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Biomedical subjects

M M Frank

Publications and source records attributed to M M Frank.

At least 19 recordsLinked to original sources
PubMed1992

The effects of intravenous immune globulin on complement-dependent immune damage of cells and tissues.

The mechanism of action of intravenous immune globulin (IVIG) in the therapy of autoimmune disease has been speculated upon for many years. Previous studies have raised the possibility that IVIG acts via an effect on IgG Fc receptors (FcRs) on phagocytic cells and B lymphocytes, on the production of anti-idiotype antibody, or on the control of the immune response. In the course of our studies of complement function we were struck by the fact that complement activation often leads to the binding of complement components to individual immunoglobulin molecules. For example, C3 has been shown to bind to the Fd fragment of IgG in the form of a C3b/IgG one-to-one complex. The C3b/IgG complex has new properties that differ from those of either IgG or C3b alone in that the complex can interact with two receptors on phagocytes: CR1, which recognizes C3b, and FcR, which recognizes the Fc fragment of IgG. Particles opsonized with IgG/C3b interact with both receptors and are phagocytized rapidly. The complex acts as a superopsonin and superlysin. IgG/C3b resists degradation by factors H and I, which also adds to its inflammatory potential. We and others have noted that bacteria coated with immunoglobulin and then incubated in serum have C3 deposited on their surfaces, which in many instances is bound to the IgG molecules. For example, we found that 30% of the C3 deposited on antibody-coated pneumococci is bound not to the pneumococcal surface but rather to the coating immunoglobulin. We reasoned that IVIG may act as a receptor for activated complement components, preventing their attachment to targets. This was tested directly in a number of animal and human models. The results of these tests and their clinical implications are presented.

Animals↗
PubMed1992

Detection of complement in relation to disease.

If a single component is lowered, it is reasonable to question whether the patient has a genetically-controlled defect. Studies of family members may be required. If split products, complexes, or neoantigens are present, it is likely that there is ongoing complement activation. If most of the components of a pathway are lowered, a reasonable supposition is that complement is being activated. We then turn to a consideration of the factors that may activate complement. When hypocomplementemia is associated with a decrease in titer of several components, it is often possible to determine whether the classic or alternative pathway is the major pathway being activated; this, in turn, may suggest certain diagnoses and rule out other diagnoses. The nature of the circulating complexes or split products may provide the same information. Thus, a consideration of the pathophysiology of the complement system and of the factors that activate complement provides an approach to an understanding of the function of complement and the role of complement causing a damage in a clinical setting.

Complement Pathway, Alternative↗
PubMed1992

The mechanism by which microorganisms avoid complement attack.

The complement system provides a critical level of defense against bacterial invasion. Various microorganisms have evolved a variety of mechanisms to allow them to avoid complement lytic and opsonic activity. These range from the formation of factors that destroy activity of complement proteins to the evolution of surface structures that fail to bind, facilitate degradation of, or shed, complement proteins. The range of factors associated with bacterial complement resistance is reviewed here.

Animals↗
PubMed1992

Regulation of complement activity by vaccinia virus complement-control protein.

A major protein secreted by vaccinia virus-infected cells has structural similarity to the super-family of complement-control proteins. This vaccinia complement-control protein (VCP) was studied to determine how it regulates complement activation. VCP was bound by C4b and C3b and served as a cofactor with factor I in cleaving these two molecules. VCP inhibited the formation and accelerated the decay of the classical C3 convertase. It also accelerated decay of the alternative pathway convertase, although higher concentrations were apparently needed. In vitro, therefore, VCP interfered with the classical and alternative complement pathways at several steps. In vivo, this interference may increase the virulence of vaccinia virus by enabling it to escape attack by the host's complement system.

Complement Activation↗
PubMed1991

The effects of IL-1, IL-2, and tumor necrosis factor on polymorphonuclear leukocyte Fc gamma receptor-mediated phagocytosis. IL-2 down-regulates the effect of tumor necrosis factor.

It has been reported that the Fc gamma R-mediated phagocytic activity of polymorphonuclear leukocytes (PMN) from patients with acute bacterial infections is markedly enhanced when compared with healthy controls. Inasmuch as several potent cytokines are known to be involved in inflammatory and infectious processes, we studied the effects of three such cytokines (IL-1 beta, IL-2, and TNF-alpha) on normal PMN Fc gamma R-mediated phagocytosis. IL-1 beta and TNF alpha both caused a significant increase in the ingestion of EIgG by adherent PMN. In combination, IL-1 beta and TNF-alpha had an additive effect, even when each was used at its optimal concentration. In contrast to the enhancing effects mediated by IL-1 beta and TNF-alpha, IL-2 alone had no significant effect on PMN phagocytosis. Notably, however, IL-2 at a concentration of 10(4) U/ml partially inhibited TNF-alpha-mediated enhancement of phagocytosis by decreasing TNF binding to the PMN cell surface. This inhibitory effect of IL-2 on TNF was reversed by anti-IL-2 antibody and mAb directed against the low affinity IL-2R (anti-Tac), whereas mAb directed against the intermediate affinity receptor (mik-beta 1) had no such effect. These findings may have important physiologic implications, because patients receiving IL-2 therapy have been shown to have increased susceptibility to infection.

Antibodies, Monoclonal↗
PubMed1991

High doses of intravenous immunoglobulin do not affect the recognition phase of the classical complement pathway.

We have recently found that intravenous immunoglobulin (IVIg) prevents deposition of C3 and C4 fragments onto antibody sensitized erythrocytes. To find out if such an effect results from the blockade of the recognition phase of the classical complement cascade, we investigated the ability of human serum containing high concentrations of IVIg to deposit the recognition subunit of the first complement component (C1q) onto targets. Normal human serum supplemented in vitro with IVIg did not demonstrate reduced C1q binding to targets as determined by radiolabeled antihuman C1q antibody uptake. Similarly, methylamine-treated normal human serum to which IVIg was added was equally effective in terms of C1q binding as the same serum without IVIg. At increasing doses of sensitizing antibody, C1q uptake decreased proportionally; however, at all antibody dilution points C1q uptake was not significantly different in the serum with IVIg in comparison with normal serum. Serum from a patient treated with IVIg did not differ in its capacity to deposit C1q from the same patient's serum before therapy. Our data suggest that IVIg does not interfere with the recognition step of classical complement pathway. This is a US government work. There are no restrictions on its use.

Complement C1↗
PubMed1991

Monokines released during short-term Fc gamma receptor phagocytosis up-regulate polymorphonuclear leukocytes and monocyte-phagocytic function.

Freshly explanted monocytes phagocytosing IgG antibody-coated erythrocyte targets (EIgG) release a factor(s) that stimulates phagocytosis by neighboring monocytes and polymorphonuclear leukocytes (PMN). Culture supernatants obtained after 30-min incubation of adherent monocytes with EIgG, but not unopsonized sheep erythrocytes, markedly up-regulated the extent of PMN phagocytosis and enhanced the rate at which monocytes ingested EIgG. The presence of this factor(s) was first evident in phagocytic studies in which monocytes were prepared by a colloidal silica-based continuous gradient technique (Sepracell-Mn). After introduction of erythrocyte targets, there was a 20- to 30-min delay before initiation of phagocytosis that was not observed with monocytes prepared by the standard Percoll-gradient technique. Experiments suggest that, when compared with monocytes prepared by the Percoll-gradient method, Sepracell-Mn monocytes are closer to a base line state of activation with regard to the expression of Fc gamma RI and the ability to ingest EIgG. The mechanism of PMN upregulation by the monocyte factor(s) was explored. Monocyte supernatants did not induce an increase in the surface expression of PMN Fc gamma RI, II, or III. Neither anti-TNF, anti-IL-2, nor anti-GM-CSF had any significant effect on monocyte supernatant activity. Neutrophil activating protein-1 was not detected by ELISA. In contrast, anti-IL-1 completely blocked the effect of the supernatant on subsequent monocyte phagocytosis, and partially inhibited its effect on PMN phagocytosis. Furthermore, it was shown that RIL-1 as well as TNF markedly enhanced monocyte and PMN ingestion of EIgG. These results suggest that monocytes, after Fc gamma R-mediated phagocytosis, release monokines, including at least IL-1, which enhance the phagocytic function of neighboring PMN and monocytes to augment the host defense process.

Antigens, Differentiation↗
PubMed1991

Aerosol alpha 1-antitrypsin treatment for cystic fibrosis.

In cystic fibrosis neutrophil-dominated inflammation on the respiratory epithelial surface results in a chronic epithelial burden of the destructive enzyme, neutrophil elastase. alpha 1-antitrypsin (alpha 1AT), the main inhibitor of neutrophil elastase in lung, was given in aerosol form to 12 cystic fibrosis patients. It suppressed neutrophil elastase in the respiratory epithelial lining fluid (ELF) and restored the ELF anti-neutrophil elastase capacity when ELF alpha 1AT reached 8 mumol/l. This treatment also reversed the inhibitory effect of cystic fibrosis ELF on pseudomonas killing by neutrophils, which suggests that it may augment host defence in cystic fibrosis.

Adult↗
PubMed1991

High doses of intravenous Ig inhibit in vitro uptake of C4 fragments onto sensitized erythrocytes.

We have recently reported that intravenous Ig (IVIg) inhibits uptake of activated C3 fragments onto antibody-sensitized red blood cells (RBCs). To elucidate the mechanism by which IVIg exerts its effect on the complement system, we examined the possible interference with the C4 step of the classical complement cascade. We examined the capacity of autologous serum containing high concentrations of human IVIg to deposit C4 fragments onto model targets (guinea pig and/or human erythrocytes sensitized with rabbit anti-guinea pig/human erythrocytes IgG antibody). C4 binding was quantified with radiolabeled anti-C4. Guinea pig serum with added IVIg suppressed C4 uptake onto IgG-sensitized guinea pig erythrocytes at all time points (0, 5, 15, and 30 minutes). Using sera of guinea pigs treated with increasing doses of IVIg, this effect was shown to be dose-responsive. Serum from a patient treated with IVIg showed reduced C4 uptake onto sensitized homologous RBCs. In comparison with the serum from the same patient before IVIg therapy was administered, levels were decreased almost to background. C4 functional titers in those two samples were not different. C3 uptake was studied in parallel with C4 to compare the degree of inhibition using sera with increasing doses of IVIg in both the human and guinea pig system. C3 and C4 inhibition curves completely overlapped. Our findings suggest that IVIg is an effective inhibitor of deposition of early complement activation products (C4b, C3b) onto target surfaces and may indicate interference of IVIg with multiple sites of complement activation.

Animals↗
PubMed1991

The role of complement in inflammation and phagocytosis.

Inflammation and phagocytosis are highly complex events involving many humoral and cellular factors, with complement components playing a key role. As described here by Mike Frank and Louis Fries, complement peptides trigger cell function, aid in the recognition of invading pathogens and regulate the phagocytic process via interactions with specific cell surface receptors.

Complement System Proteins↗
PubMed1991

Oral manifestations and dental management of patients with hereditary angioedema.

Hereditary angioedema (HAE) is a genetic disorder in which affected individuals develop extensive, spontaneous angioedema of the extremities, gastrointestinal tract, and oropharynx. Dental treatment of unmedicated patients with HAE can trigger life-threatening pharyngeal edema. Previously, it was demonstrated that the administration of fresh frozen plasma (FFP) before surgery prevented angioedema attacks in 6 patients undergoing dental extractions. The present study examines the long term effectiveness of FFP in preventing angioedema from developing in 53 patients with HAE undergoing all types of dental treatment over a ten-year period. Only 3 of 45 patients (6.7%) covered with FFP had a minor angioedema attack after dental therapy in 10 yr. No attacks of moderate or severe swelling were seen. Attacks occurred independently of the disease activity of the patient and the trauma of the dental procedure. The use of fresh frozen plasma is effective in preventing attacks of angioedema in HAE patients undergoing all types of dental procedures.

Adolescent↗
PubMed1990

Inhibition of the complement cascade by the major secretory protein of vaccinia virus.

The complement system contributes to host defenses against invasion by infectious agents. A 35-kilodalton protein, encoded by vaccinia virus and secreted from infected cells, has sequence similarities to members of a gene family that includes complement control proteins. Biochemical and genetic studies showed that the viral protein binds to derivatives of the fourth component of complement and inhibits the classical complement cascade, suggesting that it serves as a defense molecule to help the virus evade the consequences of complement activation.

Amino Acid Sequence↗
PubMed1990

The long-term safety of danazol in women with hereditary angioedema.

Although the short-term safety (less than or equal to 6 months) of danazol has been established in a variety of settings, no information exists as to its long-term safety. We therefore investigated the long-term safety of danazol by performing a retrospective chart review of 60 female patients with hereditary angioedema treated with danazol for a continuous period of 6 months or longer. The mean age of the patients was 35.2 years and the mean duration of therapy was 59.7 months. Virtually all patients experienced one or more adverse reactions. Menstrual abnormalities (79%), weight gain (60%), muscle cramps/myalgias (40%), and transaminase elevations (40%) were the most common adverse reactions. The drug was discontinued due to adverse reactions in 8 patients. No patient has died or suffered any apparent long-term sequelae that were directly attributable to the drug. We conclude that, despite a relatively high incidence of adverse reactions, danazol has proven to be remarkably safe over the long-term in this group of patients.

Adolescent↗
PubMed1989

A new simplified procedure for C1 inhibitor purification. A novel use for jacalin-agarose.

C1 inhibitor (C1-INH), the major regulatory protein of the classical pathway of complement activation, is also involved in the regulation of several other plasma proteolytic systems including the coagulation, fibrinolytic and contact systems. All the previously published methods for the purification of C1-INH are time-consuming and some do not yield highly pure protein. Recently, it was reported that Jack fruit (Artocarpus integrifolia) lectin, also called jacalin, binds C1-INH. Since jacalin binds only a small number of human serum proteins it appeared that jacalin-agarose affinity chromatography would constitute a very selective early step for the purification of C1-INH. Consequently we have designed a new, simplified three-step procedure for the purification of C1-INH which includes PEG fractionation, jacalin-agarose chromatography and hydrophobic interaction chromatography on phenyl-Sepharose which takes advantage of the marked hydrophilicity of the inhibitor. This procedure has three major advantages over those which have been the most frequently used. Firstly, it includes only two fast chromatographic steps. Secondly, because the C1-INH pool is cleanly and predictably separated from the unwanted proteins by differential elution conditions in both chromatographic steps, no antigenic or functional assays are required to define the desired peaks. Thirdly, only the final product is dialyzed while all other methods required several buffer changes. For these reasons this procedure is much faster and simpler than the previously published methods. About 10-12 mg of highly purified and fully active C1-INH can be obtained within 1 day from 120 ml of plasma giving an average yield of 40-45%. This method may thus be highly adaptable to bulk purification for clinical use or for preparation of genetically or pathologically altered C1-INH from clinical specimens.

Blotting, Western↗
PubMed1989

Isolation and characterization of a novel plasma protein which binds to activated C4 of the classical complement pathway.

We report here the isolation and partial characterization of a previously unrecognized protease-sensitive plasma protein identified during the development of a novel protocol for the purification of the second component of human complement (C2). This new protein is physicochemically similar to C2. It coprecipitates with C2 on polyethylene glycol fractionation and specifically binds, like C2, to Sepharose-bound iC4/C4b. Binding occurs both in the presence and absence of C2. The purified protein has a chain structure similar to C2 as determined by sodium dodecyl sulfate-gel electrophoresis in the presence or absence of reducing agent and has a molecular mass of 120 kDa, only somewhat greater than C2 at 95 kDa. Both proteins radioiodinate under similar conditions to the same specific activities with each of two different methods that yield 10-fold disparate results. Quantitative Mancini analysis identifies 300 micrograms/ml of the 120-kDa protein in plasma and serum. The protein is present at normal concentrations in serum from individuals genetically deficient in C2, has no C2 functional activity, and is not cleaved as is C2 when serum complement is activated. Potent monospecific polyclonal anti-serum to each do not cross-immunoprecipitate using standard gel techniques. However, these anti-sera identify epitopes in common by Western blotting. The data presented indicate that the 120-kDa protein is a distinct plasma component and suggest that the protein is not an "immature" form of C2. Initial experiments to delineate a functional role for the 120-kDa protein have demonstrated a consistent inhibition of C1 site generation on EAC4b which is dose-dependent and reversible. Thus, this protein appears to be a new complement regulatory factor.

Blood Proteins↗
PubMed1989

Studies on phagocytosis in patients with acute bacterial infections.

Polymorphonuclear leukocytes (PMN) and monocytes from 20 patients with acute bacterial infections were examined for phagocytic function. PMN of patients expressed markedly enhanced phagocytosis as measured by the ingestion of erythrocyte (E)IgG and IgG/C3b-coated E. Phagocytosis of E coated with C3b alone was not seen, while low levels of ingestion of iC3b-E by patients' PMNs was noted. Monocytes from patients and controls expressed similar phagocytic activity in a fixed endpoint assay; however, the kinetics of phagocytosis by patients' monocytes was strikingly faster. Superoxide anion (O2.) and myeloperoxidase activities were similar to controls in PMN of four patients studied on day 1 of admission. PMN from two of three patients studied longitudinally showed an initial elevation in EIgG phagocytosis, which fell to normal levels by day 4, concomitantly with increased O2. generation and clinical improvement. Phagocytosis remained elevated in the third patient who did not clear his septicemia. Surface membrane FcRII, FcRIII, CR1, and CR3 were similar on patient and control PMN. In contrast, FcRI was increased on PMN of five of seven patients by monomeric IgG binding, and on two of two patients by monoclonal anti-FcRI binding. Thus, PMN and monocytes of patients with acute bacterial infections are either upregulated with regard to phagocytic function or are less susceptible to downregulation than are normal cells. This presumably would have a beneficial effect on host defenses during infection.

Adult↗
PubMed1989

Interaction of Neisseria gonorrhoeae with classical complement components, C1-inhibitor, and a monoclonal antibody directed against the Neisserial H.8 antigen.

Strains of Neisseria gonorrhoeae were used to evaluate bactericidal and opsonic properties of McAb 10 directed against the Neisserial outer membrane antigen, H.8. Gonococci were either serum resistant in the absence but serum sensitive in the presence, of McAb 10, or serum sensitive or serum resistant regardless of the presence of McAb 10. Strain JS3, which fell in the former category, was used in subsequent studies. C1 zymogen formed by reassociation of isolated C1 subunits was not directly activated by JS3 in the presence or absence of C1-inhibitor. JS3 thus was unable to directly activate the classical pathway independently of antibody. When purified classical pathway components were used to deposit C3 on JS3 in the absence of serum regulatory proteins or antibodies, added C1-inhibitor reduced C3 binding to background levels. When McAb 10 was present, C3 binding was unaffected by C1-inhibitor. Covalently bound, large molecular weight C3 alpha-chain-gonococcal complexes were disbanded by methylamine release of ester linkages. Released 125I-C3 migrated as C3b without degradation by gonococcal proteases. Purified classical components alone or McAb 10 alone facilitated JS3 killing by neutrophils; when combined, the two provided maximal killing. Levels of McAb 10 that only slightly increase C3 deposition on JS3 are bactericidal in serum and maximally opsonic in combination with purified classical pathway components.

Antibodies, Monoclonal↗