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PubMed2026

Independent prognostic value of semaphorin-4D, interleukin-1β and complement activation in newly diagnosed multiple myeloma patients.

Multiple myeloma represents a systemic disease of the bone marrow (BM) niche, in which immune and skeletal pathways are tightly interconnected. However, the independent prognostic significance of bone and immune-related markers in newly diagnosed multiple myeloma (NDMM) remains incompletely understood. Semaphorin (Sema) 4D, activin-A, and periostin ELISA, LEGENDplex™ Human Bone Metabolism Panel and proteomic analysis for novel biomarker identification were conducted in 71 consecutive samples from NDMM patients. In 25 patients, genomic analysis was performed on sorted clonal plasma cells. NDMM patients had a median age at diagnosis of 65 years and a median follow-up of 2.5 years. Interleukin (IL)-1β and Sema4D levels predicted progression-free survival (PFS), highlighting their role in disease relapse. Proteomic profiling revealed a systemic signature associated with worse prognosis, enriched in complement activation components. Complement C5 significantly affected PFS and time to progression (TTP). IL-1β and C5 predicted PFS independently of the second revision of the International Staging System (R2-ISS) stage, and a similar trend was noted for Sema4D. Myeloma bone disease (MBD) did not significantly affect overall survival, PFS, or TTP, suggesting that contemporary treatments mitigate its impact. Genomic analyses identified variants associated with inferior PFS, including HLA-DRB5 (c.300_306delinsCGGG) and HLA-DQB1 (c.317_319delinsCGG). Sema4D and the IL-1β-complement cascade emerged as key drivers of disease progression, independent of R2-ISS stage, representing potential prognostic and therapeutic targets in NDMM.

Journal Article↗

PubMed1998

Involvement of C3a and C5a in interleukin-8 secretion by human polymorphonuclear cells in response to capsular material of Cryptococcus neoformans.

In a previous paper we demonstrated that human polymorphonuclear cells (PMN) in the presence of normal human serum (NHS) secrete proinflammatory cytokines in response to Cryptococcus neoformans or its major capsular component, glucuronoxylomannan (GXM). The hypothesis that activation of the complement system could be responsible for the observed phenomenon is supported by the fact that encapsulated and acapsular C. neoformans isolates are activators of the complement system and, in particular, large encapsulated isolates are powerful activators. In the present study we demonstrate that (i) interleukin-8 (IL-8) release in response to acapsular or encapsulated strains of C. neoformans is significantly reduced in the presence of heat-inactivated serum rather than NHS and is completely abrogated in the absence of human serum; (ii) GXM-induced IL-8 release is strictly dependent on the presence of NHS, is inhibited by specific antibodies to either C3a and C5 complement components, and is completely abrogated by the combined use of these antibodies; (iii) the addition of purified C3a and C5a directly stimulates IL-8 release by PMN; and (iv) monoclonal antibody to GXM in combination with GXM or encapsulated C. neoformans potentiates IL-8 release by PMN. These data shed light on the mechanism involved in GXM-induced IL-8 secretion by PMN, provide an additional potential role for complement in the control of C. neoformans infections, and suggest a complex interplay between the complement system, humoral immunity, and cytokine regulation.

Cells, Cultured↗

PubMed1989

Ba and Bb fragments of factor B activation: fragment production, biological activities, neoepitope expression and quantitation in clinical samples.

Factor B is a centrally important component of the alternative complement pathway. Alternative pathway activation results in factor B cleavage and production of the amino-terminal Ba and the carboxyl-terminal Bb fragments which have molecular weights of approximately 30,000 and 63,000 daltons, respectively. Both Ba and Bb fragments have been reported to express a variety of biological activities in vitro. Thus, binding of Ba and Bb fragments to specific B lymphocyte surface receptors modulates proliferation of prestimulated B cells. In addition, the enzymatically active Bb fragment induces activation and spreading of human and murine macrophages and monocytes as well as regulates C5a des Arg chemotactic activity. The fractional catabolic rate and metabolism of factor B in vivo is similar to that of C3, C4 and C5 complement proteins, which are among the most metabolically active plasma proteins in the circulatory system. Factor B hyperconsumption and increased catabolism, concomitant with factor B fragment production, occurs in a wide variety of diseases, including gram-negative sepsis, autoimmune diseases and burns. Measurement of alternative pathway activation in vivo has been attempted utilized a number of different techniques to quantitate factor B fragments in biological fluids. However, the recent development of enzyme immunoassays (EIA) employing monoclonal antibodies (MoAbs) reactive with factor B fragment neoepitopes provides the best approach currently available for the quantitation of factor B activation fragments. Results obtained using these new MoAb-based EIAs have indicated that factor B fragment concentrations were elevated, as compared with normal donor levels, in EDTA plasma samples obtained from patients with rheumatoid arthritis and systemic lupus erythematosus (SLE). Plasma concentrations of factor B fragments, especially Ba fragment levels, in these patients showed a positive correlation with disease activity scores. One of the highest disease activity correlations was obtained with Ba fragment measurements in SLE plasma samples. In fact, the results strongly suggested that quantitation of Ba fragment levels in SLE plasma samples more accurately reflected disease activity and was a more sensitive predictor of impending flare in these patients than any other test(s) currently available.

Antibodies, Monoclonal↗

PubMed1980

A hypocomplementemic vasculitic urticarial syndrome. Report of four new cases and definition of the disease.

We describe four new patients with a unique syndrome of persistent urticaria, with leukoclastic angiitis, severe angioedema, occasional life-threatening laryngeal edema, arthritis, arthralgia, neurologic abnormalities and pronounced persistent hypocomplementemia. The complement abnormalities involved markedly reduced levels of the Clq subunit of the first component of complement (Cl) in the presence of near normal levels of Clr and Cls subunits of Cl; modest to marked depletion of the fourth component of complement (C4), the second component of complement (C2) and the third component of complement (C3); and normal levels of the fifth through ninth components of complement (C5 through C9) and properdin factors B and D. A striking serologic abnormality found in all patients was the presence of low molecular weight (7S) proteins which precipitated with Clq in agarose gels; these previously were shown to be comprised at least in part of immunoglobulin G. The present experience is offered to help to define the clinical, histopathologic and serologic characteristics of this entity, designated hypocomplementemic vasculitic urticarial syndrome, and to emphasize its distinctiveness and prevalence.

Adult↗

PubMed1990

C5a-induced neutrophilia. A primary humoral mechanism for recruitment of neutrophils.

The leukocytosis activity of C5a was studied in a rabbit model. Blood samples were drawn for cell counts through a catheter placed in an artery of one rabbit ear after injection of either porcine or human C5a into a vein in the opposite ear. These studies indicate the potential of C5a to mobilize bone marrow neutrophils following transient C5a-induced neutropenia, based on counts of nonsegmented neutrophils. The numbers of circulating neutrophils can be selectively elevated by 300% to 400%, within 1 to 2 hours, in rabbits given only microgram quantities (1 to 5 x 10(-9) mol/l) of C5a or C5adesArg. These quantities of C5a are equivalent to 1% to 2% of complement C5 activation. The time-course of the induced neutrophilia is characteristic of C5a, increasing rapidly in the first 10 to 20 minutes after injection and attaining a maximum level at 2 to 5 hours, then decreasing slowly to normal levels over the next 4 to 6 hours. After boiling at 100 degrees C for 10 minutes, C5a (C5ades Arg) lost its leukocytosis activity, indicating that the cellular effect was not caused by endotoxin. Other known leukocytosis factors, such as epinephrine, dexamethasone, lipopolysaccharide, and the prostanoid 15(S)-15-methyl PGF2 alpha, produced a distinctly different profile of leukocyte mobilization than that of C5a. The C5a-induced neutrophilia was not inhibited by pretreating these animals with indomethacin, suggesting that it is not a prostanoid-induced effect. One hypothesis is that no secondary cellular mediator system is involved in C5a-mediated leukocytosis, but rather than C5a alone is responsible for a rapid mobilization of neutrophils from bone marrow pools, and perhaps marginated pools, following neutropenia. Circulating neutrophils are activated by C5a and thereby become deformed and adherent, leading to a neutropenia, sequestration, and depletion of cells. After the neutropenic event an immediate neutrophilic response is required for replacement of this particular cell population and to re-establish homeostasis. Therefore the role of C5a may be just as important as other known leukocytosis factors (fragments from C3, for example) in promoting complement-dependent neutrophil mobilization in response to tissue injury, infections, or extracorporeal blood treatments.

Animals↗

PubMed1985

Lambert-Eaton myasthenic syndrome.

The Lambert-Eaton myasthenic syndrome is associated in about 65% of cases with small cell carcinoma, a tumour of neurosecretory origin. It is characterised physiologically by a decrease in the nerve evoked quantal release of acetylcholine, and in the resting non-quantal release ("molecular leakage"). The associations with autoimmune disease, with other autoantibodies, with HLA-B8, and with the IgG heavy chain marker Glm (2) are consistent with an autoimmune aetiology. Clinical and electromyographic responses to plasma exchange point to a humorally mediated disorder. This has been substantiated by passive transfer of the the main electrophysiological features of LEMS to mice by daily injections of LEMS IgG. Plasma was no more effective in inducing the electrophysiological changes than the IgG fraction. The decrease in quantal content appeared closely to follow the level of human IgG in the mouse serum and complement (C5) deficient mice were as susceptible as normal controls. The principal physiological abnormalities are both Ca2+ dependent processes, suggesting that a defect in Ca2+ transport may underlie the disorder. Preliminary studies of quantal content at low Ca2+ concentrations in mice injected with LEMS IgG suggest the functional loss of 40% of Ca2+ channels. Electron microscopic freeze fracture studies in such animals show, as in the human disease, a significant reduction in the number of active zone particles which are believed to represent Ca2+ channels. Thus it seems likely that the disorder of acetylcholine release is due to an IgG antibody directed to nerve terminal determinants that include the Ca2+ channels or structures closely related to them. In cancer-associated LEMS, the autoantibody response may initially be made to similar determinants on the tumour cell membrane, cross-reactivity of the antibody with nerve terminal determinants leading to the disorder of transmitter release.

Antibodies↗

PubMed1995

Cellular expression of the C5a anaphylatoxin receptor (C5aR): demonstration of C5aR on nonmyeloid cells of the liver and lung.

The small-complement C5 activation fragment, C5a, is a potent phlogistic molecule that, on binding to the C5a Receptor (C5aR), mediates contraction of smooth muscle, enhances vascular permeability, and promotes leukocyte functions such as directed chemotaxis, degranulation, mediator release, and production of superoxide anions. Although C5aR expression has traditionally been thought to be limited primarily to myeloid blood cells, including neutrophils, monocytes, macrophages, and eosinophils, we report here that C5aR is expressed by liver and lung cells as well as by cells in several other tissues. By Northern blot analysis, it was determined that mouse liver, baboon liver, human liver, and the human hepatoma-derived cell line HepG2 express a normal size (2.3 kb) C5aR mRNA; in HepG2 cells, the quantity of C5aR mRNA was comparable to that contained in dbcAMP-differentiated U937 cells. HepG2 cells were demonstrated to express the C5aR on their cell surface by flow cytometric and immunofluorescence analyses as well as by 125I-C5a binding assays. The binding data indicated that HepG2 cells express a single class of C5aR with a Kd of 1.18 nM and approximately 28,000 receptors per cell. In vivo expression of C5aR in human liver cells was demonstrated by in situ hybridization and immunohistochemistry analyses. Northern blot analysis of murine and baboon organs shows that, in addition to the liver, other tissues express C5aR mRNA in significant quantities, including the spleen, lung, heart, kidney, and intestine. Moreover, mice treated with LPS show a large increase in C5aR mRNA in all these tissues except the intestine. Immunostaining of human lung tissue demonstrated that bronchial and alveolar epithelial cells, as well as vascular smooth muscle and endothelial cells, also express the C5aR. Collectively, these data indicate that the C5aR is expressed in several different types of cells in liver and lung, and in yet undetermined cell types in spleen, heart, intestine, and kidney. Furthermore, these data suggest that the C5a anaphylatoxin mediates previously unrecognized functions by binding to tissue cells that express the C5aR.

Amino Acid Sequence↗

PubMed1998

C5 convertase of the alternative pathway of complement. Kinetic analysis of the free and surface-bound forms of the enzyme.

Although proteolytic activation of the complement protein C5 initiates important defensive and occasionally pathological inflammatory reactions, the enzymatic properties of the enzymes responsible for this cleavage have never been examined. We have studied the kinetic parameters of the C5 convertase of the alternative pathway of complement, either bound to a zymosan surface or in its monomeric soluble form. C5 convertase enzymatic activity was measured as a function of C5 concentration by quantitating production of C5b,6 under physiological conditions of temperature, pH, and ionic strength. The C5 convertases appeared to follow Michaelis-Menten kinetics and exhibited similar catalytic rate constants (kcat). However, the surface-bound enzyme, ZymC3b,Bb had a Km (1.4 microM) that was 17 times lower than that of the soluble monomeric form of the enzyme, C3b,Bb (Km = 24 microM). The kcat for the cell-bound enzyme, ZymC3b,Bb was 0.0048 s-1 and that for soluble C3b,Bb was 0.0110 s-1. Both forms of the enzyme had a low turnover number at Vmax (0.23 to 0.68 C5/min/enzyme). Substituting Mg2+ for Ni2+ did not alter the kinetic parameters but lowered the half-life of the enzyme by 5-7-fold. The kinetic data presented demonstrate that the fluid phase C5 convertase, C3b,Bb, can cleave C5 without the aid of a second C3b molecule. The results also show that the greater enzymatic activity previously observed for the surface-bound C5 convertases is not due to higher catalytic efficiency but is solely due to higher affinity for the substrate C5. In blood, C5 concentrations are 3-4-fold below the Km determined for the surface-bound C5 convertase suggesting a direct correlation between the local C5 concentration and production of the anaphylatoxin C5a and the cytolytic C5b-9 complex.

Cell Membrane↗

PubMed1987

Comparison of complement activation by silicone intraocular lenses and polymethylmethacrylate intraocular lenses with polypropylene loops.

Silicone intraocular lenses are undergoing clinical investigation for use in the United States. We compared the ability of silicone intraocular lenses to activate the complement system in human sera with that of polymethylmethacrylate intraocular lenses with polypropylene loops using a radioimmunoassay that measures levels of activated complement fragments. Sera incubated with polymethylmethacrylate lenses with polypropylene loops had higher levels of C3a and C5a, but not C4a, than control sera incubated without intraocular lenses. On the other hand, there were no differences in levels of C3a, C4a, and C5a between sera incubated with silicone lenses and control sera. These results suggest that polymethylmethacrylate lenses with polypropylene loops activate the alternative pathway of complement, while silicone lenses do not.

Complement Activation↗

PubMed1985

Regulation of neutrophil superoxide production in sepsis.

Neutrophil superoxide production has been recognized as an important pathway for microbicidal activity and regulation of the local inflammatory environment. To investigate neutrophil superoxide production in sepsis, we studied 22 patients with intra-abdominal infections, and correlated superoxide production with chemotactic response and granular enzyme content. Our results showed that neutrophils from infected patients had specific loss of chemotactic response to C5a, and were deficient in the granular enzymes, lysozyme, and beta-glucuronidase. Superoxide production in response to opsonized zymosan was intact, but response to the chemoattractant N-formyl-methionyl-leucyl-phenylalanine was markedly depressed. This could be reversed in vitro by the addition of cytochalasin B. These results suggest that down regulation of exocytosis of superoxide to nonphagocytic stimuli occurs during sepsis, possibly protecting the host from tissue injury due to oxide radical release. Superoxide response to phagocytic stimulation was intact.

Abdomen↗

PubMed1985

Escherichia coli and human neutrophils. Effect of bacterial supernatant with hemolysin activity upon chemotaxin receptors.

A greater proportion of Escherichia coli strains isolated from clinical extraintestinal infections produce alpha-hemolysin than do strains isolated from normal fecal flora. Proposed mechanisms to explain this observation have stressed the fact that hemolysis liberates hemoglobin, which may provide a nutritional boost for E coli growth. Alternatively, a cytolytic effect of hemolysin upon host neutrophils has been postulated. Our previous studies have suggested a third possibility: Human neutrophils incubated in the supernatant of an alpha-hemolysin-producing E coli strain produced a selective inhibition of chemotaxis toward C5a. Bacteria-free supernatants from 14 clinical strains of E coli were therefore evaluated for an ability to lyse sheep erythrocytes, alter human polymorphonuclear neutrophil (PMN) chemotaxin receptors, and affect release of PMN enzymes. Supernatants possessing hemolytic activity decreased the C5a receptor activity of human PMNs and increased the number of peptide receptors. A stimulation of secondary granule release, as evidenced by the release of PMN lysozyme, may account for the increased expression of peptide receptors. Perturbation of host defenses through a loss of neutrophil migratory function and secondary granule contents may allow for enhanced survival of E coli, which produce alpha-hemolysin.

Bacterial Proteins↗

PubMed1986

Degranulation inhibition. A potential mechanism for control of neutrophil superoxide production in sepsis.

Previous studies with neutrophils from patients with intra-abdominal sepsis have provided convincing evidence of in vivo exposure to C5a. However, in contradistinction to normal cells pretreated with C5a, patient cells showed depressed superoxide response to N-formyl-methionyl-leucyl-phenyl-alanine (FMLP) and enhanced FMLP receptor affinity. To identify possible mechanisms responsible for these findings, we examined the effects of lysosomal alkalinization with the weak base clindamycin on normal neutrophils with and without C5a. Our results showed a specific suppression of FMLP-induced superoxide production and a loss of low-affinity FMLP receptors. These results occurred in the presence of clindamycin levels that did not interfere with other cellular processes. These findings suggest that regulation of neutrophil function during the course of intra-abdominal sepsis may be due to effectors active both at the cell surface (C5a) and within the lysosome. The clinical significance of our findings relates to a possible mechanism for specific pharmacologic suppression of oxide-radical production by neutrophils. Such oxide radicals are believed to be important in the capillary injury accompanying severe sepsis.

Blood Proteins↗

PubMed1986

Trauma serum suppresses superoxide production by normal neutrophils.

The effect of trauma serum on superoxide production by normal neutrophils was studied in 47 serum samples from 18 patients with multiple trauma. Ten patients became septic and eight patients remained nonseptic. Incubation in trauma serum significantly suppressed superoxide production by normal neutrophils compared with incubation in normal serum: 3.6 +/- 1.44 vs 4.04 +/- 1.64 nmole of superoxide produced by 10(6) neutrophils (mean +/- SD). There was no difference in the suppressive effect between septic and nonseptic trauma serum samples. The chemiluminescence response of normal neutrophils was likewise suppressed following incubation in trauma serum compared with incubation in normal serum. The chemiluminescence response correlated with superoxide reduction of cytochrome C. In addition, the chemiluminescence response was significantly less in septic-trauma serum than in nonseptic-trauma serum. Suppressive serum was found to inhibit the neutrophil-membrane depolarization response to latex particles, as measured by flow cytometry. We conclude that trauma serum suppresses superoxide production by normal neutrophils, and that such suppression can be detected reliably using the clinically applicable technique of chemiluminescence. A normal chemiluminescence response excludes serum-mediated suppression of neutrophil superoxide production. In addition, chemiluminescence may be of value in detecting altered resistance to sepsis following injury, while superoxide determinations do not seem to be helpful in this regard. The mechanism of action of the suppressor may involve reversible inhibition of membrane depolarization necessary for the production of bactericidal oxygen species.

Adolescent↗

PubMed1986

Prostaglandin and complement interaction in clinical acute respiratory failure.

This study investigated the interaction of plasma levels of circulating prostaglandins and activated complement in clinical acute respiratory failure (ARDS). Fifty patients at risk for ARDS were followed up for up to ten days. Arterial blood gases and plasma levels of complement components C3a and C5a, thromboxane B2 (TxB), and prostaglandin 6-keto-F1 alpha (PGI) and granulocyte aggregation (GA) were measured daily. Seventeen patients (34%) developed ARDS, with mortality of 41% vs 23% for patients without ARDS. Compared with patients without ARDS, the ARDS group had significantly increased plasma C3a (1,130 +/- 750 vs 636 +/- 368 ng/mL) and granulocyte aggregation (48 +/- 10 vs 17 +/- 4 percentage of the maximum light transmission [% max T]). Plasma C5a, TxB, or PGI did not change significantly with or without ARDS. No measured variable was significantly associated with mortality. Regression analysis revealed significant correlations between GA, TxB, PGI, and arterial oxygenation. Plasma C3a and GA are increased in ARDS, suggesting systemic complement activation. A complex series of interactions between the prostaglandins, complement, and GA appears to be involved in ARDS.

Acute Disease↗

PubMed1986

Leukocyte aggregation response to quantitative plasma levels of C3a and C5a.

Granulocyte aggregation (GA) response has previously been described as a sensitive assay for complement activation in sepsis. Complement component C5a has been implicated as the plasma factor responsible for GA. The quantitative interaction of complement components C3a and C5a with GA, however, is not clearly defined. This study evaluates the relationship of GA responses to plasma levels of C5a and C3a in zymosan-activated plasma (ZAP). The C3a and C5a levels were measured by radioimmunoassay in serial dilutions of ZAP. Granulocyte aggregation responses of normal human leukocytes were determined for each ZAP dilution. The C5a levels in a 1:16 dilution of ZAP were higher than in normal plasma (22 +/- 7 vs 9 +/- 3 ng/mL), as were GA responses (24 +/- 1 vs 11 +/- 2 percentage of maximum light transmission). The C3a levels in a 1:8 dilution of ZAP are elevated above those of normal plasma (656 +/- 167 vs 411 +/- 29 ng/mL). Correlation coefficients were .9809 for C3a vs GA, .9788 for C5a vs G, and .9860 for C3a vs C5a. Complement components C3a and C5a are involved in GA in vitro. Granulocyte aggregometry can detect low levels of activated complement in ZAP but may not be specific for C5a. The relative contribution of C3a and C5a to observed GA is not clear from the data.

Cell Aggregation↗

PubMed1987

Complement-mediated neutrophil activation in sepsis- and trauma-related adult respiratory distress syndrome. Clarification with radioaerosol lung scans.

Complement-mediated neutrophil activation (CMNA) has been proposed as an important pathogenic mechanism causing acute microvascular lung injury in the adult respiratory distress syndrome (ARDS). To clarify the relationship between CMNA and evolving lung injury, we studied 26 patients with multiple trauma and sepsis within 24 hours of risk establishment for ARDS. Pulmonary alveolar-capillary permeability (PACP) was quantified as the clearance rate of a particulate radioaerosol. Seventeen patients (65%) had increased PACP (six developed ARDS) while nine (35%) had normal PACP (none developed ARDS; clearance rates of 3.4%/min and 1.5%/min, respectively). These patients, regardless of evidence of early lung injury, had elevated plasma C3adesArg levels and neutrophil chemotactic desensitization to C5a/C5adesArg. Plasma C3adesArg levels correlated weakly, but significantly, with PACP. Thus, CMNA may be a necessary, but not a sufficient, pathogenic mechanism in the evolution of ARDS.

Adult↗

PubMed1988

Terminal complement complexes and anaphylatoxins in septic and ischemic patients.

Terminal complement complex (TCC) and anaphylatoxin formation in 18 patients with sepsis and 20 patients with acute limb ischemia were studied before the start of treatment and seven days later. The septic or ischemic patients had elevated levels of plasma TCC before start of therapy. In successfully treated patients these concentrations were within the normal range one week later. Similarly, the plasma anaphylatoxin level was increased before therapy and returned to the normal range within seven days. Escherichia coli incubated in vitro in fresh human serum at body temperature started formation of TCC in a dose-related manner. As complement will induce cellular lysis via TCC and edema via anaphylatoxins, anemia and impaired respiration in these patients may be influenced by increased concentrations of terminal complement complexes and of C3a and C5a.

Aged↗

PubMed1988

Effects of cardiopulmonary bypass on pulmonary leukostasis and complement activation.

We measured white blood cell counts and complement component (C3a, C4a, and C5a) and prostacyclin levels, and studied lung biopsy specimens, in 16 patients undergoing cardiopulmonary bypass and compared them with four patients undergoing other pulmonary procedures. Bypass caused no significant elevation in peripheral venous white blood cell counts. Higher counts were present in the right atrium compared with the left atrium. Patients who underwent bypass had elevated complement component and prostacyclin concentrations before operation and these levels increased further during operation. Trapping of polymorphonuclear leukocytes occurred in pulmonary alveolar capillaries and venules after bypass. We conclude that bypass activates complement components primarily of the alternative pathway and leads to increased blood prostacyclin levels. These changes are accompanied by polymorphonuclear leukocyte accumulation in the lungs and may be important in initiation of the adult respiratory distress syndrome in these patients.

6-Ketoprostaglandin F1 alpha↗