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Biomedical subjects

A R Lawton

Publications and source records attributed to A R Lawton.

At least 19 recordsLinked to original sources
PubMed2000

Muscle abnormalities in juvenile dermatomyositis patients: P-31 magnetic resonance spectroscopy studies.

OBJECTIVE: To characterize metabolic abnormalities in the muscles of children with the juvenile variant of dermatomyositis (JDM) by the use of noninvasive P-31 magnetic resonance spectroscopy (MRS). METHODS: Thirteen patients with JDM (ages 4-16 years) were studied. Biochemical status was evaluated with P-31 MRS by determining the concentrations of the high-energy phosphate compounds, ATP and phosphocreatine (PCr), ratios of inorganic phosphate (Pi) to PCr (Pi:PCr ratio), levels of free cytosolic ADP, and phosphorylation potentials (PPs) during rest, exercise, and recovery. RESULTS: Significant metabolic abnormalities were observed in the thigh muscles of 10 severely affected patients during rest, 2 graded levels of exercise, and recovery. Mean ATP and PCr levels in the muscles of JDM patients were 35-40% below the normal control values (P < 0.003). These data, along with elevated Pi:PCr ratios, higher ADP levels, and abnormal values for PPs, indicated defective oxidative phosphorylation in the mitochondria of diseased JDM muscles. MRS findings were normal in 2 additional patients who had improved with prednisone treatment and in 1 patient who had no muscle weakness (amyopathic variant of JDM). CONCLUSION: JDM patients can be monitored with noninvasive P-31 MRS without sedation. Biochemical defects in energy metabolism are concordant with the weakness and fatigue reported by JDM patients. Quantitative MRS data are useful for evaluating patients and optimizing drug treatment regimens.

Adolescent↗
PubMed1999

Periodic fever syndrome in children.

OBJECTIVES: To describe the presentation, clinical course, therapeutic response, and long-term follow-up of patients with a syndrome of periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA). STUDY DESIGN: Patients with PFAPA (n = 94) referred over a 10-year period completed a registry form and provided medical records. Follow-up telephone calls were made in late 1997 to determine the persistence of episodes and sequelae. RESULTS: PFAPA episodes lasted 4.8 days (95% confidence interval 4.5 to 5.1) and recurred every 28 days (confidence interval 26 to 30), with a maximal temperature of 40.5 degrees C (confidence interval 40. 4 degrees to 40.6 degrees ). Of the 83 children available for follow-up, 34 no longer had episodes. In the remainder the episodes did not differ in character but recurred less frequently over time. The affected children had no long-term sequelae. Glucocorticoids were highly effective in controlling symptoms. Tonsillectomy and cimetidine treatment were associated with remission in a small number of patients. CONCLUSIONS: PFAPA is a not uncommon cause of periodic fever in children. In some children the syndrome resolves, whereas symptoms in others persist. Long-term sequelae do not develop. The syndrome is easily diagnosed when regularly recurring episodes of fever are associated with aphthous stomatitis, pharyngitis, or cervical adenitis.

Age of Onset↗
PubMed1994

Increased interleukin-6 (IL-6) production in a young child with clinical and pathologic features of multicentric Castleman's disease.

A 21-month-old boy presented with a papular rash, lymphoadenopathy, and splenomegaly. He developed symmetric polyarthritis, fever, and progressive glomerulonephritis. Serologies for viral agents including HIV were negative. Antinuclear antibody was transiently positive, but no anti-DNA antibodies were present. CH50 and serum C3 values were low. Biopsies of skin, kidney, bone marrow, and lymph node were obtained. There was a perivascular and periadnexal lymphocytic infiltrate in the skin, with a normal epidermis. Renal biopsy showed proliferative mesangial glomerulonephritis. Bone marrow showed an increased number of plasma cells. Lymph node showed histologic changes described in multicentric Castleman's disease including marked follicular hyperplasia, vascular proliferation, and interfollicular expansion with numerous plasma cells. IL-6 mRNA was demonstrated in cells in the marginal zone and interfollicular regions of the node by in situ hybridization. Likewise, the serum IL-6 level was elevated during a clinical exacerbation of the patient's nephritis. These data suggest an underlying lymphoproliferative disorder, such as Castleman's disease, with overproduction of IL-6 resulting in systemic features of the disease, including glomerulonephritis.

Castleman Disease↗
PubMed1994

Immunization of the neonate.

The generation of diversity of T and B cells begins early in gestation. Selective restrictions in expression of V genes occur in fetal life, but insufficient clonal diversity is not likely to limit newborn immune capabilities. The functional immaturity of neonatal T and B cells is beginning to be defined. Virgin T cells lack the capacity to produce diverse lymphokines, whereas neonatal B cells are less responsive to the lymphokines that promote terminal differentiation to plasma cells.

Age Factors↗
PubMed1994

Hyper IgM syndrome associated with defective CD40-mediated B cell activation.

Recent studies show that most patients with X-linked hyper IgM syndrome have defects in the gene for CD40 ligand. We evaluated 17 unrelated males suspected of having X-linked hyper IgM syndrome. Activated T cells from 13 of the 17 patients failed to bind a soluble CD40 construct. In these patients, the sequence of CD40 ligand demonstrated mutations. By contrast, T cells from the remaining four patients exhibited normal binding to the CD40 construct. Sequencing of the cDNA for CD40 ligand from these patients did not show mutations. The possibility that hyper IgM syndrome in these four patients was due to abnormalities in the B cell response to CD40-mediated signals was examined. Peripheral blood lymphocytes were stimulated with anti-CD40 alone, IL4 alone or anti-CD40 plus IL4. In comparison with B cells from controls or patients with hyper IgM syndrome and mutant CD40 ligand, B cells from the patients with hyper IgM syndrome and normal CD40 ligand were defective in their ability to secrete IgE (P < 0.02) or express activation markers, CD25 and CD23 (P < 0.02) in response to stimulation with anti-CD40. The failure of these B cells to respond to CD40-mediated activation could not be attributed to a generalized deficiency in B cell activation because IL4 induced normal up-regulation of CD23 and CD25 expression. These findings indicate that hyper IgM syndrome may result from defects in expression of CD40 ligand by activated T cells or defects in CD40-mediated signal transduction in B cells.

Antigens, CD↗
PubMed1993

Coordinate transcriptional control of murine endogenous retrovirus and Ig genes during B cell differentiation.

Proliferation and differentiation of B lymphocytes are usually concurrent but independently regulated events. Anti-mu treatment of murine B lymphocytes stimulated with LPS provides a model system in which proliferation and differentiation may be independently studied. This treatment causes enhanced proliferation but with coordinate suppression of transcription of a family of unrelated genes including those for Ig heavy and light chains, J chain, and endogenous murine leukemia virus (MuLV) sequences. We show that in comparison to B lymphocytes stimulated with LPS alone cells stimulated with a combination of anti-mu and LPS exhibit relatively increased amounts of a nuclear binding factor(s), NF mu E1, which interacts with the B (mu E1) site of the IgH enhancer; binding is strongly inhibited by a synthetic probe of the B sequence. A negative regulatory sequence contained within the upstream conserved region (UCR) of the MuLV long terminal repeat (LTR) is identical to the complement of mu E1 in eight of nine bases and inhibits binding of NF mu E1 to the IgH enhancer probe. The mu E1 site is also present 3' to the kappa-light chain gene; binding of this sequence to a repressor protein may coordinately suppress the transcription of mu, kappa, and MuLV genes. Others have reported that the cDNA encoding NF mu E1, also known as mu EBP-B, CF-1, and YY-1, predicts a protein with structural features consistent with variable function as either a transcriptional activator or repressor.

Animals↗
PubMed1992

Cellular infiltration of the vitreous in a patient with X-linked immunodeficiency with increased IgM.

We studied visual impairment caused by benign lymphoid infiltration of the vitreous bilaterally, as a complication of a primary immunodeficiency, X-linked immunodeficiency with increased IgM in an 8-year-old boy. Immunophenotyping of a vitreous aspirate showed a mixed cell population, including lymphocytes (T helper, suppressor-cytotoxic T cells, and B cells) and macrophages. Cultures of the vitreous were negative for bacterial or fungal pathogens. The vitreous infiltrates have been resistant to treatment with corticosteroids and cytotoxic agents.

Agammaglobulinemia↗
PubMed1990

Hybridomas derived from lipopolysaccharide-activated anti-mu-treated B cells have active suppression of IgM secretion, demonstrable by secondary fusion.

Treatment of LPS-stimulated mouse B cells with bivalent anti-mu antibodies suppresses differentiation to Ig-secreting cells without interfering with proliferation. This treatment selectively inhibits up-regulation of transcription of differentiation-related genes. Induction of anti-mu suppression requires RNA and protein synthesis, suggesting involvement of a transcriptional repressor. We describe experiments designed to capture the repressed phenotype of anti-mu-treated cells. Fusions of anti-mu-treated cells with the B lymphoma line M12.4.5, but not plasmacytoma Ag8.653, yielded a significantly lower frequency of secretory hybridomas than did parallel fusion of cells treated with LPS only. To test for active repression, nonsecreting cloned hybridomas were secondarily fused to LPS-activated normal B cells. Secondary hybridomas with anti-mu parentage had a very low frequency of IgM secretion. Active suppression could only be demonstrated by secondary fusion. Neither supernatants nor extracts of repressor hybridomas influenced LPS-driven differentiation of normal B cells. These results confirm that this form of differentiation suppression is an active process, probably mediated by transcriptional controls. Repressor hybridomas should prove useful for studies of molecular mechanisms.

Animals↗
PubMed1989

PFAPA syndrome.

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Child, Preschool↗
PubMed1988

Differentiation of human B lymphocyte subpopulations induced by an alloreactive helper T-cell clone.

We have used cloned alloreactive helper T cells to determine if direct T cell-B cell interaction can induce differentiation of human peripheral blood B cells which do not respond to pokeweed mitogen (PWM). T-cell clone 2F8 was derived from a one-way mixed lymphocyte reaction. 2F8 cells are T3+T4+T8-IL-2R+ and proliferate in response to irradiated stimulator cells, but not autologous cells, in the absence of exogenous interleukin-2. 2F8 cells provide allospecific help for polyclonal proliferation and differentiation of B cells in the absence of any other stimulus. The magnitude of this response is comparable to that of the response of the same B cells to PWM and fresh autologous T cells. 2F8 cells could also provide nonspecific help for unrelated donor B cells in the presence of PWM, with no requirement for costimulation by irradiated stimulator cells. Allospecific stimulation of B cells was completely inhibited by antibodies to class II major histocompatibility complex (MHC) framework determinants and was abrogated by 1000-rad irradiation. Cloned 2F8 T cells stimulated differentiation of both small, high-density B cells and larger B cells, generating up to 30% plasma cells with either fraction. B cells forming rosettes with mouse erythrocytes were also induced to differentiate by the helper T cell clone. As found previously, neither small, high-density B cells nor mouse rosette+ B cells responded well to PWM. Direct interaction with allospecific T cells induces differentiation of a broader spectrum of B cells than soluble growth and differentiation factors in conjunction with polyclonal activators such as PWM and protein A containing staphylococci.

Adult↗
PubMed1988

Regulation of B-cell differentiation: anti-mu antibodies have opposite effects on differentiation stimulated by bacterial lipopolysaccharide and 8-mercaptoguanosine.

The mechanisms by which proliferation and differentiation are independently regulated are among the most interesting and complex problems in cell biology. Polyclonal activation of mouse B cells by bacterial lipopolysaccharide (LPS) has served as a useful model for study of these phenomena. Treatment of LPS-stimulated cells with high concentrations of bivalent antibodies to the IgM receptor uncouples these normally linked processes, enhancing proliferation while suppressing differentiation. A consensus summary of recent results from several laboratories suggests that modulation of the IgM receptor greatly reduces mRNA levels for mu and k chains, primarily by blocking the increased rate of transcription usually triggered by LPS. The expression of other differentiation-linked proteins, for example J chain and endogenous retroviral proteins, is similarly downregulated. Basal transcription of the mu-delta complex and other constitutively expressed genes, such as Class I and Class II MHC genes, is not affected. Both suppression of differentiation and enhancement of proliferation in this system depend upon the simultaneous presence of anti-mu and LPS--cells treated with saturating concentrations of anti-mu, washed, and then cultured in LPS are not suppressed, while cells pulsed briefly with both agents before culture with LPS are suppressed. These observations have led us to examine interactions of anti-mu antibody with another potent polyclonal B cell activator, 8-mercaptoguanosine (8SGuo). In this report, we show that anti-mu antibodies have polar effects on B-cell differentiation induced by 8SGuo and LPS. Differentiation induced by the former is strongly enhanced, while that induced by the latter is suppressed. The signal induced by co-stimulation with LPS and anti-mu is dominant, as suppression occurs when LPS is added to cells stimulated with 8SGuo and anti-mu at initiation or as late as 48 hours of a 96-hour culture. We present preliminary evidence that augmented B-cell differentiation caused by combined stimulation with 8SGuo and anti-mu is dependent upon a soluble factor released during the first 24 hours of culture. These results provide additional evidence that suppression of LPS-driven B-cell differentiation is an active process, probably mediated by a trans-acting repressor of transcription. The mechanisms by which 8SGuo and anti-mu interact to enhance B-cell differentiation remain to be determined.

Animals↗
PubMed1987

Mechanism of suppression of lipopolysaccharide-driven B cell differentiation by anti-mu antibodies. Evidence for a trans-acting repressor of transcription.

Bivalent anti-mu antibodies suppress LPS-driven B cell differentiation by inhibiting the coordinate activation of a family of differentiation-related genes, including those encoding the heavy, light, and J chains of IgM. We have shown that the presence of inhibitors of RNA or protein synthesis during a pulse with anti-mu can interfere with induction of suppression. We suggest that suppression is mediated by a trans-acting repressor protein with specificity for common motifs in regulatory regions of each of these genes.

Amanitins↗
PubMed1987

LPS augments human B-cell differentiation by direct stimulation of PWM-responsive B cells.

Bacterial lipopolysaccharide (LPS) augments production of IgM and IgG by two- to seven-fold in cultures of peripheral blood lymphocytes (PBL) stimulated by pokeweed mitogen (PWM), but only if monocytes are rigorously depleted. When PBL were separated into adherent cell (AC), B-cell-enriched, and T-cell-enriched fractions, pulsed with LPS, and recombined in culture with PWM, increased generation of plasma cells was seen only in cultures containing LPS-treated B cells. This effect of LPS appears to be independent of soluble factors. Supernatants from LPS-stimulated B cells or AC did not consistently increase PWM responses when cultured with fresh B cells in the presence of polymyxin B. Furthermore, pulsing of B cells with purified interleukin 1 from two different commercial sources failed to augment PWM-induced differentiation. When B cells were depleted of surface IgD (sIgD)-bearing cells by panning, no effect on LPS-mediated augmentation of PWM-driven differentiation was seen. B cells were also fractionated by rosetting with mouse erythrocytes. Treatment of BMR+ cells with LPS did not induce them to respond to PWM, while treatment of BMR- cells with LPS augmented generation of plasma cells. These results indicate that LPS acts directly to augment differentiation of PWM-responsive B cells, rather than recruiting sIgD+, BMR+ cells to become PWM responsive.

Adult↗
PubMed1987

Syndrome of periodic fever, pharyngitis, and aphthous stomatitis.

A syndrome of periodic fever that resembles human cyclic neutropenia in its clinical presentation has been identified in 12 children observed at two major referral centers. Attacks characterized by abrupt onset of fever, malaise, chills, aphthous stomatitis, pharyngitis, headache, and tender cervical adenopathy occur at 4- to 6-week intervals over periods of years. These episodes of illness resolve spontaneously in 4 to 5 days. Mild leukocytosis and elevation of the erythrocyte sedimentation rate during attacks are the only laboratory abnormalities. Affected children grow normally, are not unusually susceptible to infection, and exhibit no long-term sequelae. Attacks may be aborted by short courses of prednisone but do not respond to nonsteroidal anti-inflammatory agents. This syndrome is sporadic and appears to be much more common than cyclic neutropenia.

Blood Sedimentation↗
PubMed1987

Anti-mu antibody blocks LPS driven B cell differentiation by suppressing specific mRNAs.

High concentrations of anti-mu antibodies inhibit differentiation and increase proliferation of adult mouse splenic B cells stimulated by LPS. Cells from treated cultures express Ia antigens and on removal of anti-mu reexpress membrane IgM. They do not develop into plasmablasts secreting IgM. To investigate the mechanism of suppression we used Northern blots hybridized with cDNA probes to mu, kappa, J, and I-A beta chains to analyze RNAs in anti-mu suppressed and control cultures. Messenger RNAs for mu, kappa, and J chains but not I-A beta chain are diminished in anti-mu treated cells as compared to controls. Cells treated with anti-kappa antibodies have decreased mRNA levels for mu as well as kappa chains. Suppression mediated by modulation of the IgM receptor is not immunologically specific, but selectively inhibits expression of a cluster of unlinked genes which are coordinately activated during differentiation.

Animals↗
PubMed1986

Ontogeny of B cells and pathogenesis of humoral immunodeficiencies.

Studies of B-cell ontogeny have played an important role in furthering our understanding of the pathogenesis of immunodeficiencies. Development of clonal diversity for both T and B cells begins during the first trimester and is far advanced by midgestation. Fetal and neonatal B cells have a limited capacity to express IgG and IgA antibody responses, although precursors expressing these immunoglobulin classes are present. T-and B-cell interactions in the neonate are dominated by suppression. T helper cells are present and functional, but their capacity to drive IgG and IgA responses is impaired. This paper will review the major steps in ontogenetic development of B cells and the functions associated with each differentiation stage. Possible pathogenetic mechanisms of several humoral immunodeficiency diseases are reviewed from the perspective of the normal progression of B-cell differentiation.

Animals↗