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Biomedical subjects

A G Engel

Publications and source records attributed to A G Engel.

At least 19 recordsLinked to original sources
PubMed1992

Autoaggressive myocytotoxic T lymphocytes expressing an unusual gamma/delta T cell receptor.

Polymyositis mediated by gamma/delta T cells is a unique disease in which autoaggressive T lymphocytes surround, invade, and destroy muscle fibers. Histochemically, the vast majority of muscle-infiltrating T cells in a patient with polymyositis were reactive with a pan-gamma/delta T cell receptor (TCR)-specific monoclonal antibody (TCR-delta 1+), but unlike > 90% of peripheral blood gamma/delta T cells, these lymphocytes did not react with V delta 1- or V gamma 9-specific antibodies (A13- and Ti gamma A-, respectively). Differential reactivity with two different V delta 2-specific monoclonal antibodies (BB3-/TiV-delta 2+) indicated that the infiltrating T cells express a V delta 2-containing TCR with unusual additional structural features. Using conventional and anchored polymerase chain reaction for the analysis of TCR transcripts, we found a striking predominance of one unusual V delta 2-J delta 3 recombination and one V gamma 3-J gamma 1 recombination. Both the unusual phenotype (TCR-delta 1+/A13-/Ti gamma A-/BB3-/TiV-delta 2+) and the dominance of distinct TCR transcripts are compatible with the assumption that one T cell clone, which expresses a V gamma 3-J gamma 1-C gamma 2/V delta 2-J delta 3-C delta disulfide-linked TCR, dominates among the infiltrating T cells of the polymyositis muscle specimen analyzed.

Base Sequence↗
PubMed1992

Polymyositis.

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Histocompatibility Antigens Class I↗
PubMed1992

Expression of 65-kd heat shock proteins in the inflammatory myopathies.

In normal muscle, 65-kd heat shock proteins (hsp) were detected on capillary endothelial cells, the mural elements of larger vessels, and some intracellular organelles, probably mitochondria. In the inflammatory myopathies, the 65-kd hsp were detected on inflammatory cells, degenerating and regenerating fibers, and on many but not all nonnecrotic muscle fibers invaded by T cells. The expression of the 65-kd hsp may be an immune-nonspecific response to cellular "stress," but hsp determinants could possibly also serve as autoantigen(s) recognized by autoreactive T cells.

Fluorescent Antibody Technique↗
PubMed1992

The role of gamma-delta T lymphocytes in inflammatory muscle disease.

During the course of a systematic study of T cell lines derived from muscle of patients with various inflammatory myopathies, we identified a new form of polymyositis that is mediated by gamma-delta T cells. In the affected patient's muscle CD3+CD4-CD8- gamma-delta T cells surrounded and invaded nonnecrotic muscle fibers in the same way as CD3+CD8+ alpha-beta T cells surround and invade nonnecrotic muscle fibers in inclusion body myositis and other forms of polymyositis. Gamma-delta T cells were extremely rare or absent in muscles and muscle-derived T cell lines in other patients with polymyositis, inclusion-body myositis, dermatomyositis or granulomatous myopathy. This new form of polymyositis has provided us with a unique opportunity to study cytotoxic gamma-delta T cells and their muscle-fiber targets in situ. All muscle fibers expressed HLA-class I antigen and the 65-kD heat-shock protein. The autoaggressive behavior of the gamma-delta T cells is consistent with the hypothesis that in some inflammatory myopathies autoinvasive T cells recognize muscle fiber associated antigen(s). Further studies are needed to define the type of gamma-delta T cell receptor used and the antigen(s) recognized by gamma-delta T cells in this rare type of autoimmune muscle disease.

Animals↗
PubMed1991

Polymyositis mediated by T lymphocytes that express the gamma/delta receptor.

BACKGROUND: The invasion and destruction of nonnecrotic muscle fibers by CD8+ cytotoxic T cells is considered a hallmark of polymyositis. In the cases of polymyositis reported so far, the autoinvasive CD8+ T cells expressed the common form of T-cell receptor for the recognition of antigen, the so-called alpha/beta T-cell receptor. We describe a 69-year-old man with polymyositis mediated by CD4-, CD8- T cells expressing the recently discovered, uncommon gamma/delta T-cell receptor. METHODS: We used immunofluorescence or immunoperoxidase techniques to study frozen sections of muscle from our patient, who had mild weakness of cervical and proximal limb muscles, and from control patients with polymyositis, inclusion-body myositis, dermatomyositis, or granulomatous myopathy with monoclonal antibodies against T-cell-related antigens (CD2, CD3, CD4, CD8, and gamma/delta T-cell receptor), B cells (CD22), major histocompatibility complex (MHC) and MHC-related antigens (MHC Class I, CD1a, CD1b, and CD1c), and the 65-kd heat-shock protein. The membrane contacts between the autoinvasive cells and the sarcolemma were investigated by electron microscopy. RESULTS: In the patient described here, but not in 28 others with inflammatory myopathies, myriad gamma/delta T cells surrounded and invaded nonnecrotic muscle fibers. All muscle fibers were highly reactive for MHC Class I antigen and the 65-kd heat-shock protein. Treatment with prednisone improved the clinical and histologic findings. CONCLUSIONS: Polymyositis can be mediated by gamma/delta T cells. This new form of polymyositis appears to be highly responsive to steroids.

Aged↗
PubMed1991

Coculture with autologous myotubes of cytotoxic T cells isolated from muscle in inflammatory myopathies.

T-cell lines were expanded from muscle of 10 patients with polymyositis, 5 with inclusion body myositis, 5 with dermatomyositis, and 5 with other muscle diseases. All cell lines uniformly expressed T-cell antigens, but not natural killer cell or B-cell antigens. The proportion of helper (CD4+) and cytotoxic (CD8+) T cells in the expanded lines was variable and showed no correlation with the diagnosis. Sixteen cell lines (6 polymyositis, 4 inclusion body myositis, 5 dermatomyositis, 1 other muscle disease) consisted predominantly of CD8+ T cells. None of these lines displayed natural killer-like cytotoxicity but all were capable of lectin-dependent cytotoxicity. Three of 6 polymyositis, 1 of 4 inclusion body myositis, and 1 of 5 dermatomyositis lines showed low but statistically significant cytotoxicity against autologous myotubes (6 to 27% specific 51Cr release; effector-target ratio, 20:1). The results demonstrate that functionally competent cytotoxic T cells can be expanded from muscle affected by inflammatory myopathies and are consistent with the hypothesis that some cytotoxic T cells recognize an autoantigen on myotubes. Further studies of this experimental system may define the molecular mechanism of T cell-mediated muscle fiber injury and may help to identify the relevant antigens.

Antigens, Surface↗
PubMed1991

Eosinophilia myalgia syndrome: I. Immunocytochemical evidence for a T-cell-mediated immune effector response.

Specimens of muscle and fascia from 13 patients fulfilling the Centers for Disease Control criteria for the eosinophilia myalgia syndrome (EMS) were studied by quantitative immunocytochemical analysis. The immunolocalization of CD3, CD4, CD8, CD22, and CD56 markers, the gamma delta T-cell receptor, major histocompatibility complex (MHC) class I complex and class II antigens, and complement membrane attack complex (MAC) were examined. The distribution and relative proportions of T cells and T-cell subsets, B cells, macrophages, and eosinophils were determined at perivascular, perimysial, endomysial, and fascial sites of accumulation. At all sites, T cells were predominant, CD8+ cells outnumbered CD4+ cells 6- to 20-fold, and between 60 and 80% of T cells were activated. B cells and eosinophils each accounted for less than 3% of inflammatory cells. Very few cells expressed either the gamma delta T-cell receptor or natural killer cell markers. As in dermatomyositis (DM), MHC class I antigen complex expression was increased on many structurally normal muscle fibers, but in contrast to DM, microvascular MAC deposits were not a feature of EMS. The findings implicate a cellular immune response directed against a connective tissue component in EMS.

Adult↗
PubMed1991

Mitochondrial DNA deletions in mitochondrial cytopathies: observations in 19 patients.

Among 56 patients with mitochondrial myopathies or cytopathies, 19 had large-scale deletions of mitochondrial DNA (mtDNA). Consistent with previous observations, all 19 had progressive external ophthalmoplegia and 12 had complete or partial Kearns-Sayre syndrome. One of two patients in whom mitochondrial rather than whole muscle DNA was analyzed had multiple populations of deleted mtDNA (dmtDNA). In all patients, the length of dmtDNA was inversely related to age of onset, but was not related to multiplicity of organ involvement. Patients with greater than 50% dmtDNA tended to have an earlier onset of symptoms and a higher proportion of ragged-red fibers and cytochrome c oxidase (CCO)-negative fibers than patients with less than 50% dmtDNA, but these differences did not reach statistical significance. In some patients, CCO-negative fibers were more abundant than ragged-red fibers, indicating that the distribution of abnormal mitochondria can be more widespread than suggested by the frequency of ragged-red fibers. In biochemical assays, citrate synthase activity was a better reference for detecting defects in the respiratory complexes than the wet weight of muscle. Using this reference, 10 of 14 patients had one or more respiratory complex defects, and 74% of the observed defects could be correlated with an appropriate mtDNA deletion.

Adolescent↗
PubMed1991

Necrotizing myopathy with pipestem capillaries, microvascular deposition of the complement membrane attack complex (MAC), and minimal cellular infiltration.

Three adult patients, two with undifferentiated connective tissue disease and one with carcinoma, had a distinctive pathologic reaction pattern consisting of necrotizing myopathy, minimal cellular infiltration, and a microangiopathy with thick "pipestem" vessels and microvascular deposits of complement membrane attack complex. Quantitative analysis revealed focal capillary depletion. This pattern represents an immune-mediated microangiopathy and is distinct from that observed in other inflammatory myopathies.

Aged↗
PubMed1990

The clinical spectrum of the eosinophilia-myalgia syndrome associated with L-tryptophan ingestion. Clinical features in 20 patients and aspects of pathophysiology.

We describe the clinical spectrum of the L-tryptophan-associated eosinophilia-myalgia syndrome in 20 patients. In all but one case, patients met the Centers for Disease Control (CDC) case definition for the syndrome: peripheral blood eosinophilia (eosinophil count greater than 1.0 x 10(9)/L) and generalized, disabling myalgias without other recognized causes. Three patients with eosinophilia and myalgia developed eosinophilic fasciitis, and 4 other patients developed, respectively, pneumonitis and myocarditis, neuropathy culminating in respiratory failure, encephalopathy, and fibrosis about the common bile duct. No relation was apparent between dose or duration of L-tryptophan exposure and the eosinophilia-myalgia syndrome. No organic contaminants were identified in L-tryptophan preparations taken by patients or asymptomatic users when these preparations were examined by chromatography or mass spectroscopy. Biopsy specimens in 12 patients showed a mononuclear exudate with a variable admixture of eosinophils in affected tissues, including skin, fascia, muscle, and some viscera. Eosinophil toxic granule proteins, major basic protein, and eosinophil-derived neurotoxin were elevated in the serum and urine of patients compared with normal control subjects (P less than 0.01 and P less than 0.02, respectively). Immunofluorescence showed major basic protein deposited outside of eosinophils in affected tissues, indicating that toxic granule proteins are released in diseased organs. Treatment included withdrawal of L-tryptophan in all cases. Corticosteroids were prescribed for 16 patients and diuretics alone for 1 patient; no drugs were prescribed for 3 patients. Four patients have recovered fully, others are stable or slowly recovering, and 1 is gravely ill despite prolonged treatment.

Adult↗
PubMed1990

Microvascular changes in early and advanced dermatomyositis: a quantitative study.

In adult dermatomyositis 10 muscle specimens with no or minimal histological alterations were compared with 7 that showed typical alterations. Five specimens from patients with inclusion body myositis, 5 from patients with polymyositis, and 8 from normal subjects served as controls. Vascular endothelium, visualized with the lectin Ulex europaeus agglutinin I, and complement membrane attack complex were demonstrated in the same cryostat sections by paired immunofluorescence. Large randomly selected fields were analyzed to determine the number of capillaries per square millimeter of fiber area (capillary density), per 1,000-microns 2 area of each muscle fiber (capillary index), and in 100 x 100-microns grid squares. In dermatomyositis specimens with minimal structural alterations there was focal capillary depletion, the capillary density was significantly reduced, and the frequency distributions of the capillary index and grid count were shifted to the left. In advanced dermatomyositis specimens, the findings were similar but more severe. In both kinds of specimens, clusters of capillaries reacted for complement membrane attack complex. The 2 patients with the highest proportion of vessels positive for membrane attack complex had a fulminant and fatal course. In polymyositis and inclusion body myositis specimens, the capillaries had a normal overall density and none reacted for membrane attack complex. The findings imply that the capillaries are an early and specific target of the disease process in dermatomyositis.

Adult↗
PubMed1990

Adult phosphorylase b kinase deficiency.

Phosphorylase b kinase deficiency affecting muscle has been observed infrequently in children with weakness and hepatomegaly, and in 2 adults with cramps on exertion. We observed 2 additional adults with phosphorylase b kinase deficiency: Patient 1, aged 58, had progressive, predominantly distal weakness since age 46 but no cramps on exertion; Patient 2, aged 26, had cramps on exertion since age 6 but no weakness. Lactate production on ischemic exercise was impaired only in Patient 1. The serum creatine kinase level was elevated in both. Muscle specimens showed focal glycogen excess in both, and a necrotizing myopathy and mild denervation atrophy in Patient 1. Muscle phosphorylase b kinase activity was 0.5% and 8.9% of the lowest control value in Patients 1 and 2, respectively; erythrocyte phosphorylase b kinase activity was normal in both; liver phosphorylase b kinase activity, measured in Patient 1, was also normal. Other glycolytic enzymes in muscle were preserved in both.

Adult↗
PubMed1990

Neuromuscular transmission in the mdx mouse.

In both disorders, the muscle fiber plasma membrane is rendered selectively vulnerable by dystrophin deficiency. In both disorders there are also ultrastructural abnormalities involving the postsynaptic membrane of the neuromuscular junction. The object of this electrophysiologic study was to determine whether the observed ultrastructural abnormalities at the mdx neuromuscular junction are associated with an abnormality of neuromuscular transmission. In comparison with age-matched control mice, the mdx mice show an abnormal, age-dependent decrease of the amplitude of the miniature end-plate potential and a concomitant increase in the quantal content of the end-plate potential. Consequently, the safety margin of neuromuscular transmission is not impaired.

Animals↗