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The interaction of chemotactic factors (fMet-Leu-Phe and C5a) with rabbit neutrophils leads to rapid and specific release of membrane calcium, as evidenced by changes in the fluorescence of cell-associated chlorotetracycline. These two structurally different stimuli appear to interact with the same pool of membrane calcium.
The chemotaxis of neutrophils has been shown to be modulated by serum factors, tissue factors, bacterial products, and a host of other substances. In vivo, these factors may act in concert with each other to modify neutrophil movement. We examined the effect of aggregated gamma globulin-activated serum (AS), bacterial factors, and endotoxin either alone or in combination with each other, on human neutrophil chemotaxis. Exposure of neutrophils to AS resulted in deactivation to AS but not to Escherichial coli or Staphylococcus epidermis culture filtrate. Exposure of neutrophils to S. epidermis or E. coli CF or E. coli endotoxin resulted in deactivation to AS or C5a but not to E. coli or S. epidermis culture filtrate. Addition of endotoxin to AS or C5a resulted in inhibition of chemotaxis by untreated neutrophils toward this combination as compared with AS alone. These results suggest that separate mechanisms may be involved when serum or bacterial chemotactic factors initiate human neutrophil chemotaxis. Furthermore, the potent but specific inhibitory effect of endotoxin on chemotaxis toward AS may be of clinical significance.
A number of functional studies were performed on essentially pure eosinophil preparations obtained from the ascitic fluid of a patient with eosinophilic gastroenteritis. These cells responded to chemotactic factors including a bacterial factor, partially purified C5a, and factors generated from serum or ascitic fluid. The chemotactic activity generated in the patient's ascitic fluid was capable of attracting both neutrophils and eosinophils, was dependent on the presence of complement components, and was identified as C5a. Metabolic studies demonstrated that particle ingestion by eosinophils was associated with a marked increase in hexose monophosphate shunt activity ([1-14C]glucose oxidation), H2O2 formation ([14C]formate oxidation), superoxide anion generation, chemiluminescence, thyroid hormone degradation, iodination, and estrogen binding. This postphagocytic metabolic burst by eosinophils was qualitatively similar to that observed in neutrophils, but for several parameters the eosinophil response was greater than the neutrophil response.
Neutrophils are important effector cells in the defense against microorganisms. They migrate into infected sites and then phagocytose and kill bacteria. Chemotactic factors may be important for initiating neutrophil migration. We investigated whether chemotactic factors might also influence an event subsequent to chemotaxis, namely bacterial killing. It was found that preincubation (20 min at 37 degrees C) of human leukocytes with chemotactic substances such as zymosan-activated serum, a C5a-containing fraction of zymosan-activated serum, N-formyl methionyl phenylalanine or N-formyl methionyl-leucine-phenylalanine, enhanced leukocyte killing of Staphylococcus aureus, Escherichia coli, and Streptococcus faecalis in a dose-dependent fashion. The concentration of chemotactic factor required to enhance killing was similar to that required to induce neutrophil chemotaxis. In addition, zymosan-activated serum, C5a fraction, and the two N-formyl methionyl peptides increased the hexose monophosphate shunt activity of resting and phagocytosing neutrophils by two- to threefold. In contrast, bacterial killing by sodium azide-treated neutrophils and neutrophils from a patient with chronic granulomatous disease was not increased by any chemotactic factor. These findings suggest that chemotactic factors stimulate neutrophil oxygen-dependent microbicidal pathways. These observations illustrate another important contribution of biologically active molecules to effector cell function and host defense.
We reported previously that Escherichia coli endotoxin inhibited human neutrophil chemotaxis toward C5a. This effect of endotoxin was antagonized by anti-inflammatory steroids. We now report that dibutyryl cyclic adenosine 3',5'-monophosphate, prostaglandin E1, isoproterenol, and cholera toxin also antagonize the suppression of chemotaxis by endotoxin. Each compound inhibited the effect of endotoxin in a dose-dependent fashion. To be effective, each compound except cholera toxin had to be present at the time of endotoxin challenge. Furthermore, propranolol blocked the protective effect of isoproterenol against endotoxin but not the protective effect of dibutyrl cyclic adenosine 3',5'-monophosphate or prostaglandin E1. Dibutyryl cyclic guanosine 3',5'-monophosphate, adenosine 5'-monophosphate, phenylephrine, prostaglandin F2 alpha, and carbachol did not modify the suppression of chemotaxis by endotoxin. Anti-inflammatory steroids and dibutyryl cyclic adenosine 3',5'-monophosphate are thought to stabilize phospholipids in certain cell membranes. This phospholipid-stabilizing action may contribute, at least in part, to the protective effect against endotoxin-mediated suppression of neutrophil chemotaxis.
Bacteria of a wild strain of Francisella tularensis were less efficiently killed by human polymorphonuclear leukocytes than were bacteria of an attenuated strain. This finding was explained to some extent by a less efficient phagocytosis, but bacteria of the wild strain also seemed to be more resistant to killing after ingestion.
T lymphocytes and gamma interferon (IFN-gamma) are known mediators of immune resistance to Toxoplasma gondii infection, but whether B cells also play an important role is not clear. We have investigated this issue using B-cell-deficient (muMT) mice. If vaccinated with attenuated T. gondii tachyzoites, muMT mice are susceptible to a challenge intraperitoneal infection with highly virulent tachyzoites that similarly vaccinated B-cell-sufficient mice resist. Susceptibility is evidenced by increased numbers of parasites at the challenge infection site and by extensive mortality. The susceptibility of B-cell-deficient mice does not appear to be caused by deficient T-cell functions or diminished capacity of vaccinated and challenged B-cell-deficient mice to produce IFN-gamma. Administration of Toxoplasma-immune serum, but not nonimmune serum, to vaccinated B-cell-deficient mice significantly prolongs their survival after challenge with virulent tachyzoites. Vaccinated mice lacking Fc receptors or the fifth component of complement resist a challenge infection, suggesting that neither Fc-receptor-dependent phagocytosis of antibody-coated tachyzoites nor antibody-dependent cellular cytotoxicity nor antibody-and-complement-dependent lysis of tachyzoites is a crucial mechanism of resistance. However, Toxoplasma-immune serum effectively inhibits the infection of host cells by tachyzoites in vitro. Together, the results support the hypothesis that B cells are required for vaccination-induced resistance to virulent tachyzoites in order to produce antibodies and that antibodies may function protectively in vivo by blocking infection of host cells by tachyzoites.
Early control of virus replication by the innate immune response is essential to allow time for the generation of a more effective adaptive immune response. As an important component of innate immunity, complement has been shown to be necessary for protection against numerous microbial infections. This study was undertaken to investigate the role of complement in neutralizing influenza virus. Results demonstrated that the classical pathway of complement mediated serum neutralization of influenza virus. Although nonimmune serum neutralized influenza virus, the mechanism of virus neutralization (VN) required antibody, as sera from RAG1-deficient mice lacked VN activity; moreover, purified natural immunoglobulin M (IgM) restored VN activity to antibody-deficient sera. The mechanism of VN by natural IgM and complement was associated with virion aggregation and coating of the viral hemagglutinin receptor; however, viral lysis did not significantly contribute to VN. Additionally, reconstitution of RAG1-deficient mice with natural IgM resulted in delayed morbidity during influenza virus infection. Collectively, these results provide evidence that natural IgM and the early components of the classical pathway of complement work in concert to neutralize influenza virus and that this interaction may have a significant impact on the course of influenza viral pneumonia.
Four genetic loci were tested for linkage with loci that control genetic resistance to lethal ectromelia virus infection in mice. Three of the loci were selected because of concordance with genotypes assigned to recombinant inbred (RI) strains of mice derived from resistant C57BL/6 and susceptible DBA/2 (BXD) mice on the basis of their responses to challenge infection. Thirty-six of 167 male (C57BL/6 x DBA/2)F1 x DBA/2 backcross (BC) mice died (22%), of which 27 (75%) were homozygous for DBA/2 alleles at Hc and H-2D. Twenty-eight percent of sham-castrated and 6% of sham-ovariectomized BC mice were susceptible to lethal mousepox, whereas 50% of gonadectomized mice were susceptible. There was no linkage evident between Hc or H-2D and loci that controlled resistance to lethal ectromelia virus infection in 44 castrated BC mice. Mortality among female mice of BXD RI strains with susceptible or intermediate male phenotypes was strongly correlated (r = 0.834) with male mortality. Gonadectomized C57BL/6 mice were as resistant as intact mice to lethal ectromelia virus infection. These results indicate that two gonad-dependent genes on chromosomes 2 and 17 and one gonad-independent gene control resistance to mousepox virus infection, that males and females share gonad-dependent genes, and that the gonad-independent gene is fully protective.
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A 32-year-old black woman with pancreatitis developed visual loss in both eyes. On ophthalmoscopic examination she had extensive ischaemic infarcts at the posterior poles of both eyes, a clinical picture which has been reported previously in patients with pancreatitis and noted to be similar to Purtscher's retinopathy. On histopathological examination of the eyes after death there were arteriolar occlusions in both the choroid and retina and inner ischaemic infarctions with inner retinal oedema. Owing to the 23-day interval from arteriolar occlusion until death the exact nature of the original occlusion could not be determined. However, either fat emboli or activated complement C5-induced granulocyte embolus formation are possible causes.
Serum attractant activity, measured in 57 patients with chronic liver disease, was significantly reduced in 66% of the 27 patients with alcoholic liver disease and in 29% of the 17 patients with chronic active hepatitis, but was normal in 13 patients with primary biliary cirrhosis despite the presence of established cirrhosis in nearly half of them. In patients with alcoholic liver disease, but not in those with chronic active hepatitis, there was a correlation between the serum defect and severity of liver disease. The defect could not be related to the deficiency of key complement components, raised concentrations of IgA or G or the concurrent presence of bacterial infection. These findings suggest that the aetiology of liver disease may be an important factor in the development of serum attractant abnormalities.
OBJECTIVES: To clarify the dynamics of molecules composing the blood-nerve barrier (BNB) in inflammatory neuropathies. METHODS: The expression of four tight junction (TJ) proteins-claudin-1, claudin-5, occludin, and ZO-1-was analysed immunohistochemically in sural nerve biopsy specimens obtained from patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). RESULTS: Claudin-1 was detected only in perineurial cells, whereas claudin-5 was present in endothelial cells, irrespective of vessel location or size. Occludin and ZO-1 were found in perineurial cells, in addition to some epineurial and endoneurial endothelial cells. In CIDP, percentages of endoneurial small vessels immunoreactive for claudin-5 were significantly decreased, as were ZO-1 immunoreactive endoneurial small vessels, with staining localised to interfaces between cells. Claudin-1 and occludin immunoreactivity did not differ appreciably between the neuropathies examined. CONCLUSIONS: The downregulation of claudin-5 and altered localisation of ZO-1 seen in CIDP specimens may indicate that BNB derangement occurs in inflammatory neuropathies. Further investigation of TJ molecules may suggest new treatments based on properties of the BNB.
We explored the potential proinflammatory effect of prostaglandins of the E series (PGE's) in a rabbit model of acute pulmonary inflammation. The instillation of fragments of the fifth component of complement (C5f) into the lung resulted in a localized area of inflammation, the extent of which was quantified by the total number of neutrophils and protein recoverable by bronchoalveolar lavage (BAL). Utilizing 111In-labeled neutrophils and serial scintigraphy, neutrophil localization in the area of inflammation was detected as early as 20 min after C5f instillation and reached a maximum between 2 and 4 h. The simultaneous intrabronchial administration of 100 micrograms of PGE2 resulted in a twofold increase in the accumulation of neutrophils in the area of inflammation as determined scintigraphically, a fivefold increase in BAL neutrophils, and a threefold increase in BAL protein. A proinflammatory effect on lavage constituents was also seen with the intravenous administration of PGE2 (100 ng.kg-1.min-1) and PGE1 (50 ng.kg-1.min-1) as well as in animals pretreated with a PGH synthase inhibitor, meclofenamate, and a thromboxane synthase inhibitor, dazmegrel. The effect of intrabronchial PGE2 to potentiate the inflammatory response was attenuated by the intravenous administration of a vasoconstrictor (angiotensin II) and mimicked by a vasodilator (nitroprusside), suggesting an effect of vasodilation per se. Using radiolabeled microspheres, it was determined that in response to the C5f alone, there was a 50% decrease in local blood flow to the area of inflammation, a pattern different from that seen in the systemic circulation. This decrease was prevented by the concomitant administration of PGE2 or nitroprusside. We conclude that vasodilation induced by PGE2 is associated with enhancement of pulmonary inflammation.
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Generation of chemotactic activity in rat plasma or serum by aggregated rat platelets or by an extract of lysed platelets has been demonstrated. Chemotactic activity was not generated from serum either in the absence of an intact complement system or by platelet lysate pre-incubated with soya bean trypsin inhibitor. The significance of these observations is discussed in relation to some recent work on the role of platelets in inflammation.