate growth in human T cells.
MHC-class-II-positive T cells are found in tissues involved in autoimmune disorders. Stimulation of class II molecules by monoclonal antibodies (mAbs) or bacterial superantigens induces protein tyrosine phosphorylation through activation of protein tyrosine kinases in T cells, and class II signals modulate several T cell responses. Here, we studied further the role of class II molecules in the regulation of T cell growth. Costimulation of class II molecules by immobilized HLA-DR mAb significantly enhanced interleukin (IL)-2-supported T cell growth of the majority of CD4+, CD45RAlow, ROhigh T cell lines tested. Only one of three CD4+, CD45RAhigh, ROhigh T cells responded to class II costimulation. There was no correlation between T cell responsiveness to class II and the cytokine production profile of the T cell in question. Thus, T cell lines producing interferon (IFN)-gamma but not IL-4 (TH1-like) as well as T cells producing both cytokines (THO-like) responded to class II mAb. The costimulatory effect was not restricted to IL-2-driven T cell growth, since TCR/CD3-induced T cell activation was also enhanced by HLA-DR mAb. Moreover, class II costimulation potentiated CD28-mAb-induced T cell sensitivity to protein kinase C activation by phorbol 12-myristate 13-acetate. In conclusion, class II costimulation enhances T cell activation through the TCR/CD3 and IL-2 pathways and interacts with CD28 accessory signals to up-regulate growth of allospecific T cell lines.
Antibodies, Monoclonal↗
MHC class II molecules deliver costimulatory signals in human T cells through a functional linkage with IL-2-receptors.
MHC class II-positive T cells are found in tissues involved in autoimmune and infectious disorders. Because stimulation of class II molecules by mAb or bacterial superantigens induces protein tyrosine phosphorylation through activation of PTK3 in T cells, we hypothesized that class II signals play a regulatory function in T cell activation. Here, we show that cross-linking HLA-DR and -DP but not -DQ molecules by immobilized mAb enhanced proliferative T cell responses to IL-2. In contrast, class II stimulation had no effect on IL-4-induced proliferation. The costimulatory effect was most pronounced at low concentrations of IL-2, was blocked by IL-2R mAb, and was at least partly mediated through an up-regulation of IL-2 high affinity receptors. As expected, activation of IL-2R by IL-2 induced tyrosine phosphorylation of several proteins including p56lck, and class II cross-linking by mAb induced tyrosine phosphorylation of specific substrates including PLC-gamma 1. Combined stimulation of IL-2R and class II molecules had an additive effect on tyrosine phosphorylation. Pretreatment of T cells with a protein tyrosine kinase inhibitor, herbimycin A, inhibited IL-2 and class II-induced proliferation suggesting that class II costimulation of IL-2 responses may involve activation of tyrosine kinases. Taken together, the present data suggest that extensive cross-linking of class II molecules delivers costimulatory signals that enhance IL-2 sensitivity in human T cells.
Animals↗
[Deficiency of mannan-binding protein--a recently discovered complement defect syndrome].
Mannan-binding protein (MBP) is a newly discovered serum protein which activates the complement system by the classical pathway by binding to mannose-rich surfaces on microorganisms. MBP deficiency predisposes to infection in infancy. MBP is a C-type lectin with collagen structure, a so-called collection. The paper discusses the structure and physiological functions of MBP. MBP may be an important parameter in the investigation of immunodeficiencies in children.
Carrier Proteins↗
Mannan-binding protein--levels in plasma and upper-airways secretions and frequency of genotypes in children with recurrence of otitis media.
We have investigated a possible association between recurrence of otitis media and low concentrations of mannan-binding protein (MBP) in plasma and upper-airway secretions. The protein concentration was measured in plasma (n = 76), nasopharyngeal secretions (n = 83) and middle ear effusions (n = 73) from otitis-prone children, children with less recurrence of acute otitis media, children with no previous history of acute otitis media, but suffering from secretory otitis media, and healthy children. Moreover, genetic polymorphisms associated with low MBP plasma levels were investigated in DNA from nasopharyngeal tonsils of 89 children with recurrence of otitis media. A wide range of MBP plasma concentrations was found. No statistically significant differences in MBP plasma concentration were observed between patients and controls. Nor was there any increased frequency of the genotypes associated with low MBP plasma concentrations. Thus, our results do not support the assumption that low concentration and/or MBP deficiency alone predispose to recurrence of otitis media in Caucasian children. MBP was detected in both nasopharyngeal secretions (1/175 of plasma level) and middle ear effusions (1/4 of plasma level), suggesting a role for the protein in the local mucosal immune defense system at these locations. In contrast, MBP was undetectable in 53 samples of mixed-saliva.
Base Sequence↗
A low serum concentration of mannan-binding protein is not associated with serogroup B or C meningococcal disease.
The mammalian C-type serum lectin, mannan-binding protein (MBP), may induce C1q- and antibody-independent activation of the classical pathway of complement. Accordingly, MBP is considered as a member of the complement system. Complement deficiencies have been found with increased frequency in patients with meningococcal disease. Therefore, we investigated the MBP levels in patients with meningococcal disease. Ninety-nine Norwegian individuals (age 12-21 years) who survived severe systemic disease caused by serogroup B or C meningococci were investigated. No significant differences were observed in the MBP concentration between patients with serogroup B (n = 76) or C (n = 25) disease and healthy blood donor controls (n = 40) (P > 0.05). The frequency of patients with low levels of MBP (< 100 micrograms/l) was 10.1%. This was not different from controls (12.5%). Thus, low MBP concentrations do not appear to predispose to serogroup B or C meningococcal disease.
Adolescent↗
Human platelet antigen-1 (Zw) typing using PCR-RFLP.
The agreement between human platelet antigen-1 typing with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and typing with a serological ELISA method was evaluated. A total of 82 individuals were typed and an absolute correlation was found between the two typing methods. The PCR-RFLP typing method could be clinically useful in a number of immunologically mediated platelet disorders, characterized by severe thrombocytopenia and in early prenatal diagnosis of neonatal alloimmune thrombocytopenia, in which serological methods are difficult to apply because of their dependency on access to platelets and access to well-characterized anti-HPA-1b antisera.
Antigens, Human Platelet↗
Defective T-cell stimulatory pathways in patients after allogeneic bone marrow transplantation (BMT) in man.
Immunological reconstitution after allogeneic bone marrow transplantation in man is characterized by a decreased lymphocyte transformation response to various mitogens and antigens during a period of from months to years. One reason for the decreased proliferative capability could be an inverted CD4/CD8 ratio; however, the present investigation demonstrates that this is not the only explanation for the immunodeficiency, since the CD4 as well as the CD8 subset, when studied in isolation, have qualitative defects, as evidenced by a reduced response of both subsets to stimulation with PHA, anti-CD2 and anti-CD3 MABs. The reason for the qualitative defect is unknown but a distorted composition of the CD4+ as well as the CD8+ T-cell subsets is suggested by the present investigations. We also observed that the PHA response was almost completely reconstituted one year after BMT, while the PWM response was still severely affected. The present study suggests that T-cell subsets which differ in their capacity to respond to PHA and PWM have different kinetics of reconstitution after BMT.
Adolescent↗
Rapid analysis of rearranged kappa light chain genes of circulating polysaccharide-specific B lymphocytes by means of immunomagnetic beads and the polymerase chain reaction.
Analysis of rearranged immunoglobulin genes used by B lymphocytes of known specificity is an important tool for the study of diversity and selection of B lymphocytes. Usually hybridoma cell lines are used for such analyses, but they are difficult to obtain from humans and may not be representative of the B lymphocytes activated in vivo. Here, we present a method for rapid analysis of the rearranged kappa light chain genes used by human circulating antigen-specific B lymphocytes. After vaccination with Haemophilus influenzae type b capsular polysaccharide (HibCP) conjugated with protein, the HibCP-specific B lymphocytes were isolated by antigen-coated immunomagnetic beads. After the purification, at least 98% of the immunoglobulin-secreting recovered cells were HibCP specific. The RNA was isolated and amplified by cDNA synthesis using a kappa constant region primer followed by polymerase chain reaction (PCR) using in addition a degenerate kappa light chain signal peptide region primer. The PCR product was cloned into the M13mp18 phage. The cloning efficiency was 100-600 clones/ml of blood. Of the 86 clones sequenced, 90% represented rearranged kappa light chain genes from different antibody-secreting cells. Examples of rearranged kappa genes used by HibCP-specific antibody-secreting cells from 4 adult vaccinees are given, representing the 3 largest of the 4 kappa variable region families. This method is a new tool for the investigation of vaccine-induced antibody responses with special reference to immunoglobulin gene usage and variability.
Base Sequence↗
Superantigen and HLA-DR ligation induce phospholipase-C gamma 1 activation in class II+ T cells.
Bacterial enterotoxin superantigens bind directly to HLA class II molecules (HLA-DR) expressed on both APC and activated human T cells, and simultaneously bind to certain V beta chains of the TCR. In this report, we compared early T cell signaling events in human alloantigen-stimulated T cells when activated by HLA-DR ligation through antibody cross-linking or by direct enterotoxin superantigen binding. Both types of stimuli induced tyrosine phosphorylation of phosphatidylinositol-specific phospholipase C gamma 1 (PLC gamma 1) and an increase in intracellular calcium concentration; however, superantigen-induced signaling was stronger than class II ligation alone. Antibody-mediated ligation of HLA-DR with CD3 resulted in augmented PLC gamma 1 activation and increased calcium mobilization, consistent with a mechanism of superantigen activity through a combination of class II and CD3/Ti signals. In addition, down-modulation of CD3 receptors with antibody demonstrated that superantigen-induced signaling events were CD3-dependent. Superantigen signaling was also class II-dependent, in that resting T cells were not responsive to direct enterotoxin stimulation. To address how early signal transducing activity correlated with T cell responsiveness, alloantigen-primed T cells were activated with immobilized class II-specific mAb or soluble superantigen. Both HLA-DR mAb-stimulated T cells and enterotoxin-treated T cells proliferated strongly in response to co-stimulation by a combination of CD28 receptor engagement and PMA addition. In addition, superantigen-induced growth was induced by CD28 receptor ligation with antibody or the B7 counter-receptor expressed on Chinese hamster ovary cells. Taken together, these results indicate that class II molecules expressed on activated T cells are directly coupled to the PLC gamma 1 signal transduction pathway, and that coligation of HLA-DR with CD3 augments T cell signaling comparable to that induced by enterotoxin superantigen. Thus, we suggest that superantigen-induced early signaling responses in activated T cells may be due in part to class II transmembrane signals induced when HLA-DR and V beta are ligated in cis.
Antigens, Bacterial↗
Immunogenetics of multiple sclerosis and optic neuritis: DNA polymorphism of HLA class II genes.
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Alleles↗