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Biomedical subjects

R Snyderman

Publications and source records attributed to R Snyderman.

At least 19 recordsLinked to original sources
PubMed1979

Deficiency of the fifth component of complement in human subjects. Clinical, genetic and immunologic studies in a large kindred.

The discovery of a large kindred with a heritable deficiency of the fifth component of complement (C5) has permitted the accumulation of new clinical, genetic and immunologic data concerning the role of C5 in human subjects. The proband, who has had nine episodes of disseminated gonococcal infection, has a hemolytic C5 level of approximately 0.5 per cent of normal. No C5 protein was detectable, but low levels of functional C5 activity could be found using a sensitive bactericidal assay. The proband's twin as well as another sister also had extremely low levels of hemolytic C5(approximately 0.5 per cent normal), but both these subjects have been healthy. Hemolytic complement and bacteriolytic activity could be restored by the addition of purified C5. No chemotactic activity for polymorphonuclear leukocytes could be generated in the C5-deficient serums upon activation of either the classic or alternative pathways, again demonstrating the importance of C5 in human subjects for the production of chemotactic factors. The chemotactic responsiveness of the patients' polymorphonuclear leukocytes and monocytes to preformed chemotactic factors was not depressed. Twenty-two of 32 other family members from three generations had depressed whole hemolytic complement levels. In 19 of 30 family members, levels of hemolytic C5 ranged from 13 to 64 per cent of normal. No linkage for C5 deficiency and the A or B loci of the major histocompatibility complex could be found. These data suggest an autosomal codominant mode of inheritance of C5 deficiency. Deficiency of C5 is compatible with good health, but it can be associated with repeated disseminated gonococcal infection.

Adult↗
PubMed1979

Chronic mucocutaneous candidiasis. Immunologic studies of three generations of a single family.

A family consisting of eight members in three generations (age 10 months to 53 years) affected with chronic mucocutaneous candidiasis was studied along with three unaffected relatives. Dermatophytosis, loss of teeth and recurrent viral infections were present in some members. Results of tests for endocrinologic, muscle or liver disease, thymoma, iron deficiency, antitissue antibodies and malabsorption were normal in all patients. Antibody function and levels, B cell counts, serum complement, leukocyte enzymes, chemotaxis, phagocytosis and adherence were normal in all members. Plasma inhibitors to lymphocyte transformation and leukocyte inhibitory factor were not found. No unique HLA haplotype or antigen segregated in this family. Evaluation of cell-mediated immunity revealed total cutaneous anergy in three of eight whereas four of the other five had negative lymphocyte transformation and skin tests to Candida but responded normally to other antigens. Leukocyte inhibitory factor was not produced to Candida antigen in all four patients tested. T cell counts were within normal limits in all. Extensive evaluation of all limbs of the immune system in this family revealed a defect in cell-mediated immunity to Candida that appeared to be inherited as a dominant characteristic.

Adolescent↗
PubMed1979

Antibodies raised against purified beta-adrenergic receptors specifically bind beta-adrenergic ligands.

Antibodies raised against purified beta-adrenergic receptors themselves specifically bind beta-adrenergic ligands. Digitonin-solubilized frog (Rana pipiens) erythrocyte beta-adrenergic receptors, purified 100- to 200-fold by adsorption to an alprenolol-agarose affinity support and specifically eluted from the affinity resin by 1-100 mM (+/-)-isoproterenol, were used to immunize six rabbits. All immune sera, in contrast to preimmune sera, bound the beta-adrenergic antagonist [(3)H]Dihydroalprenolol binding activity was due to immunoglobulins. By competition studies, antibody [(3)H]dihydroalprenolol binding was found to display a specificity and stereoselectivity resembling that of the beta-adrenergic receptor, [i.e., (-)-isoproterenol > (-)-epinephrine > (-)-norepinephrine; alprenolol approximately propranolol >> phentolamine = aloperidol; and (-) isomers of both agonists and antagonists 10-100 times more potent than (+) isomers]. A portion of the [(3)H]dihydroalprenolol binding antibodies could be specifically adsorbed onto purified frog erythrocyte membranes, whereas Xenopus and human erythrocyte membranes, both of which are almost devoid of beta-adrenergic receptors, were ineffective in adsorbing [(3)H]dihydroalprenolol binding antibodies. We suggest that the likely immunogen was a beta-adrenergic receptor-isoproterenol complex and that immunization with drugs noncovalently bound to their receptors might be a means of raising antibodies to biologically active otherwise nonimmunogenic small molecules. Such antibodies, whose specificity mimics that of a receptor, should also provide useful models for the study of the structure of the receptor binding sites.

Adrenergic beta-Agonists↗
PubMed1979

Phospholipid methylation in macrophages is inhibited by chemotactic factors.

Chemotaxis by human monocytes has been shown to require methylation mediated by S-adenosyl-L-methionine(AdoMet), but the specific transmethylation reaction necessary for this function was not elucidated. In an attempt to define the methylation requirement for chemotaxis, we examined the effect of chemotactic agonists and antagonists on protein carboxy-O-methylation of protein and methylation of phospholipid in guinea pig macrophages. Chemotactic agents tested over a wide dose and time range produced no alteration in carboxy-O-methylation. However, these agents did produce an effect on the methylation of phosphatidylethanolamine by macrophages. AdoMet-mediated phospholipid methylation was inhibited by as much as 73% by chemotactic factors, and there was excellent correlation (r = 0.99) between their concentrations for producing half-maximal chemotactic responses and for inhibiting phospholipid methylation. The inhibition of methylation by chemotactic factors was observed at all incubation times and could not be explained by an increased turnover of membrane phospholipid. Neither the chemotaxis antagonist fPhe-Met nor the nonchemotactic tripeptide Met-Met-Met significantly depressed phospholipid methylation. Immune phagocytosis by macrophages similarly did not alter phospholipid methylation. The chemotactic factors produced no alteration in total macrophage phospholipid synthesis or in the phospholipid methylation in a nonchemotactic cell type. The formation of newly methylated derivatives of phosphatidylethanolamine in macrophages was decreased by a biologically active dose of chemotactic factor. These findings indicate that chemotactic factors are capable of altering the methylation of phosphatidylethanolamine in chemotactically responsive cells. The inhibition of phospholipid methylation by chemotactic factors may be necessary for the translation of a chemotactic signal on the surface of the cell into directional cell movement.

Animals↗
PubMed1979

Neisseria meningitidis bacteremia in association with deficiency of the sixth component of complement.

The serum of a 26-year-old black man with a recent episode of meningococcemia complicated by meningitis and arthritis was found to lack hemolytic complement activity. The sixth component of complement was not detected by functional or immunochemical assays whereas other components were normal by hemolytic assay. His fresh acute-phase serum lacked complement-mediated bactericidal activity against the homologous strain of Neisseria meningitidis, but the addition of fresh normal serum or purified C6 restored bactericidal activity as well as hemolytic activity. The absence of C6 activity could not be accounted for on the basis of an inhibitor. Opsonization and chemotaxis functioned normally. Histocompatibility typing of family members did not demonstrate evidence for genetic linkage of C6 deficiency with the major histocompatibility loci. This report represents the first published case of C6 deficiency associated with bacteremic Neisseria infections in which antimeningococcal bactericidal antibodies have been definitively demonstrated against the homologous strain in the acute phase of the illness.

Adult↗
PubMed1979

Generation of a fibroblast chemotactic factor in serum by activation of complement.

When serum complement is activated by either the classical or alternative pathways, a factor with an apparent 80,000 mol wt is generated that is chemotactic for human dermal fibroblasts. The origin of this serum-derived chemotactic factor (SDCF) is not known; however, it may be a cleavage product from C5 because it is inactivated by monospecific antiserum to human C5, and it is not generated when the complement system is activated in human serum deficient in C5. SDCF is not chemotactic for human neutrophils or monocytes. Because SDCF is generated when serum complement is activated, it may function in vivo to attract connective tissue fibroblasts to sites of inflammatory reactions in which the complement system participates.

Cells, Cultured↗
PubMed1979

Neisseria meningitidis and Neisseria gonorrhoeae bacteremia associated with C6, C7, or C8 deficiency.

We summarize data from 24 previously described or newly diagnosed cases of homozygous deficiency of the sixth, seventh, or eighth components of complement. Thirteen of 24 patients had at least one episode, and usually two or more episodes of Neisseria meningitidis or Neisseria gonorrhoeae bacteremia, or both. Deficiency of C6, C7, or C8 is a meaningful risk factor for repeated neisserial bacteremia; conversely, hemolytic complement studies are indicated in patients who develop recurrent neisserial infections. When a person with C6, C7, or C8 deficiency is identified, family members should also be studied.

Adolescent↗
PubMed1979

Hereditary C2 deficiency associated with cutaneous lupus erythematosus: clinical, laboratory, and genetic studies.

Selective congenital deficiency in the second component of complement has been described in association with lupus erythematosus (LE) and other connective tissue disorders. We identified a 59-year-old woman with a 13-year history of cutaneous LE and no detectable serum C2. The patient's photosensitivity, large polycyclic erosive cutaneous lesions, lack of renal disease, paucity of serological findings, and high incidence of bacterial infection is consistent with previously described patients with this association. Uniquely, the patient demonstrated secondary infection with Staphylococcus aureus and Trichophyton rubrum in the skin lesions themselves. Immunologic studies disclosed depression in both humoral and cellular immunity. Moderation in her clinical disease and immunologic measurements has been observed after treatment with levamisole hydrochloride. Immunogenetic studies of the patient's four-generation kindred was consistent with an autosomal recessive inheritance of C2 deficiency genetically linked to HLA, segregating with the B18 allele. Mixed lymphocyte culture determinations reinforce evidence for linkage between the HLA-D locus and the trait for C2 deficiency.

Complement C2↗
PubMed1978

Resistance of neoplasms to immunological destruction: role of a macrophage chemotaxis inhibitor.

Several tissue culture lines of 6C3HED, a murine lymphoma, were more susceptible to immunologic destruction in vivo than the highly virulent 6C3HED line maintained by serial intramuscular transplantation. The attenuated tissue culture cells were rejected by normal syngeneic recipients, but thymectomized mice were unable to reject attenuated cells. In such mice, the growth rate of attenuated cells was equivalent to the growth rate of virulent cells in normal syngeneic mice. The increased susceptibility of attenuated cells to destruction by syngeneic hosts was shown to correlate with decreased production by the tumor cells of a macrophage chemotaxis inhibitor, and not with altered antigen density. In addition, when inhibitor isolated from virulent cells was administered to mice challenged with attenuated cells, the latter cells became virulent in vivo. When attenuated and virulent cells were administered simultaneously in the same host, the attenuated cells were able to develop into progressively growing tumors. The data suggest that the successful growth of neoplastic cells in normal may require tumor cells to produce factors which subvert the ability of the host to mobilize macrophages rapidly at the tumor site.

Animals↗
PubMed1978

Requirement of S-adenosyl-L-methionine-mediated methylation for human monocyte chemotaxis.

The chemotactic response of motile bacteria requires the methylation of specific proteins by S-adenosyl-L-methionine. To determine whether methylation is required for the chemotaxis of human leukocytes, we studied the effects of inhibition of S-adenosyl-L-methionine-mediated methylation on monocyte chemotactic responsiveness. Methylation was inhibited in monocytes by treating the cells with substances that produced elevations in intracellular S-adenosyl-L-homocysteine, a competitive inhibitor of S-adenosyl-L-methionine methylation. Treatment of isolated monocytes with the adenosine deaminase inhibitor, erythro-9-(2-hydroxy-3-nonyl)adenine, plus exogenous adenosine and L-homocysteine thiolactone increased intracellular S-adenosyl-L-homocysteine levels by as much as 1500-fold. Concomitant with increases in S-adenosyl-L-homocysteine were a decrease in monocyte protein carboxy-O-methylation as well as a marked inhibition of monocyte chemotactic responsiveness. Conditions that almost completely inhibited methylation and chemotaxis did not depress monocyte phagocytosis, indicating that this latter function either is independent of S-adenosyl-L-methionine-mediated methylation or is extremely resistant to inhibition of such reactions by S-adenosyl-L-homocysteine. These studies indicate that S-adenosyl-L-methionine-mediated methylation is required for the chemotaxis of eukaryotic cells and that the chemotactic and phagocytic functions of human monocytes have different requirements for methylation.

Adenosine Deaminase Inhibitors↗
PubMed1978

Familial deficiency of the seventh component of complement associated with recurrent bacteremic infections due to Neisseria.

The serum of a 29-year old woman with a recent episode of disseminated gonococcal infection and a history of meningococcal meningitis and arthritis as a child was found to lack serum hemolytic complement activity. The seventh component of complement (C7) was not detected by functional or immunochemical assays, whereas other components were normal by hemolytic and immunochemical assessment. Her fresh serum lacked complement-mediated bactericidal activity against Neisseria gonorrhoeae, but the addition of fresh normal serum or purified C7 restored bactericidal activity as well as hemolytic activity. The absence of functional C7 activity could not be accounted for on the basis of an inhibitor. Opsonization and generation of chemotactic activity functioned normally. Complete absence of C7 was also found in one sibling who had the clinical syndrome of meningococcal meningitis and arthritis as a child and in this sibling's clinically well eight-year-old son. HLA histocompatibility typing of the family members did not demonstrate evidence for genetic linkage of C7 deficiency with the major histocompatibility loci. This report represents the first cases of C7 deficiency associated with infectious complications and suggests that bactericidal activity may be important in host defense against bacteremic neisseria infections.

Adult↗
PubMed1978

Abnormal monocyte chemotaxis in patients with breast cancer: evidence for a tumor-mediated effect.

The chemotactic responsiveness of peripheral blood monocytes was measured in 194 individuals: 37 patients with breast cancer, 17 patients with a history of breast cancer but clinically free of disease after surgery, 42 patients with benign breast masses, and 98 normal controls. Monocyte chemotactic responsiveness (MCR) in vitro was not significantly different from normal [mean = 72.8 migrating monocytes/oil immersion field, +/- 9.3 (1 SD)] in 2 groups of patients: a) those with benign breast masses (mean = 72.6 +/- 15.1; P greater than 0.3) and b) those previously having breast cancer resected and remaining clinically free of disease (mean = 69.0 +/- 12.5; P greater than 0.4). However, MCR was significantly depressed in the group of patients with active breast cancer (mean = 57.2 +/- 20.7; P less than 0.0025). Resection of malignant breast masses resulted in a significant change in MCR (P less than 0.0025), whereas resection of benign lesions did not (P greater than 0.4). MCR was abnormal in all clinical stages of breast cancer, including breast cancer without evidence of metastasis to regional lymph nodes. These data supported the hypothesis that neoplasms adversely affect monocyte function and may thereby hinder immunologically mediated destruction of malignant cells.

Adenocarcinoma↗
PubMed1978

Abortive and productive infections of human mononuclear phagocytes by type I herpes simplex virus.

The ability of Type I herpes simplex (HSV) to replicate in normal human monouclear phagocytes was investigated. Mononuclear leukocytes were obtained from the peripheral blood of patients by Ficoll-Hypaque gradient centrifugation, and the monocytes were isolated by allowing the cells to adhere to tissue culture dishes. The monocytes (10(5.0) cells) were infected (10(7.0) PFU HSV) either immediately after isolation or were cultured in vitro for varying numbers of days and were then infected. Inoculation of freshly isolated monocytes resulted primarily in an abortive infection. HSV antigens were produced by the cells, as determined by a indirect fluorescent antibody technique, and empty herpes capsid structures were detected by electron microscopy of the inoculated monocytes; however, no increase in virus titer was noted in the cultures. Inoculation of viable cells that had been maintained for 7 days in culture resulted in a productive infection. An increase in titer was noted 24 hours after inoculation, and normal virus maturation was documented by ultrastructural study of the infected cells. The experiments show that the interaction of HSV with human mononuclear phagocytes is complex, and the data suggest that whether or not the cell replicates infectious virus may depend on the functional activity of the cell.

Antigens, Viral↗