HELLP syndrome at 21 weeks' gestation in association with trisomy 13.
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Journal Article↗
Biomedical subjects
S Macphail
Publications and source records attributed to S Macphail.
Superantigens: mechanisms by which they may induce, exacerbate and control autoimmune diseases.
Superantigens are polypeptide molecules produced by a broad range of infectious microorganisms which elicit excessive and toxic T-cell responses in mammalian hosts. In light of this property and the fact that autoimmune diseases are frequently the sequelae of microbial infections, it has been suggested that superantigens may be etiologic agents of autoreactive immunological responses resulting in initiation, exacerbation or relapse of autoimmune diseases. This article relates the biology of superantigens to possible mechanisms by which they may exert these activities and reviews the evidence for their roles in various human and animal models of autoimmune disease. Finally, a mechanism of active suppression by superantigen-activated CD4+ T-cells that could be exploited for therapy as well as prophylaxis of human autoimmune diseases is proposed.
Animals↗
Prevention and treatment of experimental autoimmune encephalomyelitis by CNI-1493, a macrophage-deactivating agent.
Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are characterized by episodic neurologic dysfunction, perivascular mononuclear cell inflammation occurring mainly in white matter, and demyelination. Strong circumstantial evidence supports the conclusion that macrophage activation and local production of proinflammatory cytokines are necessary for disease induction and lesion formation. We now report that CNI-1493, a small m.w. compound, which inhibits macrophage activation and subsequent proinflammatory cytokine production, suppresses EAE induced in the genetically susceptible SJL/J mouse. Treatment with 5 mg/kg/day completely suppressed mild disease (clinical index of 1.6 +/- 0.5 in the untreated group as compared with 0.0 +/- 0.0 for the treated group) and significantly reduced acute disease (clinical index of 4.3 +/- 0.7 in the untreated group as compared with 0.5 +/- 0.3 for the treated group). Suppression of clinical manifestations of the disease correlated with a significant decrease in histopathology and proinflammatory cytokine expression at the lesion site. Moreover, drug treatment during the chronic phase resulted in amelioration of clinical signs. The data presented here should prove useful in developing novel chemotherapeutic approaches for the treatment of MS.
Animals↗
Prenatal diagnosis of mosaic trisomy 8 with investigations of the extent and origin of trisomic cells.
A case of trisomy 8 mosaicism, which presented at obstetric ultrasound at 18 weeks' gestation with a distended bladder and absence of amniotic fluid, is described. Analysis of DNA microsatellite polymorphisms indicates that the trisomic cell line most likely arose as the result of a post-fertilization non-dysjunction event in early development of a chromosomally normal pre-implantation embryo. The distribution of normal and trisomy 8 cells suggests that in this pregnancy there has been either uneven allocation of abnormal cells to the extra-embryonic mesoderm, or selection against the proliferation of trisomic cells in trophoblast derived cell lineages. This prenatal detection of trisomy would not have been possible if only analysis of direct preparations had been undertaken.
Adult↗
Laryngeal atresia or stenosis presenting as second-trimester fetal ascites--diagnosis and pathology in three independent cases.
Congenital atresia of the larynx is a rare abnormality. We describe three cases where prenatal diagnosis during the second trimester showed massive abdominal fetal ascites and at post-mortem, laryngeal atresia was identified in two cases, and severe laryngeal stenosis in the third. All were associated with pulmonary hyperplasia. No additional abnormalities were found in other systems. Overdistended lung tissue and ascites are resultant from aberrant laryngeal growth; laryngeal anomalies are a cause of isolated fetal ascites. The association of ascites and voluminous lungs should arouse suspicion of laryngeal atresia and should be an indication for careful pathological study of the fetal larynx.
Adult↗
A 15-year follow-up of AJCC stage III malignant melanoma patients treated postsurgically with Newcastle disease virus (NDV) oncolysate and determination of alterations in the CD8 T cell repertoire.
BACKGROUND: The development of effective adjuvant therapies for the treatment of high-risk melanoma patients is critical for the prevention of metastatic disease and improvement of patient survival. Active specific immunotherapy has been tested as an adjuvant treatment in numerous clinical trials with overall limited, but occasionally promising, success rates. Newcastle disease virus (NDV) oncolysate has been utilized as an adjunctive immunotherapeutic agent in the postsurgical management of these patients. A phase II study initiated in 1975 using adjuvant vaccine therapy composed of allogeneic and autologous human melanoma cells infected with live NDV (NDV oncolysate) in patients with AJCC stage III melanoma following therapeutic lymph node dissection has shown >60% survival rate at 10 years with no adverse effects. Continued long-term analysis of trials with promising early results as well as assessment of immunologic responses generated in these patients may result in improved therapeutic decisions for clinical trials in the future. MATERIALS AND METHODS: We analyzed the 15-year survival of patients treated postsurgically with NDV oncolysate in the phase II study described above. In an attempt to understand the immunological effects of this treatment, we have also carried out a comprehensive analysis of the peripheral blood T cell repertoire in these patients. RESULTS: The overall 15-year survival of this group of patients is 55%. Previous studies have suggested that improved outcome in patients undergoing immunotherapy is correlated with increased numbers of CD8(+)CD57(+) cells. In surviving patients, we observed a striking oligoclonality in the CD8(+) T cell population in peripheral blood, which reflects clonal expansions in the CD8(+)CD57(+) subset. CONCLUSIONS: The data suggest that adjuvant vaccination with NDV oncolysates is associated with prolonged survival of patients with lymph node-positive malignant melanoma and that CD8(+) T cells may be an important component of therapeutic efficacy.
Adult↗
Gene transfer directly demonstrates a role for TCR V alpha elements in superantigen recognition.
Recent structure-function studies of ours and others indicating that regions of the TCR other than V beta are involved in the TCR-superantigen (SAg)-MHC class II trimolecular interaction were correlative; thus, while the conclusions were persuasive, they were not unequivocal. The transfection experiments described in this report show that 1) responsiveness to staphylococcal enterotoxin B in V beta6 T cells was transferred by a V alpha4- but not by V alpha8- and V alpha10-containing alpha-chain cDNA constructs, 2) responsiveness was not transferred by a chimeric alpha-chain construct containing the N and J regions from a responsive T hybrid clone and the V alpha10 V alpha region from a nonresponsive clone, and 3) responsiveness was transferred by a chimeric alpha-chain construct in which most of the V alpha region (from the N terminus to the C-terminal end of the complementarity-determining region 2) was derived from the V alpha4 alpha-chain of a responsive T hybrid and the rest (framework 3, N, and J) from the V alpha8 alpha-chain of a nonresponsive T hybrid. Thus, these data provide the first direct evidence for a specific SAg response facilitating activity in a defined V alpha segment and map this activity N-terminal of framework region 3. Furthermore, the diversity in the alpha- and beta-chain junctional regions of a panel of staphylococcal enterotoxin B-responsive V beta6 T hybrid clones excludes a stringent corequirement for a particular junctional region for the V alpha4 segment to mediate its facilitating activity. Finally, a model postulating a universal role for V alpha elements in TCR recognition of SAg is presented.
Animals↗
Pregnancy in a woman with Friedreich's ataxia.
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Journal Article↗
Uncoupling IL-2 production from apoptosis and TNF production by changing the signal through the TCR.
T cells may discriminate between stimuli in a variety of ways, including the presence of cytokines or other costimulatory signals, the type of Ag (peptide, superantigen, or allorecognition), or the magnitude of the signal through the TCR. We have used anti-CD3 stimulation of T hybridomas to examine signals generated through the TCR in the absence of exogenous APCs. Soluble whole anti-CD3, but not F(ab')2 anti-CD3, was able to stimulate the T hybridomas to produce IL-2. Plastic-bound anti-CD3, in contrast, stimulated TNF production, G1 arrest, and apoptosis by the T hybridoma. Engagement of the CD4 coreceptor on these cells had no effect on the overall pattern of signaling observed. Although TNF production was correlated with apoptosis, anti-TNF treatment did not prevent cell death or G1 arrest. The response of the T hybridoma to both forms of anti-CD3 included significant IL-2 production even at the lowest dose tested. However, soluble anti-CD3 at the highest dose tested elicited only minor apoptosis, while plastic-bound anti-CD3 elicited significant apoptosis even at the lowest dose. The difference in response was not evident at the level of phosphotyrosine proteins two min after cross-linking of the TCR.
Animals↗
Serial hematologic changes and pregnancy outcome.
OBJECTIVE: To reevaluate the concept that poor maternal hematologic changes relate to increased placental protein hormones, increased birth weight, and placenta to birth weight ratio. METHODS: Sixty-nine normal women were studied prospectively. On several occasions, pre-pregnancy, during pregnancy, and post-delivery, plasma volume was measured together with maternal hematologic indices and placental protein hormone levels. Birth weight and placental weight were measured at delivery. RESULTS: The decrements in hemoglobin concentration and hematocrit were apparent by 7 weeks' gestation. By 12 weeks, these progressive changes resulted mostly from the increase in plasma volume, and both hemoglobin concentration and hematocrit continued to decrease until near term. Increments in red cell and hemoglobin mass were maximal at 12-28 weeks of pregnancy. Concentrations of the placental hormones hCG and human placental lactogen at 12 weeks showed a lack of correlation with hemoglobin concentration or any other hematologic index. The correlations of birth weight with hemoglobin concentration and hematocrit at 36 weeks were not significant when we controlled for the effect of plasma volume. Neither hemoglobin mass at 36 weeks nor the change in hemoglobin concentration, hematocrit, and mean cell volume from the pre-pregnancy value to that at 36 weeks were significantly related to birth weight, placental weight, or the placenta to birth weight ratio. CONCLUSION: Low hemoglobin in late pregnancy reflects plasma volume changes, rather than poor maternal nutrition or adaptation, and is not linked to discordant placenta to birth weight ratio.
Confidence Intervals↗
V beta-specific activation of T-cells by the HIV glycoprotein gp160.
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Cells, Cultured↗
T cell receptor V alpha 4 is expressed by a subpopulation of V beta 6 T cells that respond to the bacterial superantigen staphylococcal enterotoxin B.
A subpopulation of murine minor lymphocyte-stimulating locus Ag (Mls)-1a-responsive, TCR V beta 6-expressing T hybrids was responsive to the superantigenic bacterial toxin, staphylococcal enterotoxin B (SEB), presented by murine MHC class II molecules. Comparative functional and surface marker analyses showed that this heterogeneity was not caused by nonspecific effects. It seemed, therefore, that the ability of the TCR V beta 6 T hybrids to respond to SEB was regulated by non-V beta TCR elements. cDNA sequencing analyses of the TCR beta- and alpha-chains expressed by the V beta 6 T hybrids and a beta-chain cDNA gene transfer experiment indicated that although J beta, CDR3 beta, J alpha, and CDR3 alpha were not the relevant elements, SEB responsiveness did correlate with the expression of two different members of the V alpha 4 family. A functional analysis of a separate panel of V alpha 4 T hybrids expressing different V beta elements, including V beta 6, specifically associated SEB responsiveness with the V alpha 4, V beta 6 combination. Overall, the data obtained with both panels of T hybrids showed SEB responsiveness in five out of five V beta 6, V alpha 4 T hybrids, and not in either 11 V beta 6 T hybrids expressing a variety of other V alpha elements or four V alpha 4 T hybrids expressing V beta 11, 14, and 15 elements. Thus, our experiments show for the first time a specific, positive qualitative effect of a defined V alpha element on responsiveness to a bacterial superantigen. Finally, this study has identified four new V alpha elements.
Amino Acid Sequence↗
The HIV glycoprotein gp 160 has superantigen-like properties.
HIV infection is characterized by paralysis of the immune system and a depletion of CD4+ cells. Recent studies demonstrating modulation of the V beta T cell receptor (TCR) repertoire in HIV patients have suggested that some of these effects may be the result of action by one or more superantigens encoded by the virus. In order to determine whether the HIV envelope glycoprotein, gp160, displays properties reminiscent of a superantigen, the T cell receptor V beta repertoire of T cells from healthy, seronegative individuals activated in vitro with gp160 was determined. In five individuals of disparate HLA type, activation by gp160 resulted in a marked skewing in the relative expression of a common set of V beta gene segments. This activation was HLA class II-dependent and did not require antigen processing. Surprisingly, the V beta segments affected by gp160 bore a striking similarity to those affected by the staphylococcal superantigen SEB. These observations suggest that exposure to superantigens produced by opportunistic infection might play an important role in disease progression.
Bacterial Toxins↗
V beta-specific activation of T cells by the HIV glycoprotein gp 160.
Studies by several groups have suggested that HIV infection in vivo results in a V beta-specific alteration of the TCR repertoire and that this might play a role in the pathogenesis of AIDS. However, there is very little agreement as to which V beta segments are affected. In order to circumvent the confounding factors present in vivo we have examined the abilities of both a crude protein extract of HIV and purified gp160 to alter the V beta repertoire of normal T cells in vitro. We find that both a crude extract of HIV as well as gp160 specifically activate T cells expressing a common set of V beta segments (V beta 3, 12, 14, 15, and sometimes V beta 17 and 20) in individuals of disparate HLA type. This set of V beta segments is remarkably similar to those recognized by staphlococcal enterotoxin B and supports the hypothesis that bacterial superantigens produced by opportunistically acquired micro-organisms could have an exacerbating effect in AIDS.
Antibodies, Monoclonal↗
Use of Laplace transform analysis to describe the effect of placental embolisation on umbilical arterial Doppler waveforms in fetal sheep.
This is the first study to investigate changes in umbilical arterial Doppler shift waveforms caused by placental embolisation in fetal lambs described by a Laplace transform analysis method. The complete maximum velocity envelope of the waveform was quantified mathematically by the coefficients of the Laplace transform. The changes in the dominant coefficient were significantly correlated with changes in umbilico-placental vascular resistance. The Doppler shift waveforms reproduced those seen clinically in some growth-retarded pregnancies and were acquired in a clinically realistic manner. Increasing vascular resistance two fold in this experiment appeared to produce more consistent changes in the dominant coefficient of the Laplace transform than in the pulsatility index. Both analysis techniques correlated with umbilico-placental vascular resistance and these correlations were not significantly different from each other.
Animals↗
A serial study of erythrocyte sodium pump kinetics and sodium content in the puerperium.
OBJECTIVE: Our purpose was to describe the alterations in erythrocyte sodium pump kinetics and sodium content occurring during the puerperium. STUDY DESIGN: Twelve healthy primigravid women were studied serially from late pregnancy until 20 weeks after delivery. Erythrocyte sodium pump rate constant, maximum velocity, and sodium affinity were calculated from the ouabain-sensitive sodium flux measured in whole blood and in erythrocytes in which sodium content had been altered with the ionophore nystatin. The Student t test was used to compare the regression coefficients of the values plotted against log time for specific periods. RESULTS: The sodium pump rate constant, maximum velocity, and sodium affinity were lower 20 weeks after delivery than in late pregnancy (0.339 +/- 0.018 vs 0.399 +/- 0.016/hr, 7.02 +/- 0.08 vs 9.98 +/- 0.078 mmol/kg/hr, 2.65 +/- 0.21 vs 3.16 +/- 0.20 mmol/kg). The decrease in the rate constant commenced after 4 days of the puerperium, whereas the decrease in maximum velocity and Michaelis-Menten constant did not commence until after 2 weeks. Erythrocyte sodium content was greater 20 weeks after delivery than in late pregnancy (4.71 +/- 0.20 vs 4.14 +/- 0.15 mmol/kg cells) and the increase was gradual over the time studied. CONCLUSIONS: After delivery the rate constant of the sodium pump measured in plasma and the erythrocyte sodium content changed before any significant alteration in the maximum velocity of the pump. The return of sodium pump function to the nonpregnant state continues beyond 6 weeks after delivery.
Erythrocytes↗
H-2 I-E molecules isolated from Mls1a stimulatory cells do not activate Mls1a-responsive T cells but do present exogenous staphylococcal enterotoxins.
The T cell response to allogeneic murine Mls determinants is not H-2 restricted but is dependent on H-2 class II molecules on the Mls-expressing stimulator cells. We have tested planar membranes containing H-2 class II I-E molecules alone or with I-A molecules for their ability to activate a panel of Mls1a-specific T hybrids. Despite the ability of the planar membranes to activate an alloreactive T hybrid and to present staphylococcal enterotoxins or an antigenic peptide to appropriately responsive T hybrids, they failed to stimulate the Mls1a-specific T hybrids. These findings, in the light of the various controls demonstrating sufficiency of the I-E molecules in the planar membranes, indicate that Mls1a determinants are not covalently bound to I-E molecules; the two molecular species are thus either not physically associated or are linked by a relatively weak interaction. In addition, our experiments show that isolated I-E molecules but not I-A molecules present staphylococcal enterotoxins A and B to two independently derived T hybrids expressing T cell receptor V beta 1, V beta 2 and V beta 6 elements.
Animals↗
The role of class II molecules in Mls 1a recognition by CD4+ T cells is independent of the CD4 molecule.
The interpretation of previous antibody inhibition and cell depletion experiments was that major histocompatibility complex (MHC) class II molecules are involved in presentation of Mls molecules to T cell receptors. However, a possible conclusion of several subsequent studies was that T cell receptors may in fact recognize Mls molecules in a class II-unassociated manner. We considered that if this interpretation of the relevant data was correct, the earlier demonstrated role of MHC class II molecules on Mls 1a antigen presenting cells in the response of CD4+ T cells might be only to serve as a ligand for the CD4 molecule on the responder cells. To test the possibility that the inhibition of the anti-Mls 1a response by anti-class II antibodies solely reflected such a CD4:class II molecular interaction, we derived CD4- variants of two independent T cell receptor V beta 6-expressing, Mls 1a-responsive T hybrid clones. Since preliminary experiments to screen for responsiveness revealed that the CD4- variants of both T hybrid clones retained responsiveness to Mls 1a and the variants of one that was also responsive to staphylococcal enterotoxin B retained that responsiveness, we concluded that there is no qualitative dependency of the responses of V beta 6 T cells to these two superantigens on a CD4-mediated activity. More importantly, the responses of the CD4- variants of the two T hybrid clones to Mls 1a retain the same susceptibility to inhibition by antibodies to MHC class II molecules exhibited by the parental T hybrids. These results indicate that the blocking of responses of CD4+ T cells to Mls 1a by both anti-H-2A and anti-H-2E antibodies is not due only to disruption of interactions between CD4 and H-2A or H-2E molecules. The data are thus consistent with the class II molecule-dependent models of Mls 1a presentation to the T cell receptor which are discussed in the light of recent findings on the biochemical nature of the Mls 1a molecule.
Animals↗