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R Hohlfeld

Publications and source records attributed to R Hohlfeld.

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

Human myoblasts as antigen-presenting cells.

Human myoblasts, cultured from muscle and purified to greater than 95%, were investigated for their capacity to act as facultative APC. The myoblasts reacted with antidesmin mAb and had the capacity to fuse into multinucleated myotubes in appropriate medium. The expression of HLA class I, HLA-DR, HLA-DP, HLA-DQ, intercellular adhesion molecule-1 (ICAM-1/CD54), lymphocyte function-associated (LFA) molecules LFA-1 (CD11a/CD18), LFA-2 (CD2), and LFA-3 (CD58) was investigated by FACS analysis before and after induction for various times with human rIFN-gamma, TNF-alpha, or both. Without cytokine induction, myoblasts expressed only HLA-class I and LFA-3. IFN-gamma alone or in combination with TNF-alpha induced the expression of HLA-DR and ICAM-1 reaching a plateau after 48 h, followed by HLA-DP and even later HLA-DQ. TNF-alpha alone induced only ICAM-1. The functional capacity of myoblasts to present Ag to CD4+ T cells was investigated using autologous T cell lines specific for tuberculin, tetanus toxoid, and human myelin basic protein. Noninduced myoblasts or myoblasts treated with TNF-alpha alone could not present any of these Ag to the T cells. However, myoblasts treated with IFN-gamma induced Ag-specific proliferation. In the presence of relevant Ag, myoblasts were killed by the T cells as observed by microscopy and measured by 51Cr release. Ag-specific T cell proliferation and myoblast killing was inhibited in the presence of anti-DR mAb. These results suggest that human myoblasts may act as facultative APC during local immune reactions in muscle.

Antigen-Presenting Cells↗
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

Transplantation of thymic autoimmune microenvironment to severe combined immunodeficiency mice. A new model of myasthenia gravis.

To study the role of the thymus in the cellular pathogenesis of myasthenia gravis (MG) we transplanted thymus tissue fragments from MG thymuses beneath the kidney capsule of severe combined immunodeficiency (SCID) mice. Immunocytochemical studies documented that the human thymus tissues are accepted as long-term grafts in the host SCID mice, with human lymphocytes, thymic stroma, and thymic myoid cells demonstrable in transplanted thymus for at least 15 weeks after transplantation. Human anti-acetylcholine receptor antibodies became detectable 1 to 2 weeks after transplantation, and in most chimeras the titers increased over at least 11 weeks to reach levels typically found in severe human MG. Human Ig deposits were detected at skeletal muscle end-plates, demonstrating that the human (auto)antibodies bound to murine acetylcholine receptor. In contrast, transfers of dissociated thymus cells only lead to a transient increase of anti-acetylcholine receptor antibodies. Our data prove that myasthenia gravis thymus is able to induce and maintain autoantibody production in immunodeprived host animals, and that this tissue contains all cellular components required for autoantibody production. Transplantation of solid thymus tissue seems to transfer an autoimmune microenvironment, which will allow direct studies of the mechanism of autosensitization inside the thymus.

Animals↗
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

Myasthenia gravis: measurement of anti-AChR autoantibodies using cell line TE671.

Anti-acetylcholine receptor (AChR) antibodies in myasthenia gravis (MG) can be quantitated using AChR extracted from the human rhabdomyosarcoma cell line TE671 (AChRTE671) as a practical alternative to AChR from human amputated limbs (AChRAMP). We compared the two antigen preparations using serum samples from different clinical groups of MG patients (n = 112) and various controls (n = 189). With two exceptions, both tests were positive or negative in the same patients. However, in the generalized MG group, the TE671 assay yielded significantly lower titers than the AChRAMP assay.

Adolescent↗