ascorbic-acid and Chediak-Higashi-Syndrome

The use of cytochemical, electron microscopic, immunofluorescent, and tissue culture techniques has led to important advances in our understanding of the mechanisms underlying the pathogenesis of the Chediak-Higashi syndrome (CHS). This rare and fatal autosomal recessive disorder is clinically characterized by partial albinism, frequent pyogenic infections, and an accelerated lymphohistiocytic phase. The pathological hallmark of CHS is the presence in all white blood cells of massive lysosomal inclusions, which are formed through a combined process of fusion, cytoplasmic injury, and phagocytosis. The abnormal inclusions exhibit both azurophilic and specific granular markers, and are probably responsible for most of the impaired leukocyte and other cell functions in CHS patients. In addition, a selective profound natural killer (NK) cell function and platelet storage pool deficiencies have been described in these patients. Impaired microtubule assembly and functions, mediated by abnormal intracellular cyclic nucleotide levels, which could be corrected by treatment with ascorbic acid, were suggested to be the pathophysiological basis for CHS abnormalities. However, some recent studies have questioned this cytoskeletal model, which is suggested to be rather a secondary manifestation of CHS.

Topics: Antineoplastic Agents; Ascorbic Acid; Bacterial Infections; Bone Marrow; Chediak-Higashi Syndrome; Cytoplasmic Granules; Histocytochemistry; Humans; Killer Cells, Natural; Leukocytes; Microscopy, Electron; Microtubules

Topics: Ascorbic Acid; Chediak-Higashi Syndrome; Cysteine; Dithiothreitol; Glutathione; Humans; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Oxidation-Reduction; Protein Processing, Post-Translational; Tubulin; Tyrosine

Topics: Anaerobiosis; Antioxidants; Ascorbic Acid; Carboxypeptidases; Chediak-Higashi Syndrome; Cyclohexanones; Diamide; Granulomatous Disease, Chronic; Humans; Methylene Blue; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Oxidation-Reduction; Peptide Synthases; Protein Processing, Post-Translational; Tubulin; Tyrosine

Ascorbic acid in physiological doses is essential for the normal functioning of the human body. Larger doses are required to treat a severe deficiency of vitamin C intake, as in the case of scurvy. Occasionally, massive doses may be required to treat a metabolic defect involving ascorbic acid. There has been some mention of megadose therapy with ascorbic acid for the prevention of colds, the improved healing of wounds and even the treatment of cancer, but no acceptable scientific data have been presented. In fact, in a few instances, such therapy has proved injurious.

Topics: Ascorbic Acid; Chediak-Higashi Syndrome; Common Cold; Female; Humans; Immunity; Infant; Male; Neoplasms; Scurvy; Wound Healing

Topics: Animals; Ascorbic Acid; Chediak-Higashi Syndrome; Concanavalin A; Cyclic GMP; Disease Models, Animal; Humans; Immunity, Cellular; Leukocytes; Lupus Erythematosus, Systemic; Mice; Mice, Inbred NZB; Prostaglandins

Topics: Ascorbic Acid; Blood Bactericidal Activity; Chediak-Higashi Syndrome; Chemotaxis; Cyclic AMP; Cyclic GMP; Humans; Infant; Leukocyte Count; Leukocytes

All leukocytes are capable of responding chemotactically (oriented locomotion) and chemokinetically (stimulated nondirected or random locomotion) to a variety of chemical agents. A brief review of the in vitro and in vivo methods of studying neutrophil movement and our present knowledge of chemotactic factors is presented as well as a discussion on the mechanisms of stimulated movement. Two clinically important instances of defects in neutrophil movement, ie, the Chédiak-Higashi syndrome and a case of actin dysfunction, are herein described.

Topics: Ascorbic Acid; Calcium; Cell Movement; Chediak-Higashi Syndrome; Chemotaxis, Leukocyte; Complement C3; Complement C5; Cyclic AMP; Cyclic GMP; Cytological Techniques; Cytoskeleton; Humans; Inflammation; Kallikreins; Lysosomes; Microtubules; Neutrophils; Oligopeptides; Plasminogen Activators; Receptors, Drug; Skin Window Technique; Sodium; Structure-Activity Relationship

Sapphire mink, a mutant colour variant of American mink, is an animal model of the Chediak-Higashi syndrome (CHS). As in CHS, there are enlarged cytoplasmic granules in various cell types including leukocytes in Sapphire mink due to abnormal granulogenesis. Such cellular abnormality leads to a weakening of the immune defence as a consequence to the development of infections. A study with Sapphire mink and Standard mink was conducted to evaluate the immunostimulant effect of vitamin C (VC) supplementation (100 mg/day) on some leukocyte parameters. In the end of the 20-day treatment period, blood samples were collected to determine hematological (total and differential leukocyte counts, red blood cells (RBC) counts, and haemoglobin level) and cytochemical (activity and staining area of myeloperoxidase, eosinophilc peroxidase, alkaline phosphatase, and alpha naphthyl acetate esterase) parameters. The study showed that total leukocyte counts, segmented neutrophil counts, and monocyte counts were significantly (p < 0.05) higher in Sapphire mink from the VC-supplemented group than in those receiving the control diet. These results indicate that VC supplementation may have a positive effect on immunity in Sapphire mink. Another interesting finding is an increase in the number of neutrophils with enlarged granules and lysosomal enzyme-positive area in VC-supplemented mink as compared with those fed the control diet. These observations suggest that VC supplementation can affect the lysosomal apparatus of leukocytes.

Topics: Aluminum Oxide; Animals; Ascorbic Acid; Chediak-Higashi Syndrome; Dietary Supplements; Leukocytes; Mink

A case of Chediak-Higashi syndrome is reported in a four-year-old boy who presented with recurrent chest infection, partial albinism, hyperpigmentation of the extremities and presence of giant granules in leucocytes and melanocytes in the skin. Parental consanguinity was present. Though uncommon, hyperpigmentation of sun exposed areas may be the initial symptom in Chediak-Higashi syndrome.

Topics: Anti-Bacterial Agents; Arm; Ascorbic Acid; Blood Transfusion; Chediak-Higashi Syndrome; Child, Preschool; Combined Modality Therapy; Facial Dermatoses; Fatal Outcome; Humans; Hyperpigmentation; Leg; Male

Topics: Adult; Ascorbic Acid; Chediak-Higashi Syndrome; Cytotoxicity, Immunologic; Female; Humans; Killer Cells, Natural; Neutrophils

The numbers and length of centriole-associated microtubules of two patients with Chediak-Higashi syndrome (CHS) were examined. Detergent-extracted whole-mount preparations of adherent cells were studied by stereo high-voltage electron microscopy. Under conditions of random migration, neutrophils from both patients had a microtubule organization similar to that of the control; microtubule numbers (28 +/- 3) and length (7.0 +/- 2.8 micron) were within normal range. When cells were treated with phorbol myristate acetate (PMA), differences in the response of the two patients were noted. Neutrophils from patient No. 2 and the control showed a significant rise in numbers (38 +/- 5) and length (9.5 +/- 3.6 micron) of microtubules. In contrast, neutrophils from patient No. 1 were unresponsive to PMA treatment. Because vitamin C is used therapeutically in CHS patients and has been shown to correct microtubule-related cell function, neutrophils were exposed to ascorbic acid. A significant increase in microtubule numbers (35 +/- 6) was observed in cells from the control and patient No. 2 after ascorbate treatment; neutrophils from patient No. 1 showed no increase in microtubule numbers. While ascorbic acid did not affect microtubule length in the control cells, it caused a significant increase in microtubule length in neutrophils from both patients. Results suggest that adherent CHS neutrophils contain centriole-associated microtubules which are normal in number and length. However, differences between patients are observed regarding neutrophil responsiveness to stimuli which induce microtubule polymerization.

Topics: Ascorbic Acid; Cell Adhesion; Cell Separation; Cells, Cultured; Chediak-Higashi Syndrome; Child; Female; Humans; Microtubules; Neutrophils; Tetradecanoylphorbol Acetate

Various defects in leukocyte function have been reported in Chédiak-Higashi syndrome (CHS); however, to our knowledge, lymphocyte locomotor capacity has not been investigated. A 7-year-old boy with typical signs and symptoms of CHS showed impaired neutrophil, monocyte, and lymphocyte locomotion. Chemotaxis studies were performed by the micropore filter technique using modified Boyden chambers, and migration was measured by the leading front method. Treatment with ascorbic acid (vitamin C), 500 mg/day for five days, resulted in a significant increase in in vitro neutrophil and monocyte chemotaxis but failed to affect lymphocyte locomotion.

Topics: Ascorbic Acid; Chediak-Higashi Syndrome; Chemotaxis, Leukocyte; Child; Humans; Lymphocytes; Male; Monocytes; Neutrophils

Topics: Adult; Arthritis, Rheumatoid; Ascorbic Acid; B-Lymphocytes; Chediak-Higashi Syndrome; Concanavalin A; Cyclic GMP; Humans; Hypersensitivity, Delayed; Immunity, Cellular; Immunoglobulins; In Vitro Techniques; Lymphocytes; Middle Aged; Monocytes; Pokeweed Mitogens; T-Lymphocytes, Regulatory

We have recently reported a specific dose-dependent stimulation of posttranslational incorporation of tyrosine into tubulin alpha-chains of rabbit peritoneal leukocytes as induced by the synthetic peptide chemoattractant formyl-methionyl-leucyl-phenylalanine (FMLP). The present study reports a similar, specific stimulation of tubulin tyrosinolation in human polymorphonuclear leukocytes (PMN). When compared to normal PMN, both the resting and FMLP-stimulated levels of posttranslational tyrosine incorporation were two- to threefold higher in PMN of three patients with the Chediak-Higashi syndrome (CHS). The concentration of cellular tubulin and the specific activity of tubulin tyrosine ligase were similar in PMN of CHS patients and normal donors and resembled that of other non-neuronal cells. The high levels of tyrosine incorporation in PMN of CHS patients were normalized by the administration of ascorbate, both in vitro and in in vivo experiments. In vitro addition of ascorbate also inhibited the FMLP-induced stimulation of tyrosine incorporation in both normal and CHS cells. Normalization of higher levels of tyrosine incorporation in PMN of CHS patients and the inhibition of FMLP-induced stimulation of tubulin tyrosinolation in normal and CHS cells as observed with ascorbate could also be affected by other reducing agents such as reduced glutathione, cysteine, or dithiothreitol. These results suggest a possible relationship between cellular redox and tubulin tyrosinolation in PMN.

Topics: Ascorbic Acid; Chediak-Higashi Syndrome; Humans; Methionine; N-Formylmethionine; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Oligopeptides; Oxidation-Reduction; Peptide Hydrolases; Protein Processing, Post-Translational; Tubulin; Tyrosine

Cultured fibroblasts from a patient with the Chediak-Higashi syndrome, the mother of the patient, and a normal control were studied by light and electron microscopy. The distribution pattern of PAS-positive and acid phosphatase-containing granules in the cytoplasm differed significantly in the fibroblasts from the patient when compared with those from the mother and control. The granules in the fibroblasts from the patient were clustered in the perinuclear area, whereas the granules in the fibroblasts from the mother and control were dispersed throughout the cytoplasm. After incubation with ascorbic acid, the clustered granules in the fibroblasts of the Chediak-Higashi syndrome showed a tendency to spread throughout the cytoplasm. The distribution pattern of the granules was studied by quantitative morphology.

Topics: Ascorbic Acid; Cells, Cultured; Chediak-Higashi Syndrome; Cytoplasmic Granules; Female; Fibroblasts; Humans; Infant; Lysosomes; Skin

Topics: Ascorbic Acid; Chediak-Higashi Syndrome; Child, Preschool; Cyclophosphamide; Drug Therapy, Combination; Female; Granulocytes; Humans; Prednisone; Vincristine

A diminished chemotactic response was observed with the neutrophils of a patient with the Chediak-Higashi syndrome, who was not in the accelerated phase of the disease. An abnormally low release of myeloperoxidase from these cells during phagocytosis was also noted; this resulted in a decreased iodination capacity and probably also caused the defect in the intracellular killing of bacteria by the neutrophils. The level of cyclic AMP in these cells was elevated, but decreased after treatment with ascorbate either in vitro or in vivo. During ascorbate therapy, the bactericidal activity of the neutrophils normalized, whereas the chemotactic response remained low. Nevertheless, the patient had significantly less infections during ascorbate therapy. The bleeding tendency, due to a storage-pool disorder of the Chediak-Higashi platelets, was unaffected by treatment with ascorbate. The patient's lymphocytes did not display any activity in antibody-dependent lymphocytotoxicity. This defect was not affected by treatment with ascorbate either.

Topics: Adenosine Diphosphate; Adolescent; Ascorbic Acid; Bleeding Time; Blood Platelets; Cell Movement; Chediak-Higashi Syndrome; Chemotaxis, Leukocyte; Cyclic AMP; Cyclic GMP; Humans; Hypersensitivity, Delayed; Lymphocytes; Male; Neutrophils; Nucleotides, Cyclic; Peroxidase

Clinical studies were done on a patient with Chediak-Higashi syndrome (CHS) with special emphasis on the accelerated phase. In order to obtain further information on the accelerated phase, haematopoiesis was studied by bone marrow culture techniques. The patient was placed on ascorbic acid therapy but she entered the accelerated phase, although the therapy improved in vitro neutrophil function to some extent. Administration of microtubulytic drugs such as vincristine, vinblastine and colchicine was effective in the management of the accelerated phase. Numbers of macrophage-granulocytic (CFU-C) and erythroid (CFU-E) progenitor cells were markedly decreased or absent during the accelerated phase, being another indicator of the accelerated phase.

Topics: Ascorbic Acid; Bone Marrow; Chediak-Higashi Syndrome; Colchicine; Colony-Forming Units Assay; Female; Humans; Infant; Neutrophils

Topics: Ascorbic Acid; Chediak-Higashi Syndrome; Cyclic AMP; Cyclic GMP; Humans; Lymphocytes; Monocytes; Neutrophils

The Steinbrinck-Chediak-Higashi Syndrome is characterized by morphological and functional alterations of polymorphonuclear leukocytes. The impaired function in the polymorphonuclear leukocytes may be related to abnormal microtubular assembly. The ingestion of 200 mg/d of ascorbic acid potentiated chemotaxis and bactericidal activity of polymorphonuclear leukocytes from a patient with this disease. Furthermore, the treatment with ascorbic acid reduced the spontaneous cap formation by these leukocytes, demonstrating the improvement of microtubular assembly. The life long treatment with ascorbic acid may affect the clinical course of these patients favourably.

Topics: Ascorbic Acid; Cell Membrane; Chediak-Higashi Syndrome; Granulocytes; Humans; Infant; Lectins; Male; Microtubules; Phagocytosis; Receptors, Mitogen

Topics: Adult; Animals; Ascorbic Acid; Blood Bactericidal Activity; Candidiasis; Cell Movement; Chediak-Higashi Syndrome; Chemotaxis, Leukocyte; Cyclic AMP; Cyclic GMP; Humans; Leukocytes; Lymphocyte Activation; Male; Mice; Mice, Inbred C57BL; Neutrophils

Polymorphonuclear leukocytes from humans and mice with the Chediak-Higashi syndrome were characterized by spin label electron spin resonance spectrometry. Our results suggest that cells from afflicted mice and humans have membranes more fluid than controls. Order parameters for a spin label that probes near the membrane surface were 0.652 for normals and 0.645 for two Chediak-Higashi patients. Cells from Chediak-Higashi mice showed similar differences, as did isolated plasma membrane fractions. An increased membrane fluidity was also detected with a spin label that probes deeper in the bilayer. In vitro treatment of Chediak-Higashi mouse cells with 0.01 M ascorbate increased the order parameter to normal levels. In vitro incubation of mouse Chediak-Higashi cells with glucose oxidase increased the order parameter, similar to the effect of ascorbate. This increase was abolished when catalase was added to the incubation medium. In vitro incubation with dibutyryl cyclic guanosine monophosphate (1 muM to 0.1 mM) did not normalize order parameters. These results indicate that fluidity of Chediak-Higashi cell membranes was affected by treatments expected to alter the oxidation: reduction potential of the environment but was not affected by treatments expected to alter the ratio of intracellular cyclic nucleotides. The latter treatment would affect microtubule assembly. Therefore, it appears that the membrane fluidity abnormalities as demonstrated by electron spin resonance and the earlier demonstrated microtubule dysfunctions characteristic of Chediak-Higashi cells are coexisting defects and are probably not directly related.

Topics: Animals; Ascorbic Acid; Cell Membrane; Chediak-Higashi Syndrome; Dibutyryl Cyclic GMP; Electron Spin Resonance Spectroscopy; Female; Glucose Oxidase; Humans; Hydrogen Peroxide; In Vitro Techniques; Membrane Fluidity; Methods; Mice; Neutrophils

It was previously shown that the abnormal surface characteristics and defective bactericidal function of polymorphonuclear leucocytes (PMN) in the Chediak-Higashi syndrome (CHS) are correlated with impaired microtubule assembly, and in one patient direct electron microscopic evidence for an anomaly in microtubule assembly following surface membrane activation by concanavalin A (Con A). We show that very few microtubules are visible in CHS leucocytes from two additional patients under conditions where normal PMNs contain abundant microtubules, and that both in vivo and in vitro exposure of the CHS leucocytes to ascorbic acid promotes the assembly of microtubules. This agent, which normalizes chemotaxis and degranulation in CHS leucocytes, is shown also to correct granulocyte adherence in these leucocytes. It is suggested that the improved clinical course of patients with CHS following treatment with ascorbic acid is related at least in part to improvement of microtubule assembly and PMN function by the ascorbic acid.

Topics: Ascorbic Acid; Cell Adhesion; Chediak-Higashi Syndrome; Child, Preschool; Concanavalin A; Female; Humans; Immunologic Capping; Infant; Microscopy, Electron; Microtubules; Neutrophils

Because ascorbate potentiates chemotaxis of normal leukocytes, we examined the effect of ascorbate on polymorphonuclear leukocytes from a patient with the Chediak-Higashi syndrome. Chemotactic migration was 104+/-16 leukocytes per 10 fields (mean+/-S.D.) initially and 258+/-44 (P less than 0.001) after ascorbate, as compared to 182+/-10 in controls. There was no bactericidal activity by 40 minutes in the patient's untreated leukocytes. After ascorbate bactericidal activity of patient and untreated control cells was the same. The addition of ascorbate reduced cAMP levels in the patient's cells from a mean of 34.5 pmoles per 10(7) polymorphonuclear leukocytes to 5.9, as compared to a control value of 3.1+/-1.4. The association of elevated cAMP and impaired function in the polymorphonuclear leukocytes of patients with the Chediak-Higashi syndrome may be related to abnormal microtubular assembly.

Topics: Ascorbic Acid; Blood Bactericidal Activity; Chediak-Higashi Syndrome; Cyclic AMP; Cyclic GMP; Female; Glucuronidase; Humans; In Vitro Techniques; Infant; Leukocytes; Microtubules; Monocytes; Stimulation, Chemical

Topics: Animals; Ascorbic Acid; Chediak-Higashi Syndrome; Humans; Mice; Microtubules; Phagocytes