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J I Engelhardt

Publications and source records attributed to J I Engelhardt.

31 records · Page 2Linked to original sources
PubMed1994

Evidence for autoimmunity in amyotrophic lateral sclerosis.

Although the etiology and pathogenesis of ALS is unknown, increasing evidence supports a role for autoimmune mechanisms in motoneuron degeneration and death. An animal model, experimental autoimmune gray matter disease, can be induced by the inoculation of spinal cord gray matter. The experimental disease is characterized by weakness secondary to the loss of upper and lower motoneurons, accompanied by inflammatory foci within the spinal cord, and IgG at the neuromuscular junction and within UMN and LMN. In human ALS, IgG is present within the UMN and LMN, and T-lymphocytes and activated microglia have been identified within spinal cord gray matter and motor cortex. ALS IgG can passively transfer physiological changes of the neuromuscular junction to mice resulting in enhanced release of acetylcholine. The ALS IgG selectively interact with calcium channels and alter channel function. These data suggest a potential role for autoimmune mechanisms in the destruction and loss of motoneurons in ALS.

Amyotrophic Lateral Sclerosis↗
PubMed1993

Lymphocytic infiltrates in the spinal cord in amyotrophic lateral sclerosis.

OBJECTIVE: Immunohistochemical examination was undertaken to assess the presence of lymphocytes and lymphocyte subsets in the spinal cord in amyotrophic lateral sclerosis (ALS). DESIGN: Twenty-seven consecutive ALS autopsy cases and 11 consecutive disease--control autopsy cases were examined. Tissue sections were reacted with mouse monoclonal antibody to human leukocyte common antigen, or monoclonal antibody to human B-cell L26 antigen, and detected with immunoperoxidase techniques. Unfixed sections were reacted with antihuman Leu-3a and Leu-3b/CD4 or antihuman Leu-2a/CD8 mouse monoclonal antibody and then detected with peroxidase techniques. SETTING: Tertiary care hospital. CASES: Amyotrophic lateral sclerosis and non-ALS control autopsy specimens. MAIN OUTCOME MEASURE: Detection of lymphocytes by histological and immunohistochemical reactivity. RESULTS: Perivascular and intraparenchymal lymphocytic infiltrates were found in the spinal cord of 18 of 27 consecutive ALS autopsy cases. The lymphocytes possessed only T-cell markers; no B-cell markers could be demonstrated. T-helper cells were found in proximity to degenerating corticospinal tracts, while T-helper and T-suppressor/cytotoxic cells were demonstrated in ventral horns. Lymphocytes were present in the spinal cord of only one control specimen (multiple sclerosis) and in none of the remaining 10 control specimens. In ALS tissue, the lymphocytic infiltrates did not correlate with the rate of progression or stage of the disease or with the presence or absence of terminal infections. CONCLUSIONS: T-cell lymphocytes are present in the spinal cord of patients with ALS. T-helper cells are found in proximity to corticospinal tract degeneration, while T-helper and T-suppressor/cytotoxic cells are present in ventral horns. The role of these lymphocytes remains to be elucidated.

Adult↗
PubMed1993

Evidence for autoimmunity in amyotrophic lateral sclerosis.

Although the etiology and pathogenesis of ALS is unknown, increasing evidence supports a role for autoimmune mechanisms in motoneuron degeneration and death. An animal model, experimental autoimmune gray matter disease, can be induced by the inoculation of spinal cord gray matter. The experimental disease is characterized by weakness secondary to the loss of upper and lower motoneurons, accompanied by inflammatory foci within the spinal cord, and IgG at the neuromuscular junction and within UMN and LMN. In human ALS, IgG is present within the UMN and LMN, and T-lymphocytes and activated microglia have been identified within spinal cord gray matter and motor cortex. ALS IgG can passively transfer physiological changes of the neuromuscular junction to mice resulting in enhanced release of acetylcholine. The ALS IgG selectively interact with calcium channels and alter channel function. These data suggest a potential role for autoimmune mechanisms in the destruction and loss of motoneurons in ALS.

Amyotrophic Lateral Sclerosis↗
PubMed1993

Experimental immune-mediated motor neuron diseases: models for human ALS.

Amyotrophic lateral sclerosis is an idiopathic, ultimately fatal disease, clinically manifest as progressive weakness and spasticity, associated with the loss of motoneurons. Circumstantial evidence supports a role for autoimmune processes in the progression of this human disorder. Two immune-mediated animal models have been developed in our laboratory for motor neuron loss. Experimental autoimmune motor neuron disease is a lower motor syndrome induced in guinea pigs by the repeated injection of a purified bovine spinal motor neuron antigen. Affected animals demonstrate extremity weakness, associated with electromyographic and morphologic evidence of denervation, a loss of spinal cord motor neurons, high antibody titers against motor neurons, and localization of IgG immunoreactivity to the neuromuscular junction and motor neuron cytoplasm. Experimental autoimmune grey matter disease is a more acute and severe disorder involving both upper and lower motor neurons, induced in guinea pigs by inoculation of a bovine ventral spinal cord homogenate, in which scattered foci of denervation are observed in the motor cortex and ventral spinal cord. Similarities between these diseases and human ALS are reviewed.

Amyotrophic Lateral Sclerosis↗
PubMed1992

Nigral damage and dopaminergic hypofunction in mesencephalon-immunized guinea pigs.

To support a potential role for immune mechanisms in the destruction of substantia nigra (SN) neurons, guinea pigs were immunized with bovine mesencephalon containing SN neurons. After immunization no clinical signs of basal ganglia dysfunction appeared. However, pathological examination revealed evidence of neuronal damage in the SN in 8 of 17 guinea pigs immunized with bovine mesencephalon. No nigral pathology was noted in animals immunized with spinal cord gray matter or Freund's adjuvant alone. Accompanying the SN damage in mesencephalon-immunized guinea pigs was a 25% decrease in tyrosine hydroxylase activity in the SN and a 27% decrease in dopamine content in the striatum. Deposits of IgG were detected by immunohistochemical techniques in sections of SN from mesencephalon-immunized guinea pigs and in sections of human SN after exposure to serum from mesencephalon-immunized guinea pigs. These data document the antigenicity of SN and suggest the possibility that immune mechanisms can contribute to basal ganglia pathology.

Animals↗
PubMed1991

Immunoglobulins from animal models of motor neuron disease and from human amyotrophic lateral sclerosis patients passively transfer physiological abnormalities to the neuromuscular junction.

Amyotrophic lateral sclerosis (ALS) is a devastating human disease of upper and lower motoneurons of unknown etiology. In support of the potential role of autoimmunity in ALS, two immune-mediated animal models of motoneuron disease have been developed that resemble ALS with respect to the loss of motoneurons, the presence of IgG within motoneurons and at the neuromuscular junction, and with respect to altered physiology of the motor nerve terminal. To provide direct evidence for the primary role of humoral immunity, passive transfer with immunoglobulins from the two animal models and human ALS was carried out. Mice injected with serum or immunoglobulins from the animal disease models and human ALS but not controls demonstrated IgG in motoneurons and at the neuromuscular junction. The mice also demonstrated an increase in miniature end-plate potential (mepp) frequency, with normal amplitude and time course and normal resting membrane potential, indicating an increased resting quantal release of acetylcholine from the nerve terminal. The ability to transfer motoneuron dysfunction with serum immunoglobulins provides evidence for autoimmune mechanisms in the pathogenesis of both the animal models and human ALS.

Adult↗
PubMed1990

IgG reactivity in the spinal cord and motor cortex in amyotrophic lateral sclerosis.

The spinal cord and motor cortex of patients with amyotrophic lateral sclerosis (ALS) were examined with immunohistochemical methods for the presence of IgG. In 13 of 15 spinal cords, a population of motoneurons stained positively for IgG in a granular pattern, characteristic of binding to the rough endoplasmic reticulum. In 6 of 11 motor cortices, a proportion of pyramidal cells also stained positively for IgG. No such reactivity was noted in motoneurons of control human tissues, although positive IgG staining was present in astrocytes of ALS and control specimens. Reactive microglia and/or macrophages were detected in the territory of degenerating pyramidal tracts and ventral horns. The surface of most of these cells stained positively for IgG, and 50% stained positively for HLA-DR. The accumulation of IgG in motoneurons and the presence of immunologically active macrophages provide additional evidence for the participation of immunologic factors in the pathogenesis of ALS.

Adult↗
PubMed1990

Increased MEPP frequency as an early sign of experimental immune-mediated motoneuron disease.

Intracellular recordings of miniature end-plate potentials were performed in extensor digitorum longus muscles from guinea pigs with experimental immune-mediated motoneuron destruction. In the early stages of the disease, the miniature end-plate potential frequency was elevated compared to that in control and normal animals. The amplitude and time course of the miniature end-plate potentials as well as the resting potential of the muscle fibers were not altered, which implies integrity of the postjunctional membrane. The increase in frequency of miniature end-plate potential reflects an increase of basal acetylcholine release and documents dysfunction of the presynaptic terminal of the neuromuscular junction. The increased frequency was associated with high levels of antimotoneuronal IgG in the blood and the presence of IgG at motor end-plates. These data suggest that the presynaptic terminal of the neuromuscular junction may be involved in the immune attack in animal models of motoneuron degeneration.

Animals↗
PubMed1990

Motor neuron destruction in guinea pigs immunized with bovine spinal cord ventral horn homogenate: experimental autoimmune gray matter disease.

Guinea pigs immunized with bovine spinal cord ventral horn homogenate develop muscle weakness with electromyographic and morphologic evidence of denervation. Pathological examination demonstrates a loss of motoneurons and scattered inflammatory foci primarily localized to the spinal cord. Immunohistochemical techniques document the presence of immunoglobulin G at the motor end plate and around the external membrane and within the cytoplasm of motoneurons. This syndrome of experimental autoimmune gray matter disease (EAGMD) differs from experimental autoimmune motor neuron disease induced by inoculation with purified motoneurons and also differs from experimental autoimmune encephalomyelitis. The existence of two different forms of immune-mediated motoneuron destruction suggests that a number of cytoplasmic and membrane antigens may give rise to an immunologically based attack on the motor system.

Animals↗
PubMed1989

Experimental autoimmune motoneuron disease.

An animal model of disease of the lower motoneurons has been developed by inoculating guinea pigs with bovine motoneurons. Four of 9 immunized female animals and 4 of 5 immunized male animals developed symptoms of neuromuscular degeneration marked by weakness, evidence of denervation by electromyographic and morphological criteria, and a loss of motoneurons within the spinal cord. No inflammatory foci were noted within parenchyma or meninges of the central nervous system. The immunized guinea pigs developed high serum titers of IgG class antibodies to motoneurons. Immunohistochemical studies demonstrated the presence of IgG within spinal cord motoneurons and at the end-plates of immunized animals. This experimental autoimmune motoneuron disease may provide important insights into the cause and pathogenesis of amyotrophic lateral sclerosis, a human motoneuron disease.

Animals↗