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PubMed2001

The alternatively spliced alpha(E)C domain of human fibrinogen-420 is a novel ligand for leukocyte integrins alpha(M)beta(2) and alpha(X)beta(2).

The interaction of human plasma fibrinogen with leukocyte integrins alpha(M)beta(2) (CD11b/CD18, Mac-1) and alpha(X)beta(2) (CD11c/CD18, p150,95) is an important component of the inflammatory response. Previously, it was demonstrated that binding of fibrinogen to these integrins is mediated by gammaC, the globular C-terminal domain of the gamma chain. In this study, evidence was found of another fibrinogen domain that can serve as a ligand for the 2 leukocyte integrins: alpha(E)C, a homologous domain that extends the alpha chains in a recently discovered subclass of fibrinogen known as fibrinogen-420. Recombinant alpha(E)C supported strong adhesion and migration of cells expressing alpha(M)beta(2) and alpha(X)beta(2), including nonactivated and activated U937 and THP-1 monocytoid cells, and neutrophils. Cells transfected with complementary DNA for these integrins also bound alpha(E)C. The specificity of interaction was substantiated by inhibition of cell adhesion with antibodies against alpha(M), alpha(X), and beta(2) subunits. Also, neutrophil inhibitory factor, a specific inhibitor of alpha(M)beta(2) and alpha(X)beta(2) function, efficiently blocked cell adhesion to alpha(E)C. In alpha(M)beta(2) and alpha(X)beta(2), the I domain is the binding site for alpha(E)C, since alpha(E)C bound to recombinant alpha(M) I and alpha(X)I domains in a dose-dependent and saturable manner. Synthetic peptides that duplicated sequences gamma190 to 202 and gamma377 to 395, previously considered putative binding sites in gammaC, effectively inhibited alpha(M)beta(2)- and alpha(X)beta(2)-mediated adhesion to alpha(E)C, suggesting that recognition of alpha(E)C by the I domain involves structural features in common with those of gammaC. These findings identify alpha(E)C as a second domain in fibrinogen-420 that binds alpha(M)beta(2) and alpha(X)beta(2) and can mediate leukocyte adhesion and migration.

Alternative Splicing↗
PubMed2001

Loss of blood CD11c(+) myeloid and CD11c(-) plasmacytoid dendritic cells in patients with HIV-1 infection correlates with HIV-1 RNA virus load.

Human blood contains at least 2 subpopulations of antigen-presenting dendritic cells (DCs) that can be differentiated by their expression of CD11c. Myeloid DCs (myDCs), which are CD11c(+), trap invading pathogens in the tissues and then migrate to lymphoid tissues where they stimulate pathogen-specific T-cell responses. Plasmacytoid DCs (pcDCs), which are CD11c(-), secrete interferon-alpha in response to viral infections. This study reports that in HIV-1 infection there is a progressive depletion of both these DC populations and that this correlates with an increasing HIV-1 plasma virus load. The median numbers of myDCs and pcDCs were 6978/mL and 9299/mL, respectively, in healthy male controls and 2298/mL and 1640/mL, respectively, in patients with more than 10(5) HIV-1 RNA copies/mL. Both DC populations expressed CD4, CCR5, and CXCR4. The findings suggest that loss of DCs in HIV infection may contribute to disease progression.

CD4 Antigens↗
PubMed1998

Expression of leukocyte integrins and tissue factor in mononuclear phagocytes.

Coagulation is intimately involved in the pathology of inflammation. The leukocyte beta2-integrins have several functions, including serving as receptors for coagulation factor X and fibrinogen. Tissue factor (TF) is a receptor for factor VII and a very potent trigger of coagulation. The intention of this study was to examine a possible coexpression of beta2-integrins (CD11b/CD18 and CD11c/CD18) and the procoagulant TF in alveolar macrophages (AM) and blood monocytes, i.e. cells of the same differentiation lineage. The expression of beta2-integrins in human AM isolated by bronchoalveolar lavage and in blood monocytes was analysed by flow cytometry, whereas TF activity was analysed in a one-stage clotting assay. In monocytes, TF activity, CD11b and CD11c expression were highly inducible by lipopolysaccharide (LPS), with a 13-, 19- and four-fold increase, respectively. In AM, TF and beta2-integrins were all constitutively expressed, but the expression could not be further enhanced by LPS stimulation. CD11b and CD11c expression varied inversely with the cell size of AM, in contrast to TF activity which is known to be proportional to AM cell size. In vitro expression of beta2-integrins and tissue factor in lipopolysaccharide-stimulated blood monocytes seems to be intimately coregulated, whereas the expression of these receptors in alveolar macrophages seems to be unresponsive to lipopolysaccharide. These results indicate that blood monocytes and alveolar macrophages have different roles and use different mechanisms in cell-induced fibrin formation.

Adult↗
PubMed2006

Critical role for serum opsonins and complement receptors CR3 (CD11b/CD18) and CR4 (CD11c/CD18) in phagocytosis of Francisella tularensis by human dendritic cells (DC): uptake of Francisella leads to activation of immature DC and intracellular survival of the bacteria.

Francisella tularensis is one of the most infectious human pathogens known. Although much has been learned about the immune response of mice using an attenuated live vaccine strain (LVS) derived from F. tularensis subspecies holarctica (Type B), little is known about the responses of human monocyte-derived immature dendritic cells (DC). Here, we show that optimal phagocytosis of LVS by DC is dependent on serum opsonization. We demonstrate that complement factor C3-derived opsonins and the major complement receptors expressed by DC, the integrins CR3 (CD11b/CD18) and CR4 (CD11c/CD18), play a critical role in this adhesion-mediated phagocytosis. LVS induced proinflammatory cytokine production and up-regulation of costimulatory surface proteins (CD40, CD86, and MHC Class II) on DC but resisted killing. Once taken up, LVS grew intracellularly, resulting in DC death. DC maturation and cytokine production were induced by direct contact/phagocytosis of LVS or interaction with soluble products of the bacteria, and enhanced activation was seen when LVS was pretreated with serum. Sonicated LVS and supernatants from LVS cultures were potent activators of DC, but LVS LPS failed to activate DC maturation or cytokine production. Serum-treated LVS rapidly induced (within 6 h) a number of cytokines including IL-10, a potent suppressor of macrophage functions and down-regulator of Th1-like responses and the Th1 response inducer IL-12. These results suggest that the simultaneous production of an activating (IL-12, IL-1beta, and TNF-alpha) and a suppressing (IL-10) cytokine profile could contribute to the immunopathogenesis of tularemia.

Bacterial Vaccines↗
PubMed1998

Neonatal neutrophil activation is a function of labor length in preterm infants.

To understand better the development of the neonatal immune system, we evaluated the role of labor length, gestational age, and mode of delivery on the expression of the neonatal neutrophil cell surface antigens CD11b, CD11c, CD15, CD33, and CD66b in premature newborns. Peripheral blood samples from 68 apparently healthy preterm infants were obtained within 12 h of birth and incubated with MAb to the CD antigens. Samples were lysed, fixed, and analyzed by flow cytometry. Multivariate analysis was used to study the simultaneous effect of the labor length and gestational age on the neonatal neutrophil cell surface antigen expression. A positive correlation was demonstrated between neutrophil antigen expression and labor length (p < 0.001-0.026) but not with the mode of delivery (p = 0.191-0.638). There was no significant correlation between expression of neutrophil antigens and gestational age at delivery (p = 0.057-0.866), except for CD15 (p = 0.010). Our results indicate labor length is a significant factor in neonatal neutrophil activation at birth. These findings are independent of gestational age in preterm newborns. Mode of delivery does not seem to influence neonatal neutrophil activation. The neutrophils of premature infants can be activated antenatally and/or during labor.

Antigens, CD↗
PubMed1990

Proliferative activity of lymphoid cells in human endometrium throughout the menstrual cycle.

Human endometrium harbors a major population of lymphoid cells. The proliferation of these cells is assessed by the in situ labeling of endometrial sections for Ki67 (a proliferation marker) as well as in vitro incorporation of bromodeoxyuridine (BrdU; a thymidine analog) into S-phase cells in vibratome sections of endometria. Using the avidin-biotinperoxidase complex method, sections of endometria and vibratome sections of endometria are labeled for Ki67 and BrdU, respectively. Subsequently, they are immunostained for CD45 (a lymphoid cell marker), CD3 (a T cell marker), and CD11c (a macrophage marker) molecules. Lymphoid cells scattered or aggregated in the endometrial stroma as well as intraglandular lymphoid cells exhibit Ki67 positivity throughout the menstrual cycle. The proliferative activity of the lymphoid cells, including the CD45, CD3, and CD11c positive cells scattered in the stroma, is markedly increased in the secretory phase. Similar, however less conspicuous, increased Ki67 labeling is observed in the lymphoid cells within lymphoid aggregates. The increased proliferative activity of the lymphoid cells in the secretory phase is confirmed by BrdU labeling in the vibratome sections. In the proliferative phase the non-CD45-positive cells in the endometrial stroma exhibit low proliferative activity, and in the secretory phase, Ki67 labeling in the endometrial stroma is primarily confined to the CD45-positive cells. The findings suggest that in situ proliferation is one mechanism by which the endometrial lymphoid cell pool within endometrium is restored after each menstrual shedding.

Affinity Labels↗
PubMed1992

Risk factors in normolipidemic male patients with coronary artery disease in Japanese.

We examined serum lipids, lipoproteins, apolipoproteins (Apo), lipoprotein(a) (Lp(a)), C4b-binding protein (C4bp) and lathosterol in 22 normolipidemic (serum total cholesterol less than 220 mg/dl and serum triglycerides less than 150 mg/dl) male patients with coronary artery disease (CAD) and 33 normal male subjects. Many of the patients in the CAD group with normal total cholesterol (T-Ch) and triglycerides (TG) had higher TG, low-density lipoprotein (LDL)-Ch, beta-lipoprotein (Lipo) and Apo B values and lower high-density lipoprotein (HDL)-Ch, Apo A-I and Apo A-II values than those of the control group. Differences were also observed in the beta-Lipo/HDL-Ch, Apo B/Apo A-I, and HDL-Ch ratios and the atherogenic index [A.I. = (T-Ch--HDL-Ch)/HDL-Ch], all of which are generally accepted as indices for atherosclerosis. Even in CAD patients with normolipidemia, the HDL-Ch/T-Ch ratio and A.I. seemed to be important risk factors. In addition, Lp(a) and lathosterol, an accepted indicator of whole-body cholesterol synthesis, were higher in the CAD group. The CAD group also appeared to have a higher C4bp value, suggesting that this parameter is correlated with other lipids.

Carrier Proteins↗
PubMed2002

Abnormalities in dendritic cell and macrophage accumulation in the pancreas of nonobese diabetic (NOD) mice during the early neonatal period.

Dendritic cell (DC), macrophage (Mphi) and lymphocyte infiltrations have been observed in normal human perinatal pancreata, but have never been investigated so early in control mice. In type 1 diabetes-prone NOD mice, these cells are thought to infiltrate first the periphery of the islets of Langerhans around weaning before further islet infiltration and beta-cell destruction. We quantified, during the first month of life, the numbers of DC (characterized by CD11c positivity and dendritic morphology), histiocyte-like Mphi (characterized by ER-MP23 positivity) and Mphi with scavenging potential (characterized by BM8 positivity) in C57BL/6, DBA/2 and BALB/c control, and NOD and lymphocyte-deficient NODscid mouse pancreata. First, CD11c+ DC were present at low densities from birth onwards in control pancreata, while densities were higher in NOD and NODscid. Second, high numbers of BM8+ and ER-MP23+ Mphi were observed at birth in all strains investigated. After birth, particularly BM8+ cells disappeared progressively in control strains, but not in NOD and NODscid. Third, NOD mice also had more ER-MP23+ Mphi at birth compared to controls. Finally, DC and Mphi localizations were similar in all strains, i.e., mostly as dispersed cells in perivascular, periductular, peri-islet areas and interlobular septa. The most remarkable finding was that particularly BM8+ Mphi, were seen at sites of islet neogenesis and predominantly at the duct-islet interface. Our data showed that different types of APC were present in the pancreas during postnatal development in various control mouse strains and some differences were observed in NOD and NODscid mice from birth onwards.

Animals↗
PubMed1983

Some proteins not belonging to the clotting or to the kallikrein-kinin system altered by kallikrein.

Plasma kallikrein activation occurs frequently during blood drawing and subsequent plasma handling. The purified enzyme was incubated with ceruloplasmin, inter-alpha-trypsin inhibitor and complement factor C4. Proteolysis caused by this enzyme was compared with the degradative effects of plasmin and thrombin. Among these proteins C4 proved to be most easily degraded; its cleavage products can interact with C4-binding protein.

Blood Coagulation↗
PubMedDate not supplied

Histopathology and immunocytochemical study of type 3 and type 4 complement receptors in the liver and spleen of dogs naturally and experimentally infected with Leishmania (Leishmania) chagasi.

The objective of this study was to compare the histopathological changes and expression of CR3 and CR4 in the liver and spleen of dogs naturally and experimentally infected with L. chagasi. The basic histopathological lesions observed mainly in naturally infected dogs were: epithelioid hepatic granulomas, hyperplasia and hypertrophy of Kupffer cells, Malpigui follicles and mononucleated cells of the red pulp of the spleen. Sections from the liver and spleen by immunocytochemistry technique showed the presence of CD11b, c/CD 18 antigens in the control and infected animals and no qualitative or quantitative differences in the liver. Nevertheless, CD18 was always increased in the spleen of naturally and experimentally infected dogs. These results indicate that there is a difference in the activation of CD18 in both experimental and natural cases of canine visceral leishmaniasis that should play an important role in the immunological response to Leishmania chagasi infection.

Animals↗
PubMed1988

Increased plasma concentrations of complement modulating proteins (C1 inhibitor, C4-binding protein, factor H and factor I) in psoriasis.

By using single radial immunodiffusion we measured the plasma levels of four complement modulating proteins, i.e., C1 inhibitor, C4-binding protein, factor H and factor I in 19 psoriatic patients in comparison with those of healthy controls. Except for C1 inhibitor which was only marginally elevated, they were found to be significantly increased in psoriatic patients. When psoriatic patients were classified into subgroups based on the clinical severity, the levels of factor H and those of factor I showed a close positive correlation with the activity and extent of the skin lesions, whereas such clear relationship could not be found with C1 inactivator or with C4-binding protein. These results offer additional support for the hypothesis that the complement system is involved in psoriasis.

Adult↗
PubMed2002

Marked increase in number of dendritic cells in autoimmune-prone (NZW x BXSB)F1 mice with age.

Here, we report that the number of CD11c(+)CD3(-) B220(-) cells increases in autoimmune-prone male (NZW x BXSB)F1 (W/BF1) mice with age. The CD11c(+)CD3(-)B220(-) cells from W/BF1 mice show a typical stellate shape and induce the proliferation of T cells. In the CD11c(+)CD3(-)B220(-) cells from W/BF1 mice, CD11b (Mac-1alpha), NK 1.1, and CD95 (Fas) are upregulated in comparison with normal mice, while the expression of CD8alpha, CD117 (c-kit), CD135 (Flk-2/Flt-3), and Sca-1 decreases. There is a significant increase in Flt-3L (FL) mRNA in the bone marrow of W/BF1 mice with age. Moreover, activated hemopoietic cells express high levels of FL. The injection of CD11c(+)CD3(-)B220(-) cells from old W/BF1 mice to young W/BF1 mice transiently induces autoimmune disease (thrombocytopenia). These results suggest that hyperproduction of FL from activated hemopoietic cells induces a dramatic increase in the number of dendritic cells in aged W/BF1 mice, followed by the acceleration of autoimmunity.

Animals↗
PubMed1993

Occurrence and resolution of focal epithelial hyperplasia in two siblings with leukocyte adhesion deficiency.

Focal epithelial hyperplasia is an uncommon disorder characterized by formation of multiple asymptomatic oral mucosal papular and/or nodular lesions. This article relates the occurrence and clinical course of FEH in 2 adolescent siblings with leukocyte adhesion deficiency. Histological findings are described and insights into potential causes are discussed.

Aggressive Periodontitis↗
PubMed2002

Complement receptors in HIV infection.

Similar to other pathogens, HIV can directly activate the complement pathway even in the absence of antibodies. During and after seroconversion, HIV-specific antibodies enhance the activation of complement and increase deposition of complement fragments on virions dramatically. However, even in the presence of HIV-specific antibodies, no or only poor lysis occurs. HIV has adapted different protection mechanisms to keep complement activation under the threshold necessary to induce virolysis. In addition to its own envelope proteins, the viral envelope contains membrane-anchored host molecules. Among those are complement regulatory proteins that remain functionally active on the surface of HIV and turn down the complement cascade. In addition, serum proteins with complement regulatory activities become secondarily attached onto the virus, thereby enhancing the protection of HIV against complement-mediated damage. Therefore, opsonised virions accumulate in HIV-infected individuals, which subsequently interact with complement receptor (CR) expressing cells. This review is mainly focused on these interactions, which result either in infection of CR-positive cells with high efficiency, or retention of viral particles on their surface via CRs, thereby promoting transmission of virus to other permissive cells.

Animals↗
PubMed2003

The physiological relevance of CD4 receptor down-modulation during HIV infection.

Upon binding to the CD4 receptor the HIV envelope protein undergoes conformational changes that culminate in the fusion of the viral and cellular membranes. A few hours later, a sophisticated set of processes is initiated to ensure the down-modulation of the viral receptor. Three viral proteins participate in this process: Nef, Env, and Vpu, suggesting that this function is critical for virus replication. The mechanisms of action of these proteins have been extensively characterized. However, the physiological relevance of the virus-induced CD4 down-modulation remains a focus of controversy, and the impact of this function on the viral life cycle has been underestimated. This review summarizes current hypotheses explaining why HIV needs to reduce expression of its own receptor, and discusses the experimental evidence supporting them. Recent findings indicate that efficient CD4 down-modulation is essential for the production of infectious particles, and highlight the importance of this function in HIV pathogenesis in vivo. Progression to disease correlates with enhanced viral induced CD4 down-modulation, and a subset of long-term nonprogressors carry viruses defective in this function. To date, the HIV-induced CD4 down-modulation has not been targeted for therapeutic intervention. Addressing the reasons why this function is so critical and understanding the interplay between viral and host factors governing surface expression of CD4 may provide clues for the development of new antiviral strategies.

Down-Regulation↗
PubMed1984

The complement components of the major histocompatibility locus.

Polymorphism of complement components, recognized by differences in either their antigenic specificity or their electrophoretic mobility, together with studies of inherited deficiencies, has enabled many of their structural genes to be mapped. In humans, three genes (for C2, C4, and factor B) have been placed between HLA-D and HLA-B on chromosome 6 and in mice, C4 between H2-I and H2-D, chromosome 17. Structural studies show that these components have exceptional features. C2 and factor B which contain the proteolytic active site of the C3 and C5 convertases are of the classical and alternative pathway respectively and are similar in structure and function. Both are novel types of serine proteases. C4 (as C3) contains an intrachain thioester bond essential for hemolytic activity. Molecular genetic investigations are determining the relative positions of these genes, and their precise structure, and should clarify their relation to the inherited diseases which are associated with defects in this section of the human genome.

Amino Acid Sequence↗
PubMed2000

Expression of the CD11c antigen in B-cell chronic lymphoproliferative disorders.

This study analyzed the expression of the beta2 integrin CD11c in 155 patients with well-characterized B-cell chronic lymphoproliferative disorders: 106 B-cell chronic lymphocytic leukemias (B-CLL), 21 hairy cell leukemias (HCL), 9 B-cell prolymphocytic leukemias (PLL) and 19 low grade non-Hodgkin's lymphomas (NHL) in leukemic phase. CD11c was expressed in 100% of patients with HCL and B-PLL, while in B-CLL and NHL it was expressed in only 49 and 57%, respectively. Furthermore, in B-CLL the expression of CD11c was found mainly in patients with early stage of disease. In addition, when the fluorescence intensity of CD11c, calculated by MFI, was evaluated, it proved significantly higher in HCL and B-PLL compared to the values recorded in B-CLL and NHL (325 and 387 vs 34 and 56, respectively) (p < 0.05). Our results demonstrate that the evaluation of CD11c, both in terms of overall positivity and of fluorescence intensity, represents an additional useful parameter for a more precise differential diagnosis within the spectrum of B-cell chronic lymphoproliferative disorders.

Chronic Disease↗
PubMed1996

Granulocyte-colony stimulating factor, granulocyte-macrophage colony stimulating factor and interleukin 4 induce differentiation in the U-937 human monocytic leukemia cell line.

We studied the effect of TPA, G-CSF, GM-CSF, conditioned medium from 5637 cells (CM5637) and IL-4 on U-937 cell line proliferation and differentiation. Flow cytometry analysis showed that the expression of the CD14 cell surface antigen, initially detected in 90% of the cells, decreased when the cells were cultured with either G-CSF, GM-CSF, CM5637, or IL-4. The CD11c expression only decreased by exposure to GM-CSF and IL-4. The cells also showed a decrease in alpha-naphthylesterase (alpha-NAE) activity and an increase in peroxidase (Px) activity in the GM-CSF supplemented cultures. Remarkable changes in cell morphology were also observed. IL-4 induced morphologic features resembling histiocytic-like cells positive for the expression of alpha-NAE and negative for Px. GM-CSF induced cells with pseudopods, negative for alpha-NAE expression and positive for Px. TPA effect on U-937 cells was similar to that observed with GM-CSF. No proliferative response was detected with any of the factors assayed. These results suggest that GM-CSF and IL-4 can promote distinct changes in the differentiative pathway of U-937 cells, as evidenced by the marked morphological, immunological and cytochemical changes observed in the cell cultures.

Biomarkers↗